RBCC Red Blood Cell Collection

CASP8 (MCH5) [Confidence: low (only semi-automatic identification from reviews)]
Caspase-8; CASP-8; 3.4.22.61 (Apoptotic cysteine protease; Apoptotic protease Mch-5; CAP4; FADD-homologous ICE/ced-3-like protease; FADD-like ICE; FLICE; ICE-like apoptotic protease 5; MORT1-associated ced-3 homolog; MACH; Caspase-8 subunit p18; Caspase-8 subunit p10; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q14790
ID CASP8_HUMAN Reviewed; 479 AA.
AC Q14790; O14676; Q14791; Q14792; Q14793; Q14794; Q14795; Q14796;
read moreAC Q15780; Q15806; Q53TT5; Q8TDI1; Q8TDI2; Q8TDI3; Q8TDI4; Q8TDI5;
AC Q96T22; Q9C0K4; Q9UQ81;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1996, sequence version 1.
DT 22-JAN-2014, entry version 174.
DE RecName: Full=Caspase-8;
DE Short=CASP-8;
DE EC=3.4.22.61;
DE AltName: Full=Apoptotic cysteine protease;
DE AltName: Full=Apoptotic protease Mch-5;
DE AltName: Full=CAP4;
DE AltName: Full=FADD-homologous ICE/ced-3-like protease;
DE AltName: Full=FADD-like ICE;
DE Short=FLICE;
DE AltName: Full=ICE-like apoptotic protease 5;
DE AltName: Full=MORT1-associated ced-3 homolog;
DE Short=MACH;
DE Contains:
DE RecName: Full=Caspase-8 subunit p18;
DE Contains:
DE RecName: Full=Caspase-8 subunit p10;
DE Flags: Precursor;
GN Name=CASP8; Synonyms=MCH5;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3; 5; 6; 7 AND 8).
RC TISSUE=B-cell, and Thymus;
RX PubMed=8681376; DOI=10.1016/S0092-8674(00)81265-9;
RA Boldin M.P., Goncharov T.M., Goltsev Y.V., Wallach D.;
RT "Involvement of MACH, a novel MORT1/FADD-interacting protease, in
RT Fas/APO-1- and TNF receptor-induced cell death.";
RL Cell 85:803-815(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PARTIAL PROTEIN SEQUENCE.
RX PubMed=8681377; DOI=10.1016/S0092-8674(00)81266-0;
RA Muzio M., Chinnaiyan A.M., Kischkel F.C., O'Rourke K., Shevchenko A.,
RA Ni J., Scaffidi C., Bretz J.D., Zhang M., Gentz R., Mann M.,
RA Krammer P.H., Peter M.E., Dixit V.M.;
RT "FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited
RT to the CD95 (Fas/APO-1) death-inducing signaling complex.";
RL Cell 85:817-827(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4), AND VARIANT HIS-285.
RC TISSUE=T-cell;
RX PubMed=8755496; DOI=10.1073/pnas.93.15.7464;
RA Fernandes-Alnemri T., Armstrong R.C., Krebs J.F., Srinivasula S.M.,
RA Wang L., Bullrich F., Fritz L.C., Trapani J.A., Tomaselli K.J.,
RA Litwack G., Alnemri E.S.;
RT "In vitro activation of CPP32 and Mch3 by Mch4, a novel human
RT apoptotic cysteine protease containing two FADD-like domains.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:7464-7469(1996).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2), AND VARIANT HIS-285.
RX PubMed=9228018; DOI=10.1074/jbc.272.30.18542;
RA Srinivasula S.M., Ahmad M., Ottilie S., Bullrich F., Banks S.,
RA Wang Y., Fernandes-Alnemri T., Croce C.M., Litwack G., Tomaselli K.J.,
RA Armstrong R.C., Alnemri E.S.;
RT "FLAME-1, a novel FADD-like anti-apoptotic molecule that regulates
RT Fas/TNFR1-induced apoptosis.";
RL J. Biol. Chem. 272:18542-18545(1997).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9931493; DOI=10.1016/S0378-1119(98)00565-4;
RA Grenet J., Teitz T., Wei T., Valentine V., Kidd V.J.;
RT "Structure and chromosome localization of the human CASP8 gene.";
RL Gene 226:225-232(1999).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-285.
RX PubMed=11161814; DOI=10.1006/geno.2000.6392;
RA Hadano S., Yanagisawa Y., Skaug J., Fichter K., Nasir J.,
RA Martindale D., Koop B.F., Scherer S.W., Nicholson D.W., Rouleau G.A.,
RA Ikeda J.-E., Hayden M.R.;
RT "Cloning and characterization of three novel genes, ALS2CR1, ALS2CR2,
RT and ALS2CR3, in the juvenile amyotrophic lateral sclerosis (ALS2)
RT critical region at chromosome 2q33-q34: candidate genes for ALS2.";
RL Genomics 71:200-213(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7), AND FUNCTION (ISOFORM 7).
RC TISSUE=Leukocyte;
RX PubMed=12010809; DOI=10.1182/blood.V99.11.4070;
RA Himeji D., Horiuchi T., Tsukamoto H., Hayashi K., Watanabe T.,
RA Harada M.;
RT "Characterization of caspase-8L: a novel isoform of caspase-8 that
RT behaves as an inhibitor of the caspase cascade.";
RL Blood 99:4070-4078(2002).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2 AND 9), AND INTERACTION OF
RP ISOFORM 9 WITH BCAP31 AT THE ENDOPLASMIC RETICULUM.
RX PubMed=11917123; DOI=10.1073/pnas.072088099;
RA Breckenridge D.G., Nguyen M., Kuppig S., Reth M., Shore G.C.;
RT "The procaspase-8 isoform, procaspase-8L, recruited to the BAP31
RT complex at the endoplasmic reticulum.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:4331-4336(2002).
RN [9]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-219 AND HIS-285.
RG NIEHS SNPs program;
RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [11]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 7).
RC TISSUE=Leukocyte;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [12]
RP PARTIAL PROTEIN SEQUENCE, AND PROTEOLYTIC PROCESSING.
RX PubMed=8962078; DOI=10.1073/pnas.93.25.14486;
RA Srinivasula S.M., Ahmad M., Fernandes-Alnemri T., Litwack G.,
RA Alnemri E.S.;
RT "Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1
RT protease Mch5 is a CrmA-inhibitable protease that activates multiple
RT Ced-3/ICE-like cysteine proteases.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:14486-14491(1996).
RN [13]
RP FUNCTION.
RX PubMed=9006941; DOI=10.1074/jbc.272.5.2952;
RA Muzio M., Salvesen G.S., Dixit V.M.;
RT "FLICE induced apoptosis in a cell-free system. Cleavage of caspase
RT zymogens.";
RL J. Biol. Chem. 272:2952-2956(1997).
RN [14]
RP PROTEOLYTIC PROCESSING.
RX PubMed=9184224; DOI=10.1093/emboj/16.10.2794;
RA Medema J.P., Scaffidi C., Kischkel F.C., Shevchenko A., Mann M.,
RA Krammer P.H., Peter M.E.;
RT "FLICE is activated by association with the CD95 death-inducing
RT signaling complex (DISC).";
RL EMBO J. 16:2794-2804(1997).
RN [15]
RP CHARACTERIZATION (ISOFORM 7).
RX PubMed=10860845; DOI=10.1006/bbrc.2000.2841;
RA Horiuchi T., Himeji D., Tsukamoto H., Harashima S., Hashimura C.,
RA Hayashi K.;
RT "Dominant expression of a novel splice variant of caspase-8 in human
RT peripheral blood lymphocytes.";
RL Biochem. Biophys. Res. Commun. 272:877-881(2000).
RN [16]
RP INTERACTION WITH BCL2; BCL2L1 AND BCAP31.
RX PubMed=9334338; DOI=10.1083/jcb.139.2.327;
RA Ng F.W.H., Nguyen M., Kwan T., Branton P.E., Nicholson D.W.,
RA Cromlish J.A., Shore G.C.;
RT "p28 Bap31, a Bcl-2/Bcl-XL- and procaspase-8-associated protein in the
RT endoplasmic reticulum.";
RL J. Cell Biol. 139:327-338(1997).
RN [17]
RP INTERACTION WITH PEA15.
RX PubMed=10442631; DOI=10.1038/sj.onc.1202831;
RA Condorelli G., Vigliotta G., Cafieri A., Trencia A., Andalo P.,
RA Oriente F., Miele C., Caruso M., Formisano P., Beguinot F.;
RT "PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-
RT induced apoptosis.";
RL Oncogene 18:4409-4415(1999).
RN [18]
RP INTERACTION WITH HHV-5 PROTEIN UL36.
RX PubMed=11427719; DOI=10.1073/pnas.141108798;
RA Skaletskaya A., Bartle L.M., Chittenden T., McCormick A.L.,
RA Mocarski E.S., Goldmacher V.S.;
RT "A cytomegalovirus-encoded inhibitor of apoptosis that suppresses
RT caspase-8 activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 98:7829-7834(2001).
RN [19]
RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA Hillman R.T., Green R.E., Brenner S.E.;
RT "An unappreciated role for RNA surveillance.";
RL Genome Biol. 5:R8.1-R8.16(2004).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-334, AND MASS
RP SPECTROMETRY.
RX PubMed=15592455; DOI=10.1038/nbt1046;
RA Rush J., Moritz A., Lee K.A., Guo A., Goss V.L., Spek E.J., Zhang H.,
RA Zha X.-M., Polakiewicz R.D., Comb M.J.;
RT "Immunoaffinity profiling of tyrosine phosphorylation in cancer
RT cells.";
RL Nat. Biotechnol. 23:94-101(2005).
RN [21]
RP MUTAGENESIS OF ASP-73.
RX PubMed=15592525; DOI=10.1038/sj.onc.1208186;
RA Jun J.-I., Chung C.-W., Lee H.-J., Pyo J.-O., Lee K.N., Kim N.-S.,
RA Kim Y.S., Yoo H.-S., Lee T.-H., Kim E., Jung Y.-K.;
RT "Role of FLASH in caspase-8-mediated activation of NF-kappaB:
RT dominant-negative function of FLASH mutant in NF-kappaB signaling
RT pathway.";
RL Oncogene 24:688-696(2005).
RN [22]
RP INTERACTION WITH CASP8P2.
RX PubMed=17245429; DOI=10.1038/sj.emboj.7601504;
RA Milovic-Holm K., Krieghoff E., Jensen K., Will H., Hofmann T.G.;
RT "FLASH links the CD95 signaling pathway to the cell nucleus and
RT nuclear bodies.";
RL EMBO J. 26:391-401(2007).
RN [23]
RP PHOSPHORYLATION AT SER-387 BY CDK1.
RX PubMed=20937773; DOI=10.1128/MCB.00731-10;
RA Matthess Y., Raab M., Sanhaji M., Lavrik I.N., Strebhardt K.;
RT "Cdk1/cyclin B1 controls Fas-mediated apoptosis by regulating caspase-
RT 8 activity.";
RL Mol. Cell. Biol. 30:5726-5740(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [25]
RP INTERACTION WITH E.COLI NLEF, CATALYTIC ACTIVITY, FUNCTION, AND ENZYME
RP REGULATION.
RA Blasche S., Moertl M., Steuber H., Siszler G., Nisa S., Schwarz F.,
RA Lavrik I., Gronewold T.M.A., Maskos K., Donnenberg M.S., Ullmann D.,
RA Uetz P., Koegl M.;
RT "The E.coli effector protein NleF is a caspase inhibitor.";
RL PLoS ONE 0:0-0(2013).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS).
RX PubMed=10508784; DOI=10.1016/S0969-2126(99)80179-8;
RA Blanchard H., Kodandapani L., Mittl P.R.E., Di Marco S., Krebs J.F.,
RA Wu J.C., Tomaselli K.J., Gruetter M.G.;
RT "The three-dimensional structure of caspase-8: an initiator enzyme in
RT apoptosis.";
RL Structure 7:1125-1133(1999).
RN [27]
RP X-RAY CRYSTALLOGRAPHY (1.2 ANGSTROMS) OF 211-479, AND SUBUNIT.
RX PubMed=10508785; DOI=10.1016/S0969-2126(99)80180-4;
RA Watt W., Koeplinger K.A., Mildner A.M., Heinrikson R.L.,
RA Tomasselli A.G., Watenpaugh K.D.;
RT "The atomic-resolution structure of human caspase-8, a key activator
RT of apoptosis.";
RL Structure 7:1135-1143(1999).
RN [28]
RP VARIANT CASP8D TRP-248.
RX PubMed=12353035; DOI=10.1038/nature01063;
RA Chun H.J., Zheng L., Ahmad M., Wang J., Speirs C.K., Siegel R.M.,
RA Dale J.K., Puck J., Davis J., Hall C.G., Skoda-Smith S.,
RA Atkinson T.P., Straus S.E., Lenardo M.J.;
RT "Pleiotropic defects in lymphocyte activation caused by caspase-8
RT mutations lead to human immunodeficiency.";
RL Nature 419:395-399(2002).
RN [29]
RP VARIANT HIS-285, AND PROTECTION AGAINST BREAST CANCER.
RX PubMed=15601643; DOI=10.1093/jnci/dji001;
RA MacPherson G., Healey C.S., Teare M.D., Balasubramanian S.P.,
RA Reed M.W.R., Pharoah P.D., Ponder B.A.J., Meuth M.,
RA Bhattacharyya N.P., Cox A.;
RT "Association of a common variant of the CASP8 gene with reduced risk
RT of breast cancer.";
RL J. Natl. Cancer Inst. 96:1866-1869(2004).
RN [30]
RP VARIANT HIS-285, AND PROTECTION AGAINST BREAST CANCER.
RX PubMed=17293864; DOI=10.1038/ng1981;
RG The Kathleen Cunningham foundation consortium for research into familial breast cancer;
RG Breast cancer association consortium;
RA Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S.,
RA Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J.,
RA Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C.,
RA Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O., Johnson N.,
RA dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G.,
RA Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H.,
RA Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P.,
RA Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C.,
RA Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N.,
RA Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B.,
RA Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J.,
RA Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A.,
RA Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y.,
RA Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J.,
RA Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J.,
RA Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P.,
RA Easton D.F.;
RT "A common coding variant in CASP8 is associated with breast cancer
RT risk.";
RL Nat. Genet. 39:352-358(2007).
RN [31]
RP ERRATUM.
RG The Kathleen Cunningham foundation consortium for research into familial breast cancer;
RG Breast cancer association consortium;
RA Cox A., Dunning A.M., Garcia-Closas M., Balasubramanian S.,
RA Reed M.W.R., Pooley K.A., Scollen S., Baynes C., Ponder B.A.J.,
RA Chanock S., Lissowska J., Brinton L., Peplonska B., Southey M.C.,
RA Hopper J.L., McCredie M.R.E., Giles G.G., Fletcher O., Johnson N.,
RA dos Santos Silva I., Gibson L., Bojesen S.E., Nordestgaard B.G.,
RA Axelsson C.K., Torres D., Hamann U., Justenhoven C., Brauch H.,
RA Chang-Claude J., Kropp S., Risch A., Wang-Gohrke S., Schuermann P.,
RA Bogdanova N., Doerk T., Fagerholm R., Aaltonen K., Blomqvist C.,
RA Nevanlinna H., Seal S., Renwick A., Stratton M.R., Rahman N.,
RA Sangrajrang S., Hughes D., Odefrey F., Brennan P., Spurdle A.B.,
RA Chenevix-Trench G., Beesley J., Mannermaa A., Hartikainen J.,
RA Kataja V., Kosma V.M., Couch F.J., Olson J.E., Goode E.L., Broeks A.,
RA Schmidt M.K., Hogervorst F.B.L., Van't Veer L.J., Kang D., Yoo K.-Y.,
RA Noh D.-Y., Ahn S.-H., Wedren S., Hall P., Low Y.-L., Liu J.,
RA Milne R.L., Ribas G., Gonzalez-Neira A., Benitez J., Sigurdson A.J.,
RA Stredrick D.L., Alexander B.H., Struewing J.P., Pharoah P.D.P.,
RA Easton D.F.;
RL Nat. Genet. 39:688-688(2007).
RN [32]
RP INVOLVEMENT IN PROTECTION AGAINST LUNG CANCER.
RX PubMed=17450141; DOI=10.1038/ng2030;
RA Sun T., Gao Y., Tan W., Ma S., Shi Y., Yao J., Guo Y., Yang M.,
RA Zhang X., Zhang Q., Zeng C., Lin D.;
RT "A six-nucleotide insertion-deletion polymorphism in the CASP8
RT promoter is associated with susceptibility to multiple cancers.";
RL Nat. Genet. 39:605-613(2007).
RN [33]
RP VARIANT HIS-285, AND RISK FACTOR FOR CUTANEOUS MELANOMA.
RX PubMed=18563783; DOI=10.1002/humu.20803;
RA Li C., Zhao H., Hu Z., Liu Z., Wang L.-E., Gershenwald J.E.,
RA Prieto V.G., Lee J.E., Duvic M., Grimm E.A., Wei Q.;
RT "Genetic variants and haplotypes of the caspase-8 and caspase-10 genes
RT contribute to susceptibility to cutaneous melanoma.";
RL Hum. Mutat. 29:1443-1451(2008).
CC -!- FUNCTION: Most upstream protease of the activation cascade of
CC caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A
CC induced cell death. Binding to the adapter molecule FADD recruits
CC it to either receptor. The resulting aggregate called death-
CC inducing signaling complex (DISC) performs CASP8 proteolytic
CC activation. The active dimeric enzyme is then liberated from the
CC DISC and free to activate downstream apoptotic proteases.
CC Proteolytic fragments of the N-terminal propeptide (termed CAP3,
CC CAP5 and CAP6) are likely retained in the DISC. Cleaves and
CC activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May
CC participate in the GZMB apoptotic pathways. Cleaves ADPRT.
CC Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC.
CC Likely target for the cowpox virus CRMA death inhibitory protein.
CC Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic
CC site and may interfere with the pro-apoptotic activity of the
CC complex.
CC -!- CATALYTIC ACTIVITY: Strict requirement for Asp at position P1 and
CC has a preferred cleavage sequence of (Leu/Asp/Val)-Glu-Thr-Asp-|-
CC (Gly/Ser/Ala).
CC -!- ENZYME REGULATION: Inhibited by the effector protein NleF that is
CC produced by pathogenic E.coli; this inhibits apoptosis.
CC -!- SUBUNIT: Heterotetramer that consists of two anti-parallel
