RBCC Red Blood Cell Collection

CCDC6 (D10S170, TST1) [Confidence: low (only semi-automatic identification from reviews)]
Coiled-coil domain-containing protein 6 (Papillary thyroid carcinoma-encoded protein; Protein H4)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q16204
ID CCDC6_HUMAN Reviewed; 474 AA.
AC Q16204; Q15250; Q6GSG7;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-MAR-2010, sequence version 2.
DT 22-JAN-2014, entry version 129.
DE RecName: Full=Coiled-coil domain-containing protein 6;
DE AltName: Full=Papillary thyroid carcinoma-encoded protein;
DE AltName: Full=Protein H4;
GN Name=CCDC6; Synonyms=D10S170, TST1;
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], AND VARIANT THR-470.
RC TISSUE=Thyroid;
RX PubMed=8058316;
RA Grieco M., Cerrato A., Santoro M., Fusco A., Melillo R.M., Vecchio G.;
RT "Cloning and characterization of H4 (D10S170), a gene involved in RET
RT rearrangements in vivo.";
RL Oncogene 9:2531-2535(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-470.
RC TISSUE=Testis;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND VARIANT THR-470.
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT THR-470.
RC TISSUE=Blood, and Uterus;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-101, AND CHROMOSOMAL TRANSLOCATION
RP WITH RET.
RC TISSUE=Thyroid papillary carcinoma;
RX PubMed=2406025; DOI=10.1016/0092-8674(90)90659-3;
RA Grieco M., Santoro M., Berlingieri M.T., Melillo R.M., Donghi R.,
RA Bongarzone I., Pierotti M.A., Della Porta G., Fusco A., Vecchio G.;
RT "PTC is a novel rearranged form of the ret proto-oncogene and is
RT frequently detected in vivo in human thyroid papillary carcinomas.";
RL Cell 60:557-563(1990).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240 AND SER-244, AND
RP MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=15144186; DOI=10.1021/ac035352d;
RA Brill L.M., Salomon A.R., Ficarro S.B., Mukherji M., Stettler-Gill M.,
RA Peters E.C.;
RT "Robust phosphoproteomic profiling of tyrosine phosphorylation sites
RT from human T cells using immobilized metal affinity chromatography and
RT tandem mass spectrometry.";
RL Anal. Chem. 76:2763-2772(2004).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240 AND SER-244, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P.,
RA Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in
RT signaling networks.";
RL Cell 127:635-648(2006).
RN [9]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240 AND SER-244, AND
RP MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein
RT phosphorylation analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=17924679; DOI=10.1021/pr070152u;
RA Yu L.R., Zhu Z., Chan K.C., Issaq H.J., Dimitrov D.S., Veenstra T.D.;
RT "Improved titanium dioxide enrichment of phosphopeptides from HeLa
RT cells and high confident phosphopeptide identification by cross-
RT validation of MS/MS and MS/MS/MS spectra.";
RL J. Proteome Res. 6:4150-4162(2007).
RN [11]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52; SER-240 AND SER-244,
RP AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18220336; DOI=10.1021/pr0705441;
RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D.,
RA Yates J.R. III;
RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for
RT efficient phosphoproteomic analysis.";
RL J. Proteome Res. 7:1346-1351(2008).
RN [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-244, AND MASS
RP SPECTROMETRY.
RC TISSUE=Platelet;
RX PubMed=18088087; DOI=10.1021/pr0704130;
RA Zahedi R.P., Lewandrowski U., Wiesner J., Wortelkamp S., Moebius J.,
RA Schuetz C., Walter U., Gambaryan S., Sickmann A.;
RT "Phosphoproteome of resting human platelets.";
RL J. Proteome Res. 7:526-534(2008).
RN [13]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52; THR-349; SER-363 AND
RP SER-367, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52; SER-240; SER-244;
RP SER-254 AND SER-367, AND MASS SPECTROMETRY.
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-52; SER-240; SER-244;
RP SER-249; SER-254; SER-284; SER-323 AND SER-325, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [17]
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 [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-240; SER-244 AND
RP SER-323, AND MASS SPECTROMETRY.
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J.,
RA Johansen P.T., Kratchmarova I., Kassem M., Mann M., Olsen J.V.,
RA Blagoev B.;
RT "System-wide temporal characterization of the proteome and
RT phosphoproteome of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
CC -!- INTERACTION:
CC Q969H0:FBXW7; NbExp=9; IntAct=EBI-1045350, EBI-359574;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cytoplasm, cytoskeleton
CC (Probable). Note=May be a cytoskeletal protein.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed.
CC -!- DOMAIN: The protein has mostly an alpha helical conformation
CC similar to myosin heavy-chain tail that might adopt a coiled-coil
CC conformation.
CC -!- DISEASE: Thyroid papillary carcinoma (TPC) [MIM:188550]: A common
CC tumor of the thyroid that typically arises as an irregular, solid
CC or cystic mass from otherwise normal thyroid tissue. Papillary
CC carcinomas are malignant neoplasm characterized by the formation
CC of numerous, irregular, finger-like projections of fibrous stroma
CC that is covered with a surface layer of neoplastic epithelial
CC cells. Note=The gene represented in this entry is involved in
CC disease pathogenesis. A chromosomal aberration involving CCDC6 is
CC found in thyroid papillary carcinomas. Inversion
CC inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAC60637.1; Type=Frameshift; Positions=456;
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/H4ID280.html";
CC -----------------------------------------------------------------------
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DR EMBL; S72869; AAC60637.1; ALT_FRAME; mRNA.
DR EMBL; AK292593; BAF85282.1; -; mRNA.
DR EMBL; AC060231; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC023904; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471083; EAW54196.1; -; Genomic_DNA.
DR EMBL; BC036757; AAH36757.2; -; mRNA.
DR EMBL; BC064391; AAH64391.1; -; mRNA.
DR EMBL; M31213; AAA36524.1; ALT_TERM; mRNA.
DR PIR; I58403; I58403.
DR RefSeq; NP_005427.2; NM_005436.4.
DR UniGene; Hs.591360; -.
DR ProteinModelPortal; Q16204; -.
DR SMR; Q16204; 56-94.
DR IntAct; Q16204; 8.
DR MINT; MINT-5006123; -.
DR STRING; 9606.ENSP00000263102; -.
DR PhosphoSite; Q16204; -.
DR DMDM; 292494979; -.
DR PaxDb; Q16204; -.
DR PRIDE; Q16204; -.
DR Ensembl; ENST00000263102; ENSP00000263102; ENSG00000108091.
DR GeneID; 8030; -.
DR KEGG; hsa:8030; -.
DR UCSC; uc001jks.4; human.
DR CTD; 8030; -.
DR GeneCards; GC10M061548; -.
DR H-InvDB; HIX0008848; -.
DR HGNC; HGNC:18782; CCDC6.
DR HPA; HPA019049; -.
DR HPA; HPA019051; -.
DR MIM; 188550; phenotype.
DR MIM; 601985; gene.
DR neXtProt; NX_Q16204; -.
DR Orphanet; 146; Papillary or follicular thyroid carcinoma.
DR PharmGKB; PA134904022; -.
DR eggNOG; NOG123137; -.
DR HOGENOM; HOG000091755; -.
DR HOVERGEN; HBG050823; -.
DR InParanoid; Q16204; -.
DR KO; K09288; -.
DR OMA; CTSIPWL; -.
DR OrthoDB; EOG7SJD4M; -.
DR ChiTaRS; CCDC6; human.
DR GeneWiki; CCDC6; -.
DR GenomeRNAi; 8030; -.
DR NextBio; 30611; -.
DR PRO; PR:Q16204; -.
DR Bgee; Q16204; -.
DR CleanEx; HS_CCDC6; -.
DR Genevestigator; Q16204; -.
DR GO; GO:0005737; C:cytoplasm; IDA:HPA.
DR GO; GO:0005856; C:cytoskeleton; IEA:UniProtKB-SubCell.
DR GO; GO:0005200; F:structural constituent of cytoskeleton; TAS:ProtInc.
DR InterPro; IPR019152; DUF2046.
DR PANTHER; PTHR15276; PTHR15276; 1.
DR Pfam; PF09755; DUF2046; 1.
PE 1: Evidence at protein level;
KW Acetylation; Chromosomal rearrangement; Coiled coil;
KW Complete proteome; Cytoplasm; Cytoskeleton; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Reference proteome; Repeat; SH3-binding.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 474 Coiled-coil domain-containing protein 6.
FT /FTId=PRO_0000089398.
FT REPEAT 106 134 1.
FT REPEAT 135 163 2.
FT REPEAT 164 192 3.
FT REPEAT 193 206 4; approximate.
FT REPEAT 207 235 5.
FT REGION 106 235 5 X 29 AA tandem repeats.
FT COILED 53 237 Potential.
FT COILED 253 332 Potential.
FT MOTIF 442 451 SH3-binding (Potential).
FT COMPBIAS 17 20 Poly-Ser.
FT COMPBIAS 32 44 Poly-Gly.
FT COMPBIAS 440 448 Poly-Pro.
FT SITE 101 102 Breakpoint for translocation to form RET-
FT CCDC6 oncogene.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 52 52 Phosphoserine.
FT MOD_RES 240 240 Phosphoserine.
FT MOD_RES 244 244 Phosphoserine.
FT MOD_RES 249 249 Phosphoserine.
FT MOD_RES 254 254 Phosphoserine.
FT MOD_RES 284 284 Phosphoserine.
FT MOD_RES 323 323 Phosphoserine.
FT MOD_RES 325 325 Phosphoserine.
FT MOD_RES 349 349 Phosphothreonine.
FT MOD_RES 363 363 Phosphoserine.
FT MOD_RES 367 367 Phosphoserine.
FT VARIANT 470 470 P -> T (in dbSNP:rs1053266).
FT /FTId=VAR_062971.
FT CONFLICT 157 157 A -> G (in Ref. 1; AAC60637).
FT CONFLICT 228 228 K -> T (in Ref. 1; AAC60637).
SQ SEQUENCE 474 AA; 53291 MW; DF055DBF20304D26 CRC64;
MADSASESDT DGAGGNSSSS AAMQSSCSST SGGGGGGGGG GGGGKSGGIV ISPFRLEELT
NRLASLQQEN KVLKIELETY KLKCKALQEE NRDLRKASVT IQARAEQEEE FISNTLFKKI
QALQKEKETL AVNYEKEEEF LTNELSRKLM QLQHEKAELE QHLEQEQEFQ VNKLMKKIKK
LENDTISKQL TLEQLRREKI DLENTLEQEQ EALVNRLWKR MDKLEAEKRI LQEKLDQPVS
APPSPRDISM EIDSPENMMR HIRFLKNEVE RLKKQLRAAQ LQHSEKMAQY LEEERHMREE
NLRLQRKLQR EMERREALCR QLSESESSLE MDDERYFNEM SAQGLRPRTV SSPIPYTPSP
SSSRPISPGL SYASHTVGFT PPTSLTRAGM SYYNSPGLHV QHMGTSHGIT RPSPRRSNSP
DKFKRPTPPP SPNTQTPVQP PPPPPPPPMQ PTVPSAATSQ PTPSQHSAHP SSQP
//