CC arranged heterodimers, each one formed by a 18 kDa (p18) and a 10
CC kDa (p10) subunit. Interacts with FADD, CFLAR and PEA15. Isoform 9
CC interacts at the endoplasmic reticulum with a complex containing
CC BCAP31, BAP29, BCL2 and/or BCL2L1. Interacts with TNFAIP8L2 (By
CC similarity). Interacts with CASP8AP2. Interacts with human
CC cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits
CC CASP8 activation. Interacts with NleF from pathogenic E.coli.
CC -!- INTERACTION:
CC P51572:BCAP31; NbExp=3; IntAct=EBI-78060, EBI-77683;
CC Q92851:CASP10; NbExp=3; IntAct=EBI-78060, EBI-495095;
CC Q9UKL3:CASP8AP2; NbExp=4; IntAct=EBI-78060, EBI-2339650;
CC O15519-1:CFLAR; NbExp=2; IntAct=EBI-78060, EBI-4567563;
CC Q13618:CUL3; NbExp=6; IntAct=EBI-78060, EBI-456129;
CC Q13158:FADD; NbExp=32; IntAct=EBI-78060, EBI-494804;
CC P25445:FAS; NbExp=14; IntAct=EBI-78060, EBI-494743;
CC P48023:FASLG; NbExp=4; IntAct=EBI-78060, EBI-495538;
CC Q13418:ILK; NbExp=2; IntAct=EBI-78060, EBI-747644;
CC Q9UDY8:MALT1; NbExp=10; IntAct=EBI-78060, EBI-1047372;
CC O60936:NOL3; NbExp=3; IntAct=EBI-78060, EBI-740992;
CC P29350:PTPN6; NbExp=3; IntAct=EBI-78060, EBI-78260;
CC Q13546:RIPK1; NbExp=23; IntAct=EBI-78060, EBI-358507;
CC O00220:TNFRSF10A; NbExp=9; IntAct=EBI-78060, EBI-518861;
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=9;
CC Name=1; Synonyms=Alpha-1;
CC IsoId=Q14790-1; Sequence=Displayed;
CC Name=2; Synonyms=Alpha-2, MCH5-beta;
CC IsoId=Q14790-2; Sequence=VSP_000810;
CC Name=3; Synonyms=Alpha-3;
CC IsoId=Q14790-3; Sequence=VSP_000813;
CC Name=4; Synonyms=Alpha-4;
CC IsoId=Q14790-4; Sequence=VSP_000809, VSP_000810;
CC Name=5; Synonyms=Beta-1;
CC IsoId=Q14790-5; Sequence=VSP_000814, VSP_000815;
CC Name=6; Synonyms=Beta-2;
CC IsoId=Q14790-6; Sequence=VSP_000811, VSP_000812;
CC Name=7; Synonyms=Beta-3, 8L;
CC IsoId=Q14790-7; Sequence=VSP_000816, VSP_000817;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=8; Synonyms=Beta-4;
CC IsoId=Q14790-8; Sequence=VSP_000810, VSP_000816, VSP_000817;
CC Name=9; Synonyms=8L;
CC IsoId=Q14790-9; Sequence=VSP_000808;
CC Note=Ref.8 (AAL87628) sequence is in conflict in position:
CC 14:K->R;
CC -!- TISSUE SPECIFICITY: Isoform 1, isoform 5 and isoform 7 are
CC expressed in a wide variety of tissues. Highest expression in
CC peripheral blood leukocytes, spleen, thymus and liver. Barely
CC detectable in brain, testis and skeletal muscle.
CC -!- DOMAIN: Isoform 9 contains a N-terminal extension that is required
CC for interaction with the BCAP31 complex.
CC -!- PTM: Generation of the subunits requires association with the
CC death-inducing signaling complex (DISC), whereas additional
CC processing is likely due to the autocatalytic activity of the
CC activated protease. GZMB and CASP10 can be involved in these
CC processing events.
CC -!- PTM: Phosphorylation on Ser-387 during mitosis by CDK1 inhibits
CC activation by proteolysis and prevents apoptosis. This
CC phosphorylation occurs in cancer cell lines, as well as in primary
CC breast tissues and lymphocytes.
CC -!- POLYMORPHISM: Genetic variations in CASP8 are associated with
CC reduced risk of lung cancer [MIM:211980] in a population of Han
CC Chinese subjects. Genetic variations are also associated with
CC decreased risk of cancer of various other forms including
CC esophageal, gastric, colorectal, cervical, and breast, acting in
CC an allele dose-dependent manner.
CC -!- DISEASE: Caspase-8 deficiency (CASP8D) [MIM:607271]: Disorder
CC resembling autoimmune lymphoproliferative syndrome (ALPS). It is
CC characterized by lymphadenopathy, splenomegaly, and defective
CC CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It
CC leads to defects in activation of T-lymphocytes, B-lymphocytes,
CC and natural killer cells leading to immunodeficiency characterized
CC by recurrent sinopulmonary and herpes simplex virus infections and
CC poor responses to immunization. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase C14A family.
CC -!- SIMILARITY: Contains 2 DED (death effector) domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA66858.1; Type=Miscellaneous discrepancy;
CC Sequence=CAA66859.1; Type=Miscellaneous discrepancy;
CC -!- WEB RESOURCE: Name=CASP8base; Note=CASP8 mutation db;
CC URL="http://bioinf.uta.fi/CASP8base/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/CASP8";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/casp8/";
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DR EMBL; X98172; CAA66853.1; -; mRNA.
DR EMBL; X98173; CAA66854.1; -; mRNA.
DR EMBL; X98174; CAA66855.1; -; mRNA.
DR EMBL; X98175; CAA66856.1; -; mRNA.
DR EMBL; X98176; CAA66857.1; -; mRNA.
DR EMBL; X98177; CAA66858.1; ALT_SEQ; mRNA.
DR EMBL; X98178; CAA66859.1; ALT_SEQ; mRNA.
DR EMBL; U58143; AAC50602.1; -; mRNA.
DR EMBL; U60520; AAC50645.1; -; mRNA.
DR EMBL; AF009620; AAB70913.1; -; mRNA.
DR EMBL; AF102146; AAD24962.1; -; Genomic_DNA.
DR EMBL; AF102139; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102140; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102141; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102142; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102143; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102144; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AF102145; AAD24962.1; JOINED; Genomic_DNA.
DR EMBL; AB038985; BAB32555.1; -; Genomic_DNA.
DR EMBL; AF380342; AAK57437.1; -; mRNA.
DR EMBL; AF422925; AAL87628.1; -; mRNA.
DR EMBL; AF422926; AAL87629.1; -; mRNA.
DR EMBL; AF422927; AAL87630.1; -; mRNA.
DR EMBL; AF422928; AAL87631.1; -; mRNA.
DR EMBL; AF422929; AAL87632.1; -; mRNA.
DR EMBL; DQ355026; ABC67468.1; -; Genomic_DNA.
DR EMBL; AC007256; AAY24225.1; -; Genomic_DNA.
DR EMBL; BC028223; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_001073593.1; NM_001080124.1.
DR RefSeq; NP_001073594.1; NM_001080125.1.
DR RefSeq; NP_001219.2; NM_001228.4.
DR RefSeq; NP_203519.1; NM_033355.3.
DR RefSeq; NP_203520.1; NM_033356.3.
DR RefSeq; NP_203522.1; NM_033358.3.
DR RefSeq; XP_005246943.1; XM_005246886.1.
DR RefSeq; XP_005246944.1; XM_005246887.1.
DR RefSeq; XP_005246945.1; XM_005246888.1.
DR RefSeq; XP_005246946.1; XM_005246889.1.
DR RefSeq; XP_005246947.1; XM_005246890.1.
DR RefSeq; XP_005246948.1; XM_005246891.1.
DR RefSeq; XP_005246949.1; XM_005246892.1.
DR UniGene; Hs.599762; -.
DR PDB; 1F9E; X-ray; 2.90 A; A/C/E/G/I/K=222-374, B/D/F/H/J/L=390-478.
DR PDB; 1I4E; X-ray; 3.00 A; B=222-479.
DR PDB; 1QDU; X-ray; 2.80 A; A/C/E/G/I/K=222-374, B/D/F/H/J/L=390-477.
DR PDB; 1QTN; X-ray; 1.20 A; A=211-374, B=385-479.
DR PDB; 2C2Z; X-ray; 1.95 A; A=218-374, B=376-479.
DR PDB; 2FUN; X-ray; 3.00 A; B/D=222-479.
DR PDB; 2K7Z; NMR; -; A=217-479.
DR PDB; 2Y1L; X-ray; 1.80 A; A/C=218-374, B/D=376-479.
DR PDB; 3H11; X-ray; 1.90 A; B=217-479.
DR PDB; 3KJN; X-ray; 1.80 A; A=211-374, B=385-479.
DR PDB; 3KJQ; X-ray; 1.80 A; A=211-374, B=385-479.
DR PDB; 4JJ7; X-ray; 1.18 A; A=217-479.
DR PDBsum; 1F9E; -.
DR PDBsum; 1I4E; -.
DR PDBsum; 1QDU; -.
DR PDBsum; 1QTN; -.
DR PDBsum; 2C2Z; -.
DR PDBsum; 2FUN; -.
DR PDBsum; 2K7Z; -.
DR PDBsum; 2Y1L; -.
DR PDBsum; 3H11; -.
DR PDBsum; 3KJN; -.
DR PDBsum; 3KJQ; -.
DR PDBsum; 4JJ7; -.
DR ProteinModelPortal; Q14790; -.
DR SMR; Q14790; 223-479.
DR DIP; DIP-30915N; -.
DR IntAct; Q14790; 65.
DR MINT; MINT-91645; -.
DR BindingDB; Q14790; -.
DR ChEMBL; CHEMBL3776; -.
DR GuidetoPHARMACOLOGY; 1624; -.
DR MEROPS; C14.009; -.
DR PhosphoSite; Q14790; -.
DR DMDM; 2493531; -.
DR PaxDb; Q14790; -.
DR PRIDE; Q14790; -.
DR DNASU; 841; -.
DR Ensembl; ENST00000264274; ENSP00000264274; ENSG00000064012.
DR Ensembl; ENST00000264275; ENSP00000264275; ENSG00000064012.
DR Ensembl; ENST00000323492; ENSP00000325722; ENSG00000064012.
DR Ensembl; ENST00000358485; ENSP00000351273; ENSG00000064012.
DR Ensembl; ENST00000392258; ENSP00000376087; ENSG00000064012.
DR Ensembl; ENST00000392259; ENSP00000376088; ENSG00000064012.
DR Ensembl; ENST00000392263; ENSP00000376091; ENSG00000064012.
DR Ensembl; ENST00000392266; ENSP00000376094; ENSG00000064012.
DR Ensembl; ENST00000432109; ENSP00000412523; ENSG00000064012.
DR GeneID; 841; -.
DR KEGG; hsa:841; -.
DR UCSC; uc002uxr.1; human.
DR CTD; 841; -.
DR GeneCards; GC02P202062; -.
DR HGNC; HGNC:1509; CASP8.
DR HPA; CAB002047; -.
DR HPA; HPA001302; -.
DR HPA; HPA005688; -.
DR MIM; 211980; phenotype.
DR MIM; 601763; gene.
DR MIM; 607271; phenotype.
DR neXtProt; NX_Q14790; -.
DR Orphanet; 275517; Autoimmune lymphoproliferative syndrome with recurrent infections.
DR PharmGKB; PA26092; -.
DR eggNOG; NOG303276; -.
DR HOVERGEN; HBG050803; -.
DR InParanoid; Q14790; -.
DR KO; K04398; -.
DR OMA; IFIEMEK; -.
DR OrthoDB; EOG7CRTQM; -.
DR BRENDA; 3.4.22.61; 2681.
DR Reactome; REACT_578; Apoptosis.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q14790; -.
DR ChiTaRS; CASP8; human.
DR EvolutionaryTrace; Q14790; -.
DR GeneWiki; Caspase_8; -.
DR GenomeRNAi; 841; -.
DR NextBio; 3510; -.
DR PMAP-CutDB; Q14790; -.
DR PRO; PR:Q14790; -.
DR ArrayExpress; Q14790; -.
DR Bgee; Q14790; -.
DR Genevestigator; Q14790; -.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; IEA:Ensembl.
DR GO; GO:0044297; C:cell body; IEA:Ensembl.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0031264; C:death-inducing signaling complex; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0005741; C:mitochondrial outer membrane; TAS:Reactome.
DR GO; GO:0043005; C:neuron projection; IEA:Ensembl.
DR GO; GO:0030690; C:Noc1p-Noc2p complex; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0097342; C:ripoptosome; IDA:UniProtKB.
DR GO; GO:0097153; F:cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl.
DR GO; GO:0006921; P:cellular component disassembly involved in execution phase of apoptosis; TAS:Reactome.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB.
DR GO; GO:0007507; P:heart development; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0097193; P:intrinsic apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0030225; P:macrophage differentiation; IEA:Ensembl.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0043124; P:negative regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0001841; P:neural tube formation; IEA:Ensembl.
DR GO; GO:0070423; P:nucleotide-binding oligomerization domain containing signaling pathway; TAS:Reactome.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR GO; GO:0045651; P:positive regulation of macrophage differentiation; IMP:UniProtKB.
DR GO; GO:1900740; P:positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway; TAS:Reactome.
DR GO; GO:0045862; P:positive regulation of proteolysis; IDA:BHF-UCL.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0051603; P:proteolysis involved in cellular protein catabolic process; IMP:BHF-UCL.
DR GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR GO; GO:0046677; P:response to antibiotic; IEA:Ensembl.
DR GO; GO:0032025; P:response to cobalt ion; IEA:Ensembl.
DR GO; GO:0009409; P:response to cold; IEA:Ensembl.
DR GO; GO:0032355; P:response to estradiol stimulus; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0034612; P:response to tumor necrosis factor; IMP:BHF-UCL.
DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0035666; P:TRIF-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR Gene3D; 1.10.533.10; -; 2.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR001875; DED.
DR InterPro; IPR011600; Pept_C14_caspase.
DR InterPro; IPR001309; Pept_C14_ICE_p20.
DR InterPro; IPR016129; Pept_C14_ICE_p20_AS.
DR InterPro; IPR002138; Pept_C14_p10.
DR InterPro; IPR015917; Pept_C14A_p45_core.
DR Pfam; PF01335; DED; 2.
DR Pfam; PF00656; Peptidase_C14; 1.
DR PRINTS; PR00376; IL1BCENZYME.
DR SMART; SM00115; CASc; 1.
DR SMART; SM00031; DED; 2.
DR SUPFAM; SSF47986; SSF47986; 2.
DR PROSITE; PS01122; CASPASE_CYS; 1.
DR PROSITE; PS01121; CASPASE_HIS; 1.
DR PROSITE; PS50207; CASPASE_P10; 1.
DR PROSITE; PS50208; CASPASE_P20; 1.
DR PROSITE; PS50168; DED; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation;
KW Host-virus interaction; Hydrolase; Phosphoprotein; Polymorphism;
KW Protease; Reference proteome; Repeat; Thiol protease; Zymogen.
FT PROPEP 1 216
FT /FTId=PRO_0000004628.
FT CHAIN 217 374 Caspase-8 subunit p18.
FT /FTId=PRO_0000004629.
FT PROPEP 375 384
FT /FTId=PRO_0000004630.
FT CHAIN 385 479 Caspase-8 subunit p10.
FT /FTId=PRO_0000004631.
FT DOMAIN 2 80 DED 1.
FT DOMAIN 100 177 DED 2.
FT ACT_SITE 317 317
FT ACT_SITE 360 360
FT MOD_RES 188 188 Phosphoserine (By similarity).
FT MOD_RES 211 211 Phosphoserine (By similarity).
FT MOD_RES 334 334 Phosphotyrosine.
FT MOD_RES 387 387 Phosphoserine; by CDK1.
FT VAR_SEQ 1 1 M -> MEGGRRARVVIESKRNFFLGAFPTPFPAEHVELGRL
FT GDSETAMVPGKGGADYILLPFKKM (in isoform 9).
FT /FTId=VSP_000808.
FT VAR_SEQ 102 102 R -> RFHFCRMSWAEANSQCQTQSVPFWRRVDHLLIR
FT (in isoform 4).
FT /FTId=VSP_000809.
FT VAR_SEQ 184 267 Missing (in isoform 3).
FT /FTId=VSP_000813.
FT VAR_SEQ 184 220 ERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQ ->
FT DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH (in
FT isoform 6).
FT /FTId=VSP_000811.
FT VAR_SEQ 184 198 Missing (in isoform 2, isoform 4 and
FT isoform 8).
FT /FTId=VSP_000810.
FT VAR_SEQ 199 235 GEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGY ->
FT DFGQSLPNEKQTSGILSDHQQSQFCKSTGESAQTSQH (in
FT isoform 5).
FT /FTId=VSP_000814.
FT VAR_SEQ 221 479 Missing (in isoform 6).
FT /FTId=VSP_000812.
FT VAR_SEQ 236 479 Missing (in isoform 5).
FT /FTId=VSP_000815.
FT VAR_SEQ 269 276 ALTTTFEE -> TVEPKREK (in isoform 7 and
FT isoform 8).
FT /FTId=VSP_000816.
FT VAR_SEQ 277 479 Missing (in isoform 7 and isoform 8).
FT /FTId=VSP_000817.
FT VARIANT 219 219 S -> T (in dbSNP:rs35976359).
FT /FTId=VAR_025816.
FT VARIANT 248 248 R -> W (in CASP8D; dbSNP:rs17860424).
FT /FTId=VAR_014204.
FT VARIANT 285 285 D -> H (associated with protection
FT against breast cancer; also associated
FT with a lower risk of cutaneous melanoma;
FT dbSNP:rs1045485).
FT /FTId=VAR_020127.
FT MUTAGEN 73 73 D->A: Abolishes binding to FLASH. Induces
FT NF-kappa-B activation.
FT MUTAGEN 387 387 S->A: Impaired CDK1-mediated
FT phosphorylation and enhanced apoptosis.
FT CONFLICT 294 294 E -> D (in Ref. 5; AAD24962).
FT CONFLICT 331 331 A -> P (in Ref. 2; AAC50602 and 5;
FT AAD24962).
FT CONFLICT 343 344 LK -> FG (in Ref. 8; AAL87631).
FT STRAND 230 232
FT STRAND 235 240
FT HELIX 245 250
FT HELIX 252 254
FT STRAND 255 257
FT HELIX 263 276
FT STRAND 280 286
FT HELIX 289 301
FT HELIX 304 306
FT STRAND 310 316
FT STRAND 322 324
FT STRAND 326 328
FT STRAND 330 332
FT HELIX 333 337
FT HELIX 338 340
FT TURN 342 344
FT HELIX 346 348
FT STRAND 353 359
FT STRAND 361 364
FT STRAND 369 371
FT STRAND 377 379
FT STRAND 392 394
FT TURN 395 398
FT STRAND 399 405
FT STRAND 412 414
FT TURN 415 417
FT HELIX 420 432
FT HELIX 433 435
FT HELIX 439 450
FT TURN 456 459
FT STRAND 465 468
FT STRAND 471 473
SQ SEQUENCE 479 AA; 55391 MW; 7A5FEAA6B39B582F CRC64;
MDFSRNLYDI GEQLDSEDLA SLKFLSLDYI PQRKQEPIKD ALMLFQRLQE KRMLEESNLS
FLKELLFRIN RLDLLITYLN TRKEEMEREL QTPGRAQISA YRVMLYQISE EVSRSELRSF
KFLLQEEISK CKLDDDMNLL DIFIEMEKRV ILGEGKLDIL KRVCAQINKS LLKIINDYEE
FSKERSSSLE GSPDEFSNGE ELCGVMTISD SPREQDSESQ TLDKVYQMKS KPRGYCLIIN
NHNFAKAREK VPKLHSIRDR NGTHLDAGAL TTTFEELHFE IKPHDDCTVE QIYEILKIYQ
LMDHSNMDCF ICCILSHGDK GIIYGTDGQE APIYELTSQF TGLKCPSLAG KPKVFFIQAC
QGDNYQKGIP VETDSEEQPY LEMDLSSPQT RYIPDEADFL LGMATVNNCV SYRNPAEGTW
YIQSLCQSLR ERCPRGDDIL TILTEVNYEV SNKDDKKNMG KQMPQPTFTL RKKLVFPSD
//

MIM 211980
*RECORD*
*FIELD* NO
211980
*FIELD* TI
#211980 LUNG CANCER
ALVEOLAR CELL CARCINOMA, INCLUDED;;
ADENOCARCINOMA OF LUNG, INCLUDED;;
read moreNONSMALL CELL LUNG CANCER, INCLUDED;;
LUNG CANCER, PROTECTION AGAINST, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because mutations in several
different genes are associated with lung cancer. Both germline and
somatic mutations have been identified in the EGFR (131550) and p53
(TP53; 191170) genes, and somatic mutations have been identified in the
KRAS (190070), BRAF (164757), ERBB2 (164870), MET (164860), STK11
(602216), PIK3CA (171834), and PARK2 (602544) genes. Amplification of
several genes, including EGFR, ERBB2, MET, PIK3CA, and NKX2-1 (600635),
is also associated with lung cancer. Deletion of several genes,
including DOK2 (604977), is also associated with lung cancer. An
ALK/EML4 fusion gene (see 105590) has been identified in lung cancer.
Several polymorphisms are associated with lung cancer susceptibility,
including a 5-prime SNP in the ERCC6 gene (609413) and SNPs in the
nicotinic acetylcholine receptor gene cluster on chromosome 15q25.1 (see
LNCR2; 612052). Lung cancer susceptibility loci have been mapped to
chromosome 6q23-q25 (LNCR1; 608935), 5p15 (LNCR3; 612571), 6p21 (LNCR4;
612593), and 3q28 (LNCR5; 614210). Deletion alleles in the CYP2A6
(122720) and CASP8 (601763) genes are associated with a reduced risk of
lung cancer in Japanese and Han Chinese individuals, respectively. A SNP
in the MPO gene (606989) is associated with reduced risk of lung cancer
in smokers.

The Cancer Genome Atlas Research Network (2012) profiled 178 lung
squamous cell carcinomas to provide a comprehensive landscape of genomic
and epigenomic alterations, and showed that the tumor type is
characterized by complex genomic alterations with a mean of 360 exonic
mutations, 165 genomic rearrangements, and 323 segments of copy number
alteration per tumor. The Cancer Genome Atlas Research Network (2012)
found statistically recurrent mutations in 11 genes, including mutations
in TP53 in nearly all specimens. Previously unreported loss-of-function
mutations were seen in the HLA-A class I major histocompatibility gene
(142800). Significantly altered pathways included NFE2L2 (600492) and
KEAP1 (606016) in 34%, squamous differentiation genes in 44%,
phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A
(600160) and RB1 (614041) in 72% of tumors. The Cancer Genome Atlas
Research Network (2012) identified a potential therapeutic target in
most tumors, offering new avenues of investigation for the treatment of
squamous cell lung cancers.

DESCRIPTION

Lung cancer is the leading cause of cancer deaths in the U.S. and
worldwide. The 2 major forms of lung cancer are nonsmall cell lung
cancer and small cell lung cancer (see 182280), which account for 85%
and 15% of all lung cancers, respectively. Nonsmall cell lung cancer can
be divided into 3 major histologic subtypes: squamous cell carcinoma,
adenocarcinoma, and large cell lung cancer. Cigarette smoking causes all
types of lung cancer, but it is most strongly linked with small cell
lung cancer and squamous cell carcinoma. Adenocarcinoma is the most
common type in patients who have never smoked. Nonsmall cell lung cancer
is often diagnosed at an advanced stage and has a poor prognosis (Herbst
et al., 2008).

CLINICAL FEATURES

Joishy et al. (1977) described identical twins who developed symptoms of
alveolar cell carcinoma almost simultaneously.

Ahrendt et al. (2001) noted that incidence rates for squamous cell and
small cell lung carcinoma began falling among males in the mid-1980s,
but a decline in the incidence of primary adenocarcinoma of the lung
among males was not observed until 5 to 10 years later. Similarly,
although the incidence rates of squamous cell, large cell, and small
cell lung carcinoma among women leveled off or started to decrease, the
incidence of adenocarcinoma continued to increase. With these changes in
the incidence among the different histologic types of lung carcinoma
over the 1990s, adenocarcinoma of the lung became the most common type
of lung carcinoma in the U.S. (Wingo et al., 1999).

INHERITANCE

Braun et al. (1994) conducted a genetic analysis of lung cancer
mortality in the National Academy of Sciences/National Research Council
Twin Registry. The registry is composed of 15,924 male twin pairs who
were born in the U.S. between 1917 and 1927 and who served in the armed
forces during World War II. As evidence for a genetic effect on lung
cancer, they required concordance for lung cancer death to be greater
among monozygotic than among dizygotic twin pairs. No genetic effect on
lung cancer mortality was observed. The ratio of observed to expected
concordance among monozygotic twins did not exceed that among dizygotic
twins, even though monozygotic twin pairs were more likely to be
concordant for smoking than dizygotic twin pairs in this population. A
cohort analysis (accounting for age, sex, race, and smoking intensity)
of lung cancer mortality found no lung cancer deaths during the 300
person-years of follow-up among 47 monozygotic twins smokers whose
smoking twin died of lung cancer, even though smoking histories were
very similar within twin pairs.

In a multicenter study of lung cancer in lifetime nonsmokers in the
United States, 646 female lung cancer patients and 1,252 population
controls were interviewed regarding history of cancer in their
first-degree relatives. Wu et al. (1996) summarized the findings. A 30%
increased risk was associated with a history of respiratory tract cancer
in parents or sibs after adjustment for exposure to environmental
tobacco smoke in adult life. Lung cancer, which represented
approximately two-thirds of the respiratory tract cancers, occurred more
frequently in first-degree relatives of lung cancer patients than in
comparable relatives of population controls. A significant 3-fold
increased risk for lung cancer was associated with lung cancer diagnosed
in mothers and sisters. Wu et al. (1996) also observed the increased
risk in relation to family history of lung cancer among parents and sibs
who were smokers as well as in those who were nonsmokers. The
association with family history of lung cancer was strengthened when the
analysis was restricted to adenocarcinoma of the lung. However, the
authors pointed out that there was no association between family history
of other cancers and risk of lung cancer in nonsmokers.

POPULATION GENETICS

Haiman et al. (2006) investigated differences in the risk of lung cancer
associated with cigarette smoking in 183,813 African American, Japanese
American, Latino, Native Hawaiian, and white men and women. Their
analysis included 1,979 cases of incident lung cancer identified
prospectively over an 8-year period. They found that among cigarette
smokers, African Americans and Native Hawaiians are more susceptible to
lung cancer than whites, Japanese Americans, and Latinos. Risch (2006)
discussed the problems of dissecting racial and ethnic differences in
relation to the frequency of disease. He stated that it is 'difficult to
discuss the role of genetics in differences among groups, because of the
fear that such discourse may reinforce notions of biologic determinism.
Some insist that racial and ethnic categories are purely social and
devoid of genetic content, or at least of minimal relevance.'

PATHOGENESIS

In the DNA from 1 colon and 2 lung carcinoma cell lines, Perucho et al.
(1981) demonstrated the same or closely related transforming elements.
By DNA-mediated gene transfer, mouse fibroblasts could be
morphologically transformed and rendered tumorigenic in nude mice.

Starting from studies of lung adenocarcinomas, Ramaswamy et al. (2003)
explored the molecular differences between human primary tumors and
metastases by comparing their gene expression profiles. They found a
17-gene-expression signature that distinguished primary from metastatic
adenocarcinomas. Notably, they found that a subset of primary tumors
resembled metastatic tumors with respect to this gene-expression
signature. They confirmed their findings by applying the expression
signature to data on 279 primary solid tumors of diverse types. They
found that solid tumors carrying the gene-expression signature were most
likely to be associated with metastasis and poor clinical outcome (P
less than 0.03). These results suggested that the metastatic potential
of human tumors is encoded in the bulk of a primary tumor, thus
challenging the notion that metastases arise from rare cells within a
primary tumor that have the ability to metastasize. The results
supported the idea that some primary tumors are preconfigured to
metastasize, and that this propensity is detectable at the time of
initial diagnosis.

A considerable proportion of the refined gene-expression signature that
Ramaswamy et al. (2003) found to be associated with metastasis seemed to
be derived from nonepithelial components of the tumor. Specifically,
these included genes encoding the type 1 collagens (COL1A1, 120150;
COL1A2, 120160) whose expression is restricted to fibroblasts. Some of
the 17 genes constituting the signature were upregulated in metastases,
others were downregulated. The upregulation of collagen genes in primary
tumors with metastatic potential is consistent with observations that
epithelial-mesenchymal interactions are critical determinants of tumor
cell behavior. High levels of type 1 collagen in metastatic lesions and
in the serum of individuals with metastatic disease have been reported.
In general, the findings were consistent with the existence of a
molecular program of metastasis that is shared by multiple solid-tumor
types, suggesting the possible existence of therapeutic targets common
to different cancers.

Brock et al. (2008) analyzed methylation of 7 genes in tumor tissue and
lymph nodes from 51 patients with stage I nonsmall cell lung cancer
(NSCLC) who underwent curative resection but had a recurrence within 40
months and from 116 age-, sex-, NSCLC stage-, and date of
surgery-matched patients who underwent curative resection and did not
have a recurrence within 40 months. In a multivariate model, the authors
found that promoter methylation of the CDKN2A (600160), CDH13 (601364),
RASSF1A (605082), and APC (611731) genes in tumors and in histologically
tumor-negative lymph nodes was associated with tumor recurrence,
independently of NSCLC stage, age, sex, race, smoking history, and
histologic characteristics of the tumor. Methylation of the promoter
regions of CDKN2A and CDH13 in both tumor and mediastinal lymph nodes
was associated with an odds ratio of recurrent cancer of 15.50 in the
original cohort and an OR of 25.25 when the original cohort was combined
with an independent validation cohort of 20 patients with stage I NSCLC.

Winslow et al. (2011) modeled human lung adenocarcinoma, which
frequently harbors activating point mutations in KRAS (190070) and
inactivation of the p53 (191170) pathway, using conditional alleles in
mice. Lentiviral-mediated somatic activation of oncogenic Kras and
deletion of p53 in the lung epithelial cells of
Kras(LSL-G12D/+);p53(flox/flox) mice initiates lung adenocarcinoma
development. Although tumors are initiated synchronously by defined
genetic alterations, only a subset becomes malignant, indicating that
disease progression requires additional alterations. Identification of
the lentiviral integration sites allowed Winslow et al. (2011) to
distinguish metastatic from nonmetastatic tumors and determine the gene
expression alterations that distinguish these tumor types. Cross-species
analysis identified the NK2-related homeobox transcription factor Nkx2-1
(600635) as a candidate suppressor of malignant progression. In this
mouse model, Nkx2-1 negativity is pathognomonic of high-grade poorly
differentiated tumors. Gain- and loss-of-function experiments in cells
derived from metastatic and nonmetastatic tumors demonstrated that
Nkx2-1 controls tumor differentiation and limits metastatic potential in
vivo. Interrogation of Nkx2-1-regulated genes, analysis of tumors at
defined developmental stages, and functional complementation experiments
indicated that Nkx2-1 constrains tumors in part by repressing the
embryonically restricted chromatin regulator Hmga2 (600698). Whereas
focal amplification of NKX2-1 in a fraction of human lung
adenocarcinomas had focused attention on its oncogenic function, Winslow
et al. (2011) stated that their data specifically linked Nkx2-1
downregulation to loss of differentiation, enhanced tumor seeding
ability, and increased metastatic proclivity. Winslow et al. (2011)
concluded that the oncogenic and suppressive functions of Nkx2-1 in the
same tumor type substantiate its role as a dual function lineage factor.

- Reviews of Lung Cancer Pathogenesis

Herbst et al. (2008) reviewed lung cancer with a focus on the origins
and biology of squamous cell carcinoma and adenocarcinoma, which
constitute the majority of diagnosed lung cancers.

CLINICAL MANAGEMENT

In a multiinstitutional phase II trial, Fukuoka et al. (2003) found a
higher rate of response to the tyrosine kinase inhibitor gefitinib
(Iressa) in Japanese patients with nonsmall cell lung cancer (NSCLC)
than in a predominantly European-derived population (27.5% vs 10.4%).
See 'EGFR Mutations and Lung Cancer' in MOLECULAR GENETICS for
information on EGFR (131550) mutations associated with
gefitinib-responsive lung cancer.

In a randomized control trial of 1,217 East Asian patients with nonsmall
cell lung cancer, Mok et al. (2009) found that the 12-month rate of
progression-free survival was 24.9% in patients treated with gefitinib
and 6.7% in those treated with carboplatin-paclitaxel. In the subgroup
of 261 patients who were positive for an EGFR mutation, progression-free
survival was significantly longer among those who received gefitinib
than among those who received carboplatin-paclitaxel, whereas in the
subgroup of 176 patients who were negative for a mutation,
progression-free survival was significantly longer among those who
received carboplatin-paclitaxel. The findings indicated that gefitinib
is superior to carboplatin-paclitaxel as an initial treatment for
pulmonary adenocarcinoma among nonsmokers or former light smokers in
East Asia, and showed that the presence in the tumor of an EGFR mutation
is a strong predictor of a better outcome with gefitinib.

Rosell et al. (2009) concluded that large-scale screening of patients
with lung cancer for EGFR mutations is feasible and can have a role in
treatment decisions. EGFR mutations were identified in tumor tissue of
350 (16.6%) of 2,105 Spanish patients with nonsmall cell lung cancer.
Mutations were more frequent in women (69.7%), in patients who had never
smoked (66.6%), and in those with adenocarcinomas (80.9%). The mutations
were deletions in exon 19 (62.2%) and L858R (131550.0002) (37.8%).
Median progression-free survival and overall survival for 217 patients
who received erlotinib were 14 months and 27 months, respectively.
Multivariate analysis showed an association between poor
progression-free survival and male sex (hazard ratio of 2.94), and the
presence of the L858R mutation (hazard ratio of 1.92) as compared with a
deletion in exon 19. The most common adverse events were mild rashes and
diarrhea. The results suggested that EGFR-mutant lung cancer is a
distinct class of nonsmall cell lung cancer.

Bivona et al. (2011) used a pooled RNAi screen to show that knockdown of
FAS (134637) and several components of the NF-kappa-B pathway (see
164011) specifically enhanced cell death induced by the EGFR (131550)
tyrosine kinase inhibitor (TKI) erlotinib in EGFR-mutant lung cancer
cells. Activation of NF-kappa-B through overexpression of c-FLIP
(603599) or IKK (603258), or silencing of I-kappa-B (see 164008),
rescued EGFR-mutant lung cancer cells from EGFR TKI treatment. Genetic
or pharmacologic inhibition of NF-kappa-B enhanced erlotinib-induced
apoptosis in erlotinib-sensitive and erlotinib-resistant EGFR-mutant
lung cancer models. Increased expression of the NF-kappa-B inhibitor
I-kappa-B predicted improved response and survival in EGFR-mutant lung
cancer patients treated with EGFR TKI. Bivona et al. (2011) concluded
that their data identified NF-kappa-B as a potential companion drug
target, together with EGFR, in EGFR-mutant lung cancers and provided
insight into the mechanisms by which tumor cells escape from oncogene
dependence.

Zhang et al. (2012) reported increased activation of AXL (109135) and
evidence for epithelial-to-mesenchymal transition (EMT) in multiple in
vitro and in vivo EGFR-mutant lung cancer models with acquired
resistance to erlotinib in the absence of the EGFR T790M alteration
(131550.0006) or MET activation. Genetic or pharmacologic inhibition of
AXL restored sensitivity to erlotinib in these tumor models. Increased
expression of AXL and, in some cases, of its ligand GAS6 (600441) was
found in EGFR-mutant lung cancers obtained from individuals with
acquired resistance to tyrosine kinase inhibitors.

MAPPING

In 3 varieties of nonsmall cell cancer of the lung, Weston et al. (1989)
found evidence of loss of heterozygosity in chromosome 17p and
chromosome 11. Only a minority had loss of heterozygosity involving a
chromosomal locus on 3p previously shown to be lost consistently in
small cell cancer of the lung (SCLC1; 182280).

Dai et al. (2003) used restriction landmark genomic scanning (RLGS) to
identify novel amplified sequences in primary lung carcinomas and lung
cancer cell lines. Enhanced RLGS fragments indicative of gene
amplification were observed in tumors and cell lines of both nonsmall
cell lung cancer and small cell lung cancer. The authors identified a
novel amplicon on chromosome 11q22, in addition to previously reported
amplicons that include oncogenes MYC (190080), MYCL1 (164850), and
previously identified amplification of chromosomal regions 6q21 and
3q26-27. The amplified region of 11q22 was refined to 0.92 Mb in 1
patient sample. Immunohistochemistry and Western blot analysis
identified CIAP1 (BIRC2; 601712) and CIAP2 (BIRC3; 601721) as potential
oncogenes in this region, since both are overexpressed in multiple lung
cancers with or without higher copy numbers.

Bailey-Wilson et al. (2004) mapped a major lung cancer susceptibility
locus to chromosome 6q23-q25 (LNCR1; 608935).

MOLECULAR GENETICS

Ding et al. (2008) sequenced 623 genes with known or potential
relationship to cancer in 188 human lung adenocarcinomas. Their analysis
identified 26 genes that are mutated at significantly high frequencies
and are probably involved in carcinogenesis. The frequently mutated
genes include tyrosine kinases, among them the EGFR homolog ERBB4
(600543); multiple ephrin receptor genes, notably EPHA3 (179611); KDR
(191306); and NTRK (191315). Their data provide evidence of somatic
mutations in primary lung adenocarcinoma for several tumor suppressor
genes involved in other cancers, including NF1 (613113), APC (611731),
RB1 (614041), and ATM (607585), and for sequence changes in PTPRD
(601598) as well as the frequently deleted gene LRP1B (608766). The
observed mutational profiles correlate with clinical features, smoking
status, and DNA repair defects. In general, Ding et al. (2008) found
that genetic alterations in lung adenocarcinoma frequently occur in
genes of the MAPK (see 176948), p53 (191170), WNT (see 164820), cell
cycle, and mTOR (601231) signaling pathways.

In affected members of 2 families with idiopathic pulmonary fibrosis
(178500), some of whom also had lung cancer, Wang et al. (2009)
identified 2 heterozygous missense mutations in the SFTPA2 gene (see
178642.0001 and 178642.0002, respectively).

Kan et al. (2010) reported the identification of 2,576 somatic mutations
across approximately 1,800 megabases of DNA representing 1,507 coding
genes from 441 tumors comprising breast, lung, ovarian, and prostate
cancer types and subtypes. Kan et al. (2010) found that mutation rates
and the sets of mutated genes varied substantially across tumor types
and subtypes. Statistical analysis identified 77 significantly mutated
genes including protein kinases, G protein-coupled receptors such as
GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other
druggable targets. Integrated analysis of somatic mutations and copy
number alterations identified another 35 significantly altered genes
including GNAS (see 139320), indicating an expanded role for G-alpha
subunits in multiple cancer types. Experimental analyses demonstrated
the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335)
in oncogenesis.

- p53 Mutations and Lung Cancer

Among members of 97 families enrolled in a cohort study of families
ascertained through childhood soft tissue sarcoma patients, Hwang et al.
(2003) studied the role of cigarette smoking and lung cancer risk in
people with a genetic susceptibility based on a p53 germline mutation.
They assessed the incidence of lung and smoking-related cancers in 33
carriers of germline p53 mutations and in 1,230 noncarriers from the
same families. They observed an increased risk of a variety of
histologic types of lung cancer in the carriers of the p53 mutations.
Mutation carriers who smoked had a 3.16-fold (95% CI = 1.48-6.78) higher
risk for lung cancer than the mutation carriers who did not smoke.

- EGFR Mutations and Lung Cancer

In tumors from patients with NSCLC responsive to the tyrosine kinase
inhibitor gefitinib, Lynch et al. (2004) and Paez et al. (2004)
identified mutations in the EGFR gene (131550.0001-131550.0005). Paez et
al. (2004) found somatic mutations in EGFR in 15 of 58 unselected NSCLC
tumors from Japan and 1 of 61 from the United States. EGFR mutations
showed a striking correlation with patient characteristics. Mutations
were more frequent in adenocarcinomas than in other NSCLCs, being
present in 15 (21%) of 70 and 1 (2%) of 49, respectively; more frequent
in women than in men, being present in 9 (20%) of 45 and 7 (9%) of 74,
respectively; and more frequent in patients from Japan than in those
from the United States, being present in 15 (26%) of 58 and 14 (32%) of
41 adenocarcinomas versus 1 (2%) of 61 and 1 (3%) of 29 adenocarcinomas,
respectively. The patient characteristics that correlated with the
presence of EGFR mutations were those that correlated with clinical
response to gefitinib treatment. The striking difference in the
frequency of EGFR mutation and response to gefitinib between Japanese
and U.S. patients raised general questions regarding variation in the
molecular pathogenesis of cancer in different ethnic, cultural, and
geographic groups and argued for the benefit of population diversity in
cancer clinical trials.

Pao et al. (2004) found that in-frame deletions in exon 19 of the EGFR
gene and somatic point mutations in codon 858 (exon 21) were common
particularly in lung cancers from 'never smokers' and were associated,
as found by others, with sensitivity to the tyrosine kinase inhibitors
gefitinib and erlotinib. Pao et al. (2004) found EGFR tyrosine kinase
domain mutations in 7 of 10 gefitinib-sensitive tumors and 5 of 7
erlotinib-sensitive tumors. No mutations were found in 8
gefitinib-refractory tumors and 10 erlotinib-refractory tumors. Because
most of the mutation-positive tumors were adenocarcinomas from 'never
smokers' (defined as patients who smoked less than 100 cigarettes in a
lifetime), Pao et al. (2004) screened EGFR exons 2 through 28 for
mutations in 15 adenocarcinomas resected from untreated 'never smokers.'
Seven tumors had tyrosine kinase domain mutations, in contrast to 4 of
81 nonsmall cell lung cancers resected from untreated former or current
smokers. Collectively the data showed that adenocarcinomas from 'never
smokers' comprise a distinct subset of lung cancers, frequently
containing mutations within the tyrosine kinase domain of EGFR that are
associated with kinase inhibitor sensitivity.

Maheswaran et al. (2008) identified the EGFR T790M (131550.0006)
mutation in pretreatment tumor samples from 10 (38%) of 26 patients with
nonsmall cell lung cancer. Although low levels of the drug-resistant
mutation did not preclude response to treatment, it was highly
correlated with reduced progression-free survival. Use of a
microfluidic-based isolation device and sequence amplification
technology allowed for detection of EGFR mutations in circulating tumor
cells from 11 (92%) of 12 patients. Serial analysis of circulating tumor
cells showed that a reduction in the number of captured cells was
associated with a radiographic tumor response; an increase in the number
of cells was associated with tumor progression, with the emergence of
additional EGFR mutations in some cases. Maheswaran et al. (2008)
concluded that molecular analysis of circulating tumor cells from the
blood of patients with EGFR-related nonsmall cell lung cancer could
offer the possibility of monitoring changes in tumor genotype.

- MET Amplification and Drug Resistance in Lung Cancer

The EGFR kinase inhibitors gefitinib and erlotinib are effective
treatments for lung cancers with EGFR activating mutations, but these
tumors invariably develop drug resistance. Engelman et al. (2007)
described a gefitinib-sensitive lung cancer cell line that developed
resistance to gefitinib as a result of focal amplification of the MET
(164860) protooncogene. Inhibition of MET signaling in these cells
restored their sensitivity to gefitinib. MET amplification was detected
in 4 (22%) of 18 lung cancer specimens that had developed resistance to
gefitinib or erlotinib. Engelman et al. (2007) found that amplification
of MET caused gefitinib resistance by driving ERBB3 (190151)-dependent
activation of phosphoinositide 3-kinase, a pathway thought to be
specific to EGFR/ERBB family receptors. Thus, Engelman et al. (2007)
proposed that MET amplification may promote drug resistance in other
ERBB-driven cancers as well.

- KRAS Mutations and Lung Adenocarcinoma

In a study of 106 prospectively enrolled patients with primary
adenocarcinoma of the lung, Ahrendt et al. (2001) found that 92 (87%)
were smokers. KRAS mutations were detected in 40 (38%) of 106 tumors and
were significantly more common in smokers compared with nonsmokers (43%
vs 0%; P = 0.001). Thirty-nine of the 40 tumors with KRAS mutations had
1 of 4 changes in codon 12, the most common being gly12 to cys
(190070.0001), which was present in 25.

- BRAF Mutations and Lung Adenocarcinoma

Mutations of the BRAF protein serine/threonine kinase gene (164757) have
been identified in a variety of human cancers, most notably melanomas.
Naoki et al. (2002) analyzed the BRAF sequence in 127 primary human lung
adenocarcinomas and found mutations in 2 tumor specimens, one in exon 11
(164757.0006) and another in exon 15 (164757.0007). The specimens
belonged to the same adenocarcinoma subgroup as defined by clustering of
gene expression data. The authors proposed that BRAF may provide a
target for anticancer chemotherapy in a subset of lung adenocarcinoma
patients.

- ERBB2 Mutations and Lung Cancer

The Cancer Genome Project and Collaborative Group (2004) sequenced the
ERBB2 gene from 120 primary lung tumors and identified 4% that had
mutations within the kinase domain; in the adenocarcinoma subtype of
lung cancer, 10% of cases had mutations. In-frame deletions within the
kinase domain of EGFR (e.g., 131550.0001) are associated with lung
tumors that respond to therapy with gefitinib, an EGFR inhibitor. The
Cancer Genome Project and Collaborative Group (2004) suggested that
ERBB2 inhibitors, which had to that time proved to be ineffective in
treating lung cancer, should be clinically reevaluated in the specific
subset of patients with lung cancer whose tumors carry ERBB2 mutations.

- STK11 Mutations and Lung Cancer

Ji et al. (2007) used a somatically activatable mutant Kras-driven model
of mouse lung cancer to compare the role of Lkb1 (STK11; 602216) to
other tumor suppressors in lung cancer. Although Kras mutation
cooperated with loss of p53 or Ink4a/Arf (CDKN2A; 600160), in this
system, the strongest cooperation was seen with homozygous inactivation
of Lkb1. Lkb1-deficient tumors demonstrated shorter latency, an expanded
histologic spectrum (adeno-, squamous, and large-cell carcinoma), and
more frequent metastasis compared to tumors lacking p53 or Ink4a/Arf.
Pulmonary tumorigenesis was also accelerated by hemizygous inactivation
of Lkb1. Consistent with these findings, inactivation of LKB1 was found
in 34% and 19% of 144 analyzed human lung adenocarcinomas and squamous
cell carcinomas, respectively. Expression profiling in human lung cancer
cell lines and mouse lung tumors identified a variety of
metastasis-promoting genes, such as NEDD9 (602265), VEGFC (601528), and
CD24 (600074), as targets of LKB1 repression in lung cancer. Ji et al.
(2007) concluded that their studies establish LKB1 as a critical barrier
to pulmonary tumorigenesis, controlling initiation, differentiation, and
metastasis.

- PIK3CA Mutations and Lung Cancer

Samuels et al. (2004) identified a somatic mutation in the PIK3CA gene
(171834) in 1 (4%) of 24 lung cancers examined.

- NKX2-1 Amplification and Lung Adenocarcinoma

Weir et al. (2007) reported a large-scale project to characterize copy
number alterations in primary lung adenocarcinomas. By analysis of 371
tumors using dense single-nucleotide polymorphism arrays, Weir et al.
(2007) identified 57 significantly recurrent events. Weir et al. (2007)
found that 26 of 39 autosomal chromosome arms showed consistent
large-scale copy number gain or loss, of which only a handful had been
linked to a specific gene. They also identified 31 recurrent focal
events, including 24 amplifications and 7 homozygous deletions. Only 6
of these focal events were associated with mutations in lung carcinomas.
The most common event, amplification of chromosome 14q13.3, was found in
about 12% of samples. On the basis of genomic and functional analyses,
Weir et al. (2007) identified NKX2-1 (600635), which lies in the minimal
14q13.3 amplification interval and encodes a lineage-specific
transcription factor, as a novel candidate protooncogene involved in a
significant fraction of lung adenocarcinomas.

- HMOX1 Polymorphism and Susceptibility to Lung Adenocarcinoma

Kikuchi et al. (2005) screened the heme oxygenase-1 gene (HMOX1; 141250)
for (GT)n repeat length in 151 Japanese patients with lung
adenocarcinoma and 153 controls. The proportion of L allele carriers was
significantly higher among patients than controls (p = 0.02); the
adjusted odds ratio for lung adenocarcinoma for L allele carriers was
1.8 (95% CI, 1.1-3.0) compared with non-L allele carriers. The risk of
lung adenocarcinoma for L allele carriers versus non-L allele carriers
was greatly increased in the group of male smokers (OR = 3.3; 95% CI,
1.5-7.4; p = 0.004); however, in female nonsmokers, the proportion of L
allele carriers did not differ between patients and controls, nor did it
differ between 108 patients with lung squamous cell carcinoma and 100
controls. Kikuchi et al. (2005) suggested that a large (GT)n repeat in
the HMOX1 gene promoter may be associated with the development of lung
adenocarcinoma in Japanese male smokers.

- CDKN1A Polymorphism and Susceptibility to Lung Cancer

Sjalander et al. (1996) found an increased frequency of the p21 arg31
allele (116899.0001) in lung cancer patients, especially in comparison
with patients with chronic obstructive pulmonary disease (COPD); p =
0.004. Thus allelic variants of both p53 and its effector protein p21
may have an influence on lung cancer.

- GSTM1 Polymorphism and Susceptibility to Lung Cancer

Bennett et al. (1999) studied genes whose products activate (CYP1A1;
108330) or detoxify (GSTM1, 138350; GSTT1, 600436) chemical carcinogens
found in tobacco smoke in never-smoking women who were exposed to
environmental tobacco smoke (ETS) and developed lung cancer. Archival,
paraffin-embedded, and DNA yielding, surgically resected lung cancer
tissues were obtained from 106 white women who never smoked and
developed lung cancer. When compared with 55 never smokers who developed
lung cancer without ETS exposure, 51 never smokers who developed lung
cancer with ETS exposure were more likely to be GSTM1-null homozygotes
(OR, 2.6; 95% CI, 1.1-6.1). No evidence was found of associations
between lung cancer risk due to ETS exposure and GSTT1 deficiency or the
CYP1A1 valine variant. The authors concluded that white women who never
smoke and are homozygous for the GSTM1 null allele, which occurs in
about 50% of the white population, have a statistically significant
greater risk of developing lung cancer from ETS.

- FAS and FASL Polymorphisms and Susceptibility to Lung Cancer

Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer patients and
1,270 controls for 2 functional polymorphisms in the promoter regions of
the FAS and FASL genes, -1377G-A (TNFRSF6; 134637.0021) and -844T-C
(TNFSF6; 134638.0002), respectively. Compared to noncarriers, there was
a 1.6-fold increased risk of developing lung cancer for carriers of the
FAS -1377AA genotype and a 1.8-fold increased risk for carriers of the
FASL -844CC genotype. Carriers of both homozygous genotypes had a more
than 4-fold increased risk, indicative of multiplicative gene-gene
interaction; the increased risk was consistently observed in all
subtypes of lung cancer. Zhang et al. (2005) stated that these results
support the hypothesis that the FAS- and FASL-triggered apoptosis
pathway plays an important role in human carcinogenesis.

- CASP8 Polymorphism and Protection Against Lung Cancer

Caspases are important in the life and death of immune cells and
therefore influence immune surveillance of malignancies. Using a
haplotype-tagging SNP approach, Sun et al. (2007) identified a
6-nucleotide deletion (-652 6N del) variant in the CASP8 promoter
(601763.0004) associated with decreased risk of lung cancer in a
population of Han Chinese subjects. The deletion destroyed a binding
site for stimulatory protein-1 (SP1; 189906) and decreased
transcription. Biochemical analyses showed that T lymphocytes with the
deletion variant had lower caspase-8 activity and activation-induced
cell death upon stimulation with cancer cell antigens. Case-control
analyses of 4,995 individuals with cancer and 4,972 controls in a
Chinese population showed that this genetic variant is associated with
reduced susceptibility to multiple cancers, including lung, esophageal,
gastric, colorectal, cervical, and breast cancers, acting in an allele
dose-dependent manner.

- CYP2A6 Polymorphism and Protection Against Lung Cancer

Miyamoto et al. (1999) studied the relationship between genetic
polymorphism of the CYP2A6 gene (122720) and lung cancer risk in a
case-control study of Japanese. They found that the frequency of
subjects homozygous for the CYP2A6 gene deletion (122720.0002), which
causes lack of the enzyme activity, was lower in the lung cancer
patients than in the healthy control subjects. These findings suggested
that deficient CYP2A6 activity due to genetic polymorphism reduces lung
cancer risk. Oscarson et al. (1999) found that this deletion allele was
rare in Europeans but had a frequency of 15.1% among 96 Chinese
subjects.

- MPO Polymorphism and Protection Against Lung Cancer in Smokers

Taioli et al. (2007) found that the -463G/A polymorphism in the MPO gene
(606989.0008) conferred resistance to lung cancer among smokers.

- SOX2 Amplification in Lung Cancer

Bass et al. (2009) showed that a peak of genomic amplification on
chromosome 3q26.33 found in squamous cell carcinomas of the lung and
esophagus contains the transcription factor gene SOX2 (184429), which is
necessary for normal esophageal squamous development (Que et al., 2007)
and differentiation and proliferation of basal tracheal cells (Que et
al., 2009), and cooperates in induction of pluripotent stem cells, as
summarized by Bass et al. (2009). Bass et al. (2009) found that SOX2
expression is required for proliferation and anchorage-independent
growth of lung and esophageal cell lines, as shown by RNA interference
experiments. Furthermore, ectopic expression of SOX2 in this study
cooperated with FOXE1 (602617) or FGFR2 (176943) to transform
immortalized tracheobronchial epithelial cells. SOX2-driven tumors
showed expression of markers of both squamous differentiation and
pluripotency. Bass et al. (2009) concluded that these characteristics
identified SOX2 as a lineage-survival oncogene in lung and esophageal
squamous cell carcinoma.

- DOK2 Deletion in Lung Cancer

Berger et al. (2010) showed that, of 199 primary human lung
adenocarcinoma samples, 37% showed a deletion of 1 copy of the DOK2 gene
(604997) , which maps to chromosome 8p21.3, one of the regions most
frequently deleted in human lung cancer. The deletion correlated with
loss of DOK2 protein expression. Loss of the DOK1 gene (602919), which
maps to chromosome 2p13.1, occurred in 1.5% of samples, and loss of the
DOK3 gene (6111435), which maps to chromosome 5q35.3, occurred in 7.0%
of samples. Further studies in mice showed that haploinsufficiency of
Dok2 was sufficient for tumor formation, as the wildtype allele was
retained in most tumor samples. Berger et al. (2010) suggested a
tumor-suppressor role for DOK2 in human lung cancer.

- C10ORF97 Polymorphism and Susceptibility to Nonsmall Cell
Lung Cancer

Shi et al. (2011) identified a 216C-T SNP (dbSNP rs2297882) in the
promoter region of the C10ORF97 gene (611649) that affected the
efficiency of translation. The T allele was associated with lower
protein levels than the C allele. Genotyping of 418 Chinese patients
with nonsmall cell lung cancer and 743 controls showed an association
between the TT genotype and lung cancer compared to the TC or CC
genotype (odds ratio of 1.73, p = 4.6 x 10(-5)). The findings suggested
that C10ORF97 may act as a tumor suppressor gene, and that low levels of
it may be associated with tumorigenesis.

CYTOGENETICS

- ALK/EML4 Fusion Gene

Soda et al. (2007) identified a fusion gene, ALK/EML4 (see 105590), that
was present in 5 of 75 Japanese nonsmall cell lung cancer patients
examined. None of these patients had mutations in EGFR.

- Copy Number Variation at the MAPKAPK2 Locus

Liu et al. (2012) investigated the role in lung cancer of a copy number
variant (CNV), g.CNV-30450, which spans the MAPKAPK2 (602006) promotor
region and has 1.7-kb sequences from -1098 to approximately +664
nucleotides to the initiation transcription codon. This variant was
found to have an allele frequency of 6/30 (0.20) in the Database of
Genetic Variants. The authors detected 2, 3, or 4 copies of g.CNV-30450
among 4,789 Chinese individuals. Liu et al. (2012) investigated the
association between cancer risk and g.CNV-30450 in 3 independent
case-control studies of 2,332 individuals with lung cancer and 2,457
controls, and also studied the effects of this CNV on cancer prognosis
in 1,137 individuals with lung cancer with survival data in Southern and
Eastern Chinese populations. Liu et al. (2012) found that those subjects
who had 4 copies of g.CNV-30450 had an increased cancer risk (OR = 1.94,
95% CI = 1.61-2.35) and, in individuals with lung cancer, a worse
prognosis (with a median survival time of only 9 months) (hazard ratio =
1.47, 95% CI = 1.22-1.78) compared with those with 2 or 3 copies (with a
median survival time of 14 months). Liu et al. (2012) also showed that 4
copies of g.CNV-30450 significantly increased MAPKAPK2 expression, both
in vitro and in vivo, compared with 2 or 3 copies.

*FIELD* SA
Brisman et al. (1967); Goffman et al. (1982)
*FIELD* RF
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52. Zhang, Z.; Lee, J. C.; Lin, L.; Olivas, V.; Au, V.; LaFramboise,
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resistance to EGFR-targeted therapy in lung cancer. Nature Genet. 44:
852-860, 2012.

*FIELD* CS

Lung:
Alveolar cell carcinoma;
Non-small-cell cancer

Inheritance:
Autosomal recessive

*FIELD* CN
Ada Hamosh - updated: 10/15/2013
Ada Hamosh - updated: 2/26/2013
Ada Hamosh - updated: 10/9/2012
Cassandra L. Kniffin - updated: 6/19/2012
Ada Hamosh - updated: 7/8/2011
Ada Hamosh - updated: 5/9/2011
Ada Hamosh - updated: 9/21/2010
Cassandra L. Kniffin - updated: 5/14/2010
Ada Hamosh - updated: 2/16/2010
Cassandra L. Kniffin - updated: 9/3/2009
Marla J. F. O'Neill - updated: 2/19/2009
Ada Hamosh - updated: 11/26/2008
Matthew B. Gross - reorganized: 10/2/2008
Matthew B. Gross - updated: 10/2/2008
Cassandra L. Kniffin - updated: 8/20/2008
Ada Hamosh - updated: 7/29/2008
Ada Hamosh - updated: 5/21/2008
Ada Hamosh - updated: 4/16/2008
Marla J. F. O'Neill - updated: 3/24/2008
Cassandra L. Kniffin - updated: 3/20/2008
Ada Hamosh - updated: 8/13/2007
Ada Hamosh - updated: 6/14/2007
Victor A. McKusick - updated: 2/9/2006
Marla J. F. O'Neill - updated: 7/21/2005
Marla J. F. O'Neill - updated: 6/21/2005
George E. Tiller - updated: 2/28/2005
Victor A. McKusick - updated: 2/7/2005
Victor A. McKusick - updated: 9/8/2004
Victor A. McKusick - updated: 7/15/2004
Victor A. McKusick - updated: 8/13/2003
Victor A. McKusick - updated: 3/3/2003
Victor A. McKusick - updated: 12/10/2002
Wilson H. Y. Lo - updated: 4/7/2000

*FIELD* CD
Victor A. McKusick: 6/3/1986

*FIELD* ED
alopez: 10/15/2013
tpirozzi: 9/30/2013
alopez: 3/4/2013
terry: 2/26/2013
alopez: 10/24/2012
terry: 10/9/2012
alopez: 8/8/2012
carol: 6/21/2012
ckniffin: 6/19/2012
alopez: 9/2/2011
alopez: 7/8/2011
terry: 7/8/2011
carol: 6/17/2011
alopez: 5/11/2011
terry: 5/9/2011
alopez: 9/23/2010
terry: 9/21/2010
wwang: 5/21/2010
ckniffin: 5/14/2010
terry: 4/2/2010
alopez: 3/2/2010
terry: 2/16/2010
ckniffin: 1/15/2010
carol: 11/23/2009
wwang: 9/22/2009
ckniffin: 9/3/2009
wwang: 6/12/2009
terry: 6/3/2009
terry: 2/19/2009
wwang: 2/12/2009
ckniffin: 2/9/2009
alopez: 12/5/2008
terry: 11/26/2008
mgross: 10/3/2008
mgross: 10/2/2008
wwang: 8/26/2008
ckniffin: 8/20/2008
alopez: 8/19/2008
terry: 7/29/2008
alopez: 5/21/2008
alopez: 5/16/2008
terry: 4/16/2008
wwang: 3/25/2008
terry: 3/24/2008
wwang: 3/20/2008
alopez: 1/24/2008
ckniffin: 1/16/2008
carol: 8/14/2007
terry: 8/13/2007
alopez: 7/31/2007
alopez: 6/28/2007
terry: 6/14/2007
alopez: 6/6/2007
alopez: 10/25/2006
alopez: 2/14/2006
terry: 2/9/2006
wwang: 7/25/2005
terry: 7/21/2005
wwang: 6/29/2005
terry: 6/21/2005
wwang: 2/28/2005
carol: 2/28/2005
wwang: 2/7/2005
alopez: 9/21/2004
terry: 9/8/2004
tkritzer: 7/15/2004
tkritzer: 8/19/2003
terry: 8/13/2003
carol: 3/11/2003
tkritzer: 3/10/2003
terry: 3/3/2003
alopez: 1/2/2003
alopez: 12/11/2002
terry: 12/10/2002
terry: 3/5/2002
carol: 1/3/2002
carol: 9/18/2001
carol: 7/6/2000
terry: 4/7/2000
mgross: 2/2/2000
mark: 12/9/1996
mark: 4/30/1996
carol: 12/30/1994
terry: 12/22/1994
mimadm: 2/19/1994
supermim: 3/16/1992
carol: 2/11/1992
supermim: 3/20/1990

MIM 601763
*RECORD*
*FIELD* NO
601763
*FIELD* TI
*601763 CASPASE 8, APOPTOSIS-RELATED CYSTEINE PROTEASE; CASP8
;;MORT1-ASSOCIATED CED3 HOMOLOG; MACH;;
read moreFADD-HOMOLOGOUS ICE/CED3-LIKE PROTEASE;;
FADD-LIKE ICE; FLICE;;
MCH5
*FIELD* TX

DESCRIPTION

A cascade of protease reactions is believed to be responsible for the
apoptotic changes observed in mammalian cells undergoing programmed cell
death. This cascade involves members of the aspartate-specific cysteine
proteases of the ICE/CED3 (147678) family, also known as the caspase
family.

CLONING

Fernandes-Alnemri et al. (1996) identified the novel gene MCH5 when they
found a human EST sequence with significant homology to the newly
identified cysteine protease MCH4 (601762). They used PCR to clone a
cDNA of the MCH5 gene from a Jurkat T-cell cDNA library. Sequence
analysis revealed that it encodes a polypeptide of 496 amino acids with
greatest homology to MCH4. The authors found that MCH4 and MCH5 both
contain the active site pentapeptide QACQG instead of the QACRG present
in all other known members of the family. Furthermore, the authors found
that the sequences of MCH4 and MCH5 contain Fas-associating protein with
death domain (FADD)-like domains, suggesting possible interaction with
FADD. Fernandes-Alnemri et al. (1996) stated that MCH5, like other
members of the ICE/CED3 family, forms an active protease only after
cleavage of its proenzyme into 2 subunits which dimerize to form the
active enzyme.

Using MORT1 (FADD; 602457) in a yeast 2-hybrid screen of a B-cell cDNA
library, Boldin et al. (1996) cloned several splice variants of CASP8,
which they called MACH. The isoforms could be divided into 2 main
subgroups. All isoforms share a common 182-amino acid N-terminal region,
including 2 MORT modules (i.e., death effector domains, or DEDs), but
they have different C termini. Subgroup alpha isoforms have C termini
containing a CED3/ICE homology domain that contains the catalytic site
and the substrate-binding pocket, while subgroup beta isoforms are
truncated and lack the CED3/ICE homology domain. The longest isoform,
MACH-alpha-1, encodes a deduced 479-amino acid protein. The CED3/ICE
domain of MACH-alpha-1 shares 41% and 34% identity with the homologous
regions in CPP32 (CASP3; 600636) and C. elegans CED3, respectively.
Northern blot analysis detected MACH transcripts ranging in size between
2.85 and 3.5 kb in all tissues examined, with highest levels in resting
peripheral blood mononuclear leukocytes and lowest levels in testis and
skeletal muscle.

Eckhart et al. (2001) identified several CASP8 splice variants that
preferentially use a distant splice donor site at the 3-prime end of
exon 8. Use of this distant site, which they called exon 8b, results in
mRNAs with truncated open reading frames. RT-PCR indicated equal
expression of both mRNA species in tonsil, spleen, bone marrow, thymus,
and lymph nodes. Peripheral blood leukocytes, heart, and epidermis
predominantly expressed mRNA containing exon 8b, as did a promyelocytic
cell line and a T-cell line. Liver and nearly all immortalized cell
lines, as well as primary endothelial cells, fibroblasts, and
keratinocytes, expressed mRNA lacking the 8b extension.

GENE FUNCTION

Using fluorogenic peptide substrates corresponding to a sequence within
the nuclear protein PARP (173870), Boldin et al. (1996) confirmed that
MACH-alpha-1 is a thiol protease. By site-directed mutagenesis, they
identified cys360 as the catalytic cysteine. Using mutation analysis,
Boldin et al. (1996) determined that MACH binds to the N terminus of
MORT1. They also found that it self-associates, but it does not interact
directly with FAS/APO1 (TNRFSF6; 134637). Transfection of human
embryonic kidney cells and breast carcinoma cells with MACH-alpha-1 or
MACH-alpha-2 resulted in massive cell death.

Muzio et al. (1996) determined that CASP8, which they called FLICE,
interacts with wildtype FADD but not with FADD lacking the DED. They
also determined that granzyme B (GZMB; 123910) can remove the prodomain
and generate the active p20/p10 dimeric cysteine protease. Cleavage of
PARP by CASP8 resulted in the appearance of signature apoptotic
fragments. Transfection and overexpression of CASP8 in transfected
breast cancer cells resulted in apoptosis.

Expression of cDNAs that encode truncated polypeptides containing mostly
expanded polyglutamine repeats, but not of those that encode the
corresponding full-length proteins, has been shown to induce cell death
by apoptosis. Such truncated proteins have been shown to form aggregates
or inclusions (Ikeda et al., 1996). Sanchez et al. (1999) studied the
role of caspases in polyglutamine-induced cell death in established
cultures of primary cortical, striatal, and cerebellar neurons from
embryonic day 17 rat embryos, transfected with an expression construct
encoding truncated ataxin-3 that contained 79 glutamine (Q79) residues.
The authors showed that the apoptosis inhibitors Bcl2, CrmA, and a
truncated Fas/APO1-associated death domain protein (FADD DN) inhibited
polyglutamine repeat-induced neuronal cell death. A mutant Jurkat cell
line specifically lacking caspase-8 was resistant to
polyglutamine-induced cell death. Cells transfected with Q79 showed
insoluble inclusions. Caspase-8 was recruited and activated by these Q79
inclusions. Western blot analysis revealed the presence of activated
caspase-8 in the insoluble fraction of affected brain regions from
Huntington disease (143100) patients but not in those from controls. The
authors suggested that caspase-8 has an essential role in
Huntington-related neurodegenerative diseases.

Eckhart et al. (2001) found that different CASP8 isoforms were expressed
in resting and activated lymphocytes. Activation of lymphocytes shifted
the expression from mRNA species containing an exon 8b extension to
mRNAs that lack it. Differentiation in a promyelocytic cell line was
associated with the opposite shift, from mRNAs containing the shorter
exon 8 to mRNAs that include the exon 8b extension.

Gervais et al. (2002) found that HIP1 (601767) binds to the HIP1 protein
interactor (HIPPI; 606621), which has partial sequence homology to HIP1
and similar tissue and subcellular distribution. The availability of
free HIP1 is modulated by polyglutamine length within huntingtin
(613004), with disease-associated polyglutamine expansion favoring the
formation of proapoptotic HIPPI-HIP1 heterodimers. This heterodimer can
recruit procaspase-8 into a complex of HIPPI, HIP1, and procaspase-8,
and launch apoptosis through components of the extrinsic cell death
pathway. Gervais et al. (2002) proposed that huntingtin polyglutamine
expansion liberates HIP1 so that it can form a caspase-8 recruitment
complex with HIPPI, possibly contributing to neuronal death in
Huntington disease.

Yu et al. (2004) defined a novel molecular pathway in which activation
of the receptor-interacting protein (RIP; 603453), a serine-threonine
kinase, and Jun amino-terminal kinase (601158) induced cell death with
the morphology of autophagy. Autophagic death required the genes ATG7
(GSA7; 608760) and beclin-1 (604378) and was induced by caspase-8
inhibition. Yu et al. (2004) cautioned that clinical therapies involving
caspase inhibitors may arrest apoptosis but also have the unanticipated
effect of promoting autophagic cell death.

Poulaki et al. (2005) found that human retinoblastoma (RB1; 614041) cell
lines were resistant to death receptor (see DR5; 603612)-mediated
apoptosis because of a deficiency of CASP8 expression secondary to
epigenetic gene silencing by overmethylation. Treatment with a
demethylating agent restored CASP8 expression and sensitivity to
apoptosis.

Su et al. (2005) showed that caspase-8 deficiency (607271) in humans and
mice specifically abolishes activation of the transcription factor NF
kappa-B (164011) after stimulation through antigen receptors, Fc
receptors, or Toll-like receptor-4 (TLR4; 603030) in T, B, and natural
killer cells. Caspase-8 also causes the alpha-beta complex of the
inhibitor of NF-kappa-B kinase (IKK; 600644 and 300248, respectively) to
associate with the upstream BCL10 (603517)-MALT1 (604860) adaptor
complex. Recruitment of the IKK-alpha,beta complex, its activation, and
the nuclear translocation of NF-kappa-B require enzyme activity of
full-length caspase-8. Su et al. (2005) concluded that their findings
explained the paradoxical association of defective apoptosis and
combined immunodeficiency in human caspase-8 deficiency.

Stupack et al. (2006) showed that suppression of caspase-8 expression
occurs during the establishment of neuroblastoma (256700) metastases in
vivo, and that reconstitution of caspase-8 expression in deficient
neuroblastoma cells suppressed their metastases. Caspase-8 status was
not a predictor of primary tumor growth; rather, caspase-8 selectively
potentiated apoptosis in neuroblastoma cells invading the collagenous
stroma at the tumor margin. Apoptosis was initiated by unligated
integrins (see 605025) by means of a process known as integrin-mediated
death. Loss of caspase-8 or integrin rendered the cells refractory to
integrin-mediated death, allowed cellular survival in the stromal
microenvironment, and promoted metastases. Stupack et al. (2006)
concluded that these findings define caspase-8 as a metastasis
suppressor gene that, together with integrins, regulates the survival
and invasive capacity of neuroblastoma cells.

Oberst et al. (2011) showed that development of caspase-8-deficient mice
is completely rescued by ablation of receptor-interacting protein
kinase-3 (RIPK3; 605817). Adult animals lacking both caspase-8 and Ripk3
displayed a progressive lymphoaccumulative disease resembling that seen
with defects in Cd95 (FAS; 134637) or Cd95 ligand (FASL; 134638), and
resisted the lethal effects of Cd95 ligation in vivo. Oberst et al.
(2011) found that caspase-8 prevents RIPK3-dependent necrosis without
inducing apoptosis by functioning in a proteolytically active complex
with CFLAR (603599) and that this complex is required for the protective
function.

Kaiser et al. (2011) found that Ripk3 is responsible for the
midgestational death of Casp8-deficient embryos. Remarkably,
Casp8-null/Rip3-null-double mutant mice were viable and matured into
fertile adults with a full immune complement of myeloid and lymphoid
cell types. These mice seemed immunocompetent but developed
lymphadenopathy by 4 months of age marked by accumulation of abnormal T
cells in the periphery, a phenotype reminiscent of mice with Fas
deficiency. Thus, Kaiser et al. (2011) concluded that Casp8 contributes
to homeostatic control in the adult immune system; however, RIPK3 and
CASP8 are together completely dispensable for mammalian development.

Burguillos et al. (2011) showed that the orderly activation of caspase-8
and caspase-3/7 (600636/601761), known executioners of apoptotic cell
death, regulate microglia activation through a protein kinase C-delta
(PPKCD; 176977)-dependent pathway. Burguillos et al. (2011) found that
stimulation of microglia with various inflammogens activates caspase-8
and caspase-3/7 in microglia without triggering cell death in vitro and
in vivo. Knockdown or chemical inhibition of each of these caspases
hindered microglia activation and consequently reduced neurotoxicity.
The authors observed that these caspases are activated in microglia in
the ventral mesencephalon of Parkinson disease (168600) and the frontal
cortex of individuals with Alzheimer disease (104300). Burguillos et al.
(2011) concluded that caspase-8 and caspase-3/7 are involved in
regulating microglia activation, and suggested that inhibition of these
caspases could be neuroprotective by targeting the microglia rather than
the neurons themselves.

Gunther et al. (2011) demonstrated a critical role for caspase-8 in
regulating necroptosis of intestinal epithelial cells (IECs) and
terminal ileitis. Mice with a conditional deletion of caspase-8 in the
intestinal epithelium (Casp8-delta-IEC) spontaneously developed
inflammatory lesions in the terminal ileum were highly susceptible to
colitis. These mice lacked Paneth cells and showed reduced numbers of
goblet cells, indicating dysregulated antimicrobial immune cell
functions of the intestinal epithelium. Casp8-delta-IEC mice showed
increased cell death in the Paneth cell area of small intestinal crypts.
Epithelial cell death was induced by tumor necrosis factor-alpha (TNFA;
191160), was associated with increased expression of
receptor-interacting protein-3 (RIP3; 605817) and could be inhibited on
blockade of necroptosis. Lastly, Gunther et al. (2011) identified high
levels of RIP3 in human Paneth cells and increased necroptosis in the
terminal ileum of patients with Crohn disease, suggesting a potential
role of necroptosis in the pathogenesis of this disease. Gunther et al.
(2011) concluded that their data demonstrated a critical function of
caspase-8 in regulating intestinal homeostasis and in protecting IECs
from TNFA-induced necroptotic cell death.

GENE STRUCTURE

By genomic sequence analysis, Varfolomeev et al. (1998) determined that
the CASP8 gene contains 8 exons. Hadano et al. (2001) determined that
the CASP8 gene contains 13 exons and spans 51.2 kb.

MAPPING

By fluorescence in situ hybridization (FISH), Kischkel et al. (1998)
mapped the CASP8 gene to human chromosome 2q33-q34 and mouse chromosome
1B-proximal C. This mapping further extended the known homology of
synteny between these regions of human chromosome 2 and mouse chromosome
1. By FISH, Grenet et al. (1999) also mapped the CASP8 gene to 2q33-q34.
They noted that CASP10 (601762), whose product is closely related to
that of CASP8, has been mapped to the same location, indicating that the
2 genes have evolved by tandem duplication.

MOLECULAR GENETICS

Liu et al. (2002) identified a naturally occurring deletion of leu62
within the first DED of CASP8 in A431 human vulva squamous carcinoma
cells. This deletion resulted in defective CASP8-dependent apoptosis.
Unlike wildtype CASP8, CASP8 lacking leu62 failed to form oligomers with
wildtype CASP8 and failed to interact with FADD. The mutation did not
effect proteolytic activation by granzyme B, nor did it effect catalytic
activity against PARP.

In 2 affected sibs from a consanguineous family with caspase-8
deficiency (607271), Chun et al. (2002) identified a homozygous mutation
in the CASP8 gene (601763.0001). The patients had defects in the
activation of T and B lymphocytes and natural killer cells, which led to
immunodeficiency.

Soung et al. (2005) analyzed the entire coding region of the CASP8 gene
in 69 hepatocellular carcinomas (HCC; 114550), 2 with low-grade
dysplastic nodule (LGDN), 2 with high-grade dysplastic nodule (HGDN),
and 65 without dysplastic nodules, and detected a total of 9 somatic
mutations (13%). All 9 mutations were an identical 2-bp deletion
(nucleotides 1225-1226; 601763.0002), which was predicted to result in
frameshift and premature termination of amino acid synthesis in the p10
protease subunit. The change was detected both in HCC and in LGDN
lesions, suggesting that CASP8 mutation may be involved in the early
stage of HCC carcinogenesis. Soung et al. (2005) found that expression
of the tumor-derived caspase-8 mutant in cells abolished cell death
activity of caspase-8.

Cox et al. (2007) reported the findings of the Breast Cancer Association
Consortium (BCAC), which had been established to conduct combined
case-control analyses with augmented statistical power to try to confirm
putative genetic associations with breast cancer. They genotyped 9 SNPs
for which there was some prior evidence of an association with breast
cancer (114480). They included data from 9 to 15 studies, comprising
11,391 to 18,290 cases and 14,753 to 22,670 controls. They found
evidence of a protective association with breast cancer for a D302H
polymorphism in CASP8 (601763.0003), and weaker evidence for an L10P SNP
in the TGFB1 gene (190180.0007). These results demonstrated that common
breast cancer susceptibility alleles with small effects on risk can be
identified, given sufficiently powerful studies.

Caspases are important in the life and death of immune cells and
therefore influence immune surveillance of malignancies. Sun et al.
(2007) tested whether genetic variants in CASP8, CASP10, (601762), and
CFLAR (603599), 3 genes important for death receptor-induced cell
killing residing in tandem order on chromosome 2q33, are associated with
cancer susceptibility. Using a haplotype-tagging SNP approach, they
identified a 6-nucleotide deletion (-652 6N del) variant in the CASP8
promoter (601763.0004) associated with decreased risk of lung cancer.
The deletion destroyed a binding site for stimulatory protein-1 (SP1;
189906) and decreased transcription. Biochemical analyses showed that T
lymphocytes with the deletion variant had lower caspase-8 activity and
activation-induced cell death upon stimulation with cancer cell
antigens. Case-control analyses of 4,995 individuals with cancer and
4,972 controls in a Chinese population showed that this genetic variant
is associated with reduced susceptibility to multiple cancers, including
lung, esophageal, gastric, colorectal, cervical, and breast cancers,
acting in an allele dose-dependent manner. The results supported the
hypothesis that genetic variants influencing immune status modify cancer
susceptibility. Haiman et al. (2008) did not find an association between
this SNP and breast (114480), colorectal (114500), or prostate (176807)
cancer among 2,098, 1,139, and 2,825 patients, respectively. The study
included patients in Hawaii and California of various ethnic groups.

ANIMAL MODEL

Varfolomeev et al. (1998) generated mice deficient in Casp8 by
disrupting exons 1 and 2, which encode the N-terminal death effector
domains (DEDs) that interact with MORT1/FADD. Whereas wildtype and
heterozygous mice appeared normal, no homozygous mutant mice survived
beyond approximately embryonic day 13.5. Histopathologic analysis
revealed marked abdominal hyperemia with erythrocytosis in the liver,
major blood vessels, capillaries, and other organs. Cardiac ventricular
musculature was thin and similar to early mesenchyme. Colony forming
assays showed that hemopoietic precursor cells were markedly reduced in
the mutant mice. Immunoprecipitation and Western blot analysis indicated
that fibroblasts from mutant mice responded normally to the noncytocidal
effects of tumor necrosis factor receptor (TNFR; 191190) and death
receptor-3 (DR3, or TNFRSF12; 603366) stimulation, whereas wildtype
fibroblasts were killed by TNF (191160) treatment or FAS cross-linking.
Agents such as ultraviolet irradiation and protein kinase inhibitors
were lethal for mutant and normal fibroblasts. Varfolomeev et al. (1998)
concluded that CASP8 is necessary for death induction by receptors of
the TNF/nerve growth factor (see NGFR; 162010) family and is vital in
embryonal development.

Zender et al. (2003) evaluated the efficacy of small interfering RNA
(siRNA) in vivo in different mouse models with acute liver failure. They
directed 21-nucleotide siRNAs against caspase-8, which is a key enzyme
in death receptor-mediated apoptosis. Systemic administration of
caspase-8 siRNA resulted in inhibition of caspase-8 gene expression in
the liver, therefore preventing CD95-mediated apoptosis. Protection of
hepatocytes by caspase-8 siRNA significantly attenuated acute liver
damage induced by CD95 antibody or by adenovirus expressing FAS ligand.
In a clinical situation, siRNAs would most likely be administered after
the onset of acute liver failure. Therefore, Zender et al. (2003)
injected caspase-8 siRNA at a time during experimentally-induced liver
failure with already elevated liver transaminases. Improvement of
survival due to RNA interference was significant even when caspase-8
siRNA was applied during ongoing acute liver failure.

Salmena and Hakem (2005) used the Cre/lox recombinase system to generate
mice lacking Casp8 only in T cells (Tcasp8 -/- mice). Tcasp8 -/- mice
developed an age-dependent lethal lymphoproliferative and
lymphoinfiltrative immune disorder characterized by lymphoadenopathy,
splenomegaly, and T-cell infiltrates in lung, liver, and kidney.
Although there was lymphopenia in young Tcasp8 -/- mice, peripheral T
cells in old Tcasp8 -/- mice proliferated in the absence of infection or
stimulation. Salmena and Hakem (2005) proposed that Tcasp8 -/- mice may
serve as a model of human CASP8 deficiency and that CASP8 in T cells is
required for lymphocyte homeostasis.

To define the contribution of reduced caspase-8 to a wound healing
response, Lee et al. (2009) generated an epidermal knockout of
caspase-8. By postnatal day 10 the conditional knockout mouse had flaky
skin throughout its body, was slightly runted, and its epidermis was
dramatically thickened. Lee et al. (2009) found that even though
caspase-8 is normally expressed in the granular layer, it was the basal
and spinous layers that were markedly expanded in the knockout
epidermis. Lee et al. (2009) demonstrated that the loss of epidermal
caspase-8, an important mediator of apoptosis, recapitulated several
phases of a wound healing response in the mouse. The epidermal
hyperplasia in the caspase-8 null skin is the culmination of signals
exchanged between epidermal keratinocytes, dermal fibroblasts, and
leukocytic cells. This reciprocal interaction is initiated by the
paracrine signaling of interleukin 1-alpha (IL1-alpha; 147760), which
activates both skin stem cell proliferation and cutaneous inflammation.
The noncanonical secretion of IL1-alpha is induced by a p38-MAPK
(600289)-mediated upregulation of NALP3 (606416), leading to
inflammasome assembly and caspase-1 activation. Notably, the increased
proliferation of basal keratinocytes is counterbalanced by the growth
arrest of suprabasal keratinocytes in the stratified epidermis by
IL1-alpha-dependent NF-kappa-B (see 164011) signaling. Lee et al. (2009)
concluded that their findings illustrated how the loss of caspase-8 can
affect more than programmed cell death to alter the local
microenvironment and elicit processes common to wound repair and many
neoplastic skin disorders.

*FIELD* AV
.0001
CASPASE 8 DEFICIENCY
CASP8, ARG248TRP

In 2 affected sibs from a consanguineous family with caspase-8
deficiency (607271), Chun et al. (2002) identified a homozygous C-to-T
transition in the CASP8 gene, resulting in an arg248-to-trp (R248W)
substitution within the p18 protease subunit of the protein. The
asymptomatic mother, father, and sister were heterozygous carriers of
the mutation. In 13 extended family members, Chun et al. (2002)
identified 7 asymptomatic heterozygous carriers but found no additional
homozygous or immunodeficient individuals.

.0002
HEPATOCELLULAR CARCINOMA, SOMATIC
CASP8, 2-BP DEL, 1225TG

In 9 unrelated patients with hepatocellular carcinoma (114550) and HBV
infection, Soung et al. (2005) identified the same somatic mutation, a
2-bp deletion (1225_1226delTG) in exon 7 that was predicted to result in
frameshift and premature termination of amino acid synthesis in the p10
protease subunit.

.0003
BREAST CANCER, PROTECTION AGAINST
CASP8, ASP302HIS

MacPherson et al. (2004) and Frank et al. (2005) found evidence that the
presence of a single-nucleotide polymorphism (SNP) in the CASP8 gene
resulting in an asp302-to-his (D302H) substitution (dbSNP rs1045485)
could reduce susceptibility to breast cancer (114480) in British and
German cohorts, respectively. Cox et al. (2007) found evidence for a
protective effect of the D302H polymorphism in an allele dose-dependent
manner in 16,423 cases and 17,109 controls from 14 studies that
contributed data to the Breast Cancer Association Consortium (BCAC). The
study achieved odds ratios of 0.89 and 0.74 for heterozygotes and rare
homozygotes, respectively, compared with common homozygotes. This site
was not found to be polymorphic in Korean, Han Chinese, or Japanese
women. Cox et al. (2007) noted that the functional consequences of the
aspartic acid-to-histidine substitution were not known, and further
experiments were required to establish whether D302H itself or another
variant in strong linkage disequilibrium with it is causative.

.0004
LUNG CANCER, PROTECTION AGAINST
CASP8, 6-BP DEL, NT-652

Sun et al. (2007) identified a 6-nucleotide insertion/deletion
polymorphism in the CASP8 promoter, -652 AGTAAG ins/del (dbSNP
rs3834129), the deletion variant of which was associated with decreased
risk of developing lung cancer (211980) in a population of Han Chinese
subjects. The -652 6N deletion was also associated with decreased risk
of cancer of various other forms including esophageal, gastric,
colorectal, cervical, and breast, acting in an allele dose-dependent
manner. The frequency of the -652 6N deletion was significantly lower in
individuals with lung cancer (P = 4.1 x 10(-5)).

Haiman et al. (2008) did not find an association between this SNP and
breast (114480), colorectal (114500), or prostate (176807) cancer among
2,098, 1,139, and 2,825 patients, respectively. The study included
patients in Hawaii and California of various ethnic groups.

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gene silencing. Invest. Ophthal. Vis. Sci. 46: 358-366, 2005.

22. Salmena, L.; Hakem, R.: Caspase-8 deficiency in T cells leads
to a lethal lymphoinfiltrative immune disorder. J. Exp. Med. 202:
727-732, 2005.

23. Sanchez, I.; Xu, C.-J.; Juo, P.; Kakizaka, A.; Blenis, J.; Yuan,
J.: Caspase-8 is required for cell death induced by expanded polyglutamine
repeats. Neuron 22: 623-633, 1999.

24. Soung, Y. H.; Lee, J. W.; Kim, S. Y.; Sung, Y. J.; Park, W. S.;
Nam, S. W.; Kim, S. H.; Lee, J. Y.; Yoo, N. J.; Lee, S. H.: Caspase-8
gene is frequently inactivated by the frameshift somatic mutation
1225_1226delTG in hepatocellular carcinomas. Oncogene 24: 141-147,
2005.

25. Stupack, D. G.; Teitz, T.; Potter, M. D.; Mikolon, D.; Houghton,
P. J.; Kidd, V. J.; Lahti, J. M.; Cheresh, D. A.: Potentiation of
neuroblastoma metastasis by loss of caspase-8. Nature 439: 95-99,
2006.

26. Su, H.; Bidere, N.; Zheng, L.; Cubre, A.; Sakai, K.; Dale, J.;
Salmena, L.; Hakem, R.; Straus, S.; Lenardo, M.: Requirement for
caspase-8 in NF-kappa-B activation by antigen receptor. Science 307:
1465-1468, 2005.

27. Sun, T.; Gao, Y.; Tan, W.; Ma, S.; Shi, Y.; Yao, J.; Guo, Y.;
Yang, M.; Zhang, X.; Zhang, Q.; Zeng, C.; Lin, D.: A six-nucleotide
insertion-deletion polymorphism in the CASP8 promoter is associated
with susceptibility to multiple cancers. Nature Genet. 39: 605-613,
2007.

28. Varfolomeev, E. E.; Schuchmann, M.; Luria, V.; Chiannilkulchai,
N.; Beckmann, J. S.; Mett, I. L.; Rebrikov, D.; Brodianski, V. M.;
Kemper, O. C.; Kollet, O.; Lapidot, T.; Soffer, D.; Sobe, T.; Avraham,
K. B.; Goncharov, T.; Holtmann, H.; Lonai, P.; Wallach, D.: Targeted
disruption of the mouse Caspase 8 gene ablates cell death induction
by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:
267-276, 1998.

29. Yu, L.; Alva, A.; Su, H.; Dutt, P.; Freundt, E.; Welsh, S.; Baehrecke,
E. H.; Lenardo, M. J.: Regulation of an ATG7-beclin 1 program of
autophagic cell death by caspase-8. Science 304: 1500-1502, 2004.

30. Zender, L.; Hutker, S.; Liedtke, C.; Tillmann, H. L.; Zender,
S.; Mundt, B.; Waltemathe, M.; Gosling, T.; Flemming, P.; Malek, N.
P.; Trautwein, C.; Manns, M. P.; Kuhnel, F.; Kubicka, S.: Caspase
8 small interfering RNA prevents acute liver failure in mice. Proc.
Nat. Acad. Sci. 100: 7797-7802, 2003.

*FIELD* CN
Ada Hamosh - updated: 11/22/2011
Ada Hamosh - updated: 7/8/2011
Ada Hamosh - updated: 6/7/2011
Ada Hamosh - updated: 4/28/2009
Cassandra L. Kniffin - updated: 5/19/2008
Victor A. McKusick - updated: 5/24/2007
Victor A. McKusick - updated: 4/4/2007
Ada Hamosh - updated: 5/1/2006
Paul J. Converse - updated: 4/3/2006
Ada Hamosh - updated: 4/8/2005
Jane Kelly - updated: 3/25/2005
Victor A. McKusick - updated: 3/15/2005
Victor A. McKusick - updated: 10/22/2004
Ada Hamosh - updated: 6/22/2004
Victor A. McKusick - updated: 7/16/2003
Patricia A. Hartz - updated: 11/11/2002
Ada Hamosh - updated: 10/1/2002
Paul J. Converse - updated: 4/25/2002
Ada Hamosh - updated: 1/16/2002
Wilson H. Y. Lo - updated: 4/5/2000
Carol A. Bocchini - updated: 3/24/1999
Carol A. Bocchini - updated: 11/17/1998

*FIELD* CD
Jennifer P. Macke: 4/18/1997

*FIELD* ED
carol: 02/06/2012
carol: 2/6/2012
alopez: 11/30/2011
terry: 11/22/2011
alopez: 7/12/2011
terry: 7/8/2011
alopez: 6/17/2011
alopez: 6/14/2011
terry: 6/7/2011
carol: 9/15/2009
alopez: 5/4/2009
terry: 4/28/2009
wwang: 5/19/2008
ckniffin: 5/19/2008
alopez: 6/6/2007
terry: 5/24/2007
alopez: 4/10/2007
terry: 4/4/2007
alopez: 5/3/2006
terry: 5/1/2006
mgross: 4/3/2006
carol: 1/20/2006
tkritzer: 4/8/2005
carol: 4/1/2005
wwang: 3/25/2005
wwang: 3/22/2005
wwang: 3/21/2005
wwang: 3/18/2005
terry: 3/15/2005
carol: 11/18/2004
ckniffin: 11/3/2004
tkritzer: 11/2/2004
terry: 10/22/2004
alopez: 6/22/2004
terry: 6/22/2004
cwells: 7/22/2003
terry: 7/16/2003
mgross: 11/11/2002
alopez: 10/2/2002
cwells: 10/1/2002
mgross: 4/25/2002
alopez: 2/5/2002
alopez: 1/17/2002
terry: 1/16/2002
carol: 6/15/2000
terry: 4/5/2000
terry: 3/25/1999
carol: 3/24/1999
alopez: 12/21/1998
terry: 11/17/1998
carol: 11/16/1998
alopez: 6/5/1997
alopez: 5/30/1997

MIM 607271
*RECORD*
*FIELD* NO
607271
*FIELD* TI
#607271 CASPASE 8 DEFICIENCY
;;CEDS;;
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IIB; ALPS2B
read more*FIELD* TX
A number sign (#) is used with this entry because caspase-8 deficiency
can be caused by homozygous mutation in the CASP8 gene (601763) on
chromosome 2q33.

DESCRIPTION

Caspase 8 deficiency is a syndrome of lymphadenopathy and splenomegaly,
marginal elevation of 'double-negative T cells' (DNT; T-cell receptor
alpha/beta+, CD4-/CD8-), defective FAS-induced apoptosis, and defective
T-, B-, and natural killer (NK)-cell activation, with recurrent
bacterial and viral infections (summary by Madkaikar et al., 2011).

CLINICAL FEATURES

Chun et al. (2002) reported 2 sibs, a 12-year-old female and an
11-year-old male, born of consanguineous parents, who presented with
lymphadenopathy and splenomegaly associated with an immunodeficiency
characterized by recurrent sinopulmonary and herpes simplex virus
infections. Both sibs showed poor responses to immunization. The
affected sibs had defects in activation of T lymphocytes, B lymphocytes,
and natural killer cells, and defective CD95-mediated apoptosis. The
unaffected mother, father, and sister were clinically well, although
their peripheral blood lymphocytes showed partial defects in
CD95-mediated apoptosis.

MOLECULAR GENETICS

In 2 affected sibs from a consanguineous family with caspase-8
deficiency, Chun et al. (2002) identified a homozygous mutation in the
CASP8 gene (601763.0001). The unaffected mother, father, and sister were
heterozygous for the mutation.

NOMENCLATURE

Puck and Straus (2004) referred to caspase 8 deficiency as autoimmune
lymphoproliferative syndrome type IIB; see 601859. In review articles,
Teachey et al. (2009) stated that caspase 8 deficiency is distinct from
ALPS and Madkaikar et al. (2011) stated that caspase 8 deficiency is an
'ALPS-related' disorder.

*FIELD* RF
1. Chun, H. J.; Zheng, L.; Ahmad, M.; Wang, J.; Speirs, C. K.; Siegel,
R. M.; Dale, J. K.; Puck, J.; Davis, J.; Hall, C. G.; Skoda-Smith,
S.; Atkinson, T. P.; Straus, S. E.; Lenardo, M. J.: Pleiotropic defects
in lymphocyte activation caused by caspase-8 mutations lead to human
immunodeficiency. Nature 419: 395-399, 2002.

2. Madkaikar, M.; Mhatre, S.; Gupta, M.; Ghosh, K.: Advances in autoimmune
lymphoproliferative syndromes. Europ. J. Haemat. 87: 1-9, 2011.

3. Puck, J. M.; Straus, S. E.: Somatic mutations--not just for cancer
anymore. New Eng. J. Med. 351: 1388-1390, 2004.

4. Teachey, D. T.; Seif, A. E.; Grupp, S. A.: Advances in the management
and understanding of autoimmune lymphoproliferative syndrome (ALPS). Brit.
J. Haemat. 148: 205-216, 2009.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Height];
Short stature;
[Other];
Failure to thrive

RESPIRATORY:
[Nasopharynx];
[Airways];
Reactive airway disease;
Asthma;
[Lung];
Pneumonia

ABDOMEN:
[Spleen];
Splenomegaly;
[Gastrointestinal];
Diarrhea, chronic

SKIN, NAILS, HAIR:
[Skin];
Eczema

IMMUNOLOGY:
Lymphadenopathy;
Recurrent sinopulmonary infections;
Herpes simplex virus infection, mucocutaneous;
Defective CD95-induced apoptosis of peripheral blood lymphocytes;
No response to pneumococcal vaccination;
Defective T cell activation;
Defective B cell activation;
Defective natural killer cell (NK) activation;
Decreased cellular caspase-8 levels

MOLECULAR BASIS:
Caused by mutation in the caspase 8 gene (CASP8, 601763.0001)

*FIELD* CD
Cassandra L. Kniffin: 11/3/2004

*FIELD* ED
joanna: 10/31/2006
ckniffin: 11/3/2004

*FIELD* CD
Ada Hamosh: 10/2/2002

*FIELD* ED
carol: 02/06/2012
carol: 2/6/2012
mgross: 4/3/2006
terry: 4/3/2006
carol: 1/20/2006
carol: 11/19/2004
carol: 11/18/2004
ckniffin: 11/3/2004
alopez: 10/2/2002