MIM 188550
*RECORD*
*FIELD* NO
188550
*FIELD* TI
#188550 THYROID CARCINOMA, PAPILLARY
;;PAPILLARY CARCINOMA OF THYROID; PACT; PTC; TPC;;
read moreFAMILIAL NONMEDULLARY THYROID CANCER, PAPILLARY;;
NONMEDULLARY THYROID CARCINOMA, PAPILLARY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
papillary thyroid carcinoma is caused by a number of different genetic
changes, particularly by chimeric oncogenes formed by fusion of the
tyrosine kinase domain of a membrane receptor protein with the 5-prime
terminal region of another gene. Oncogenic rearrangements involving the
RET gene (164761) on chromosome 10 are found in about 35% of cases, and
rearrangements involving the NTRK1 gene (191315) on chromosome 1 are
involved in about 15% of cases (Pierotti et al., 1996).

A susceptibility gene for familial nonmedullary thyroid carcinoma with
or without cell oxyphilia (TCO; 603386) has been mapped to chromosome
19p.

A susceptibility gene for familial nonmedullary thyroid carcinoma has
been mapped to 2q21 (NMTC1; 606240).

DESCRIPTION

Nonmedullary thyroid cancer (NMTC) comprises thyroid cancers of
follicular cell origin and accounts for more than 95% of all thyroid
cancer cases (summary by Vriens et al., 2009). The remaining cancers
originate from parafollicular cells (medullary thyroid cancer, MTC;
155240). NMTC is classified into 4 groups: papillary, follicular
(188470), Hurthle cell (607464), and anaplastic. Approximately 5% of
NMTC is hereditary, occurring as a component of a familial cancer
syndrome (e.g., familial adenomatous polyposis 175100, Carney complex
160980) or as a primary feature (familial NMTC or FNMTC). Papillary
thyroid cancer (PTC) is the most common histologic subtype of FNMTC,
accounting for approximately 85% of cases.

PTC is characterized by distinctive nuclear alterations including
pseudoinclusions, grooves, and chromatin clearing (summary by Bonora et
al., 2010). PTCs smaller than 1 cm are referred to as papillary
microcarcinomas. These tumors have been identified in up to 35% of
individuals at autopsy, suggesting that they may be extremely common
although rarely clinically relevant. PTC can also be multifocal but is
typically slow-growing with a tendency to spread to lymph nodes and
usually has an excellent prognosis.

CLINICAL FEATURES

Lote et al. (1980) identified 2 kindreds with 7 and 4 cases of papillary
carcinoma in otherwise healthy, nonirradiated subjects. All grew up in 1
of 2 small fishing villages in northern Norway. The familial cases
showed an earlier mean age at diagnosis (37.6 years) than did sporadic
cases from the same region (52.8 years). Multiple endocrine
adenomatosis, Gardner syndrome (175100), and arrhenoblastoma (see
138800) were excluded.

Phade et al. (1981) described 3 affected sibs, of normal parents, with
discovery of cancer at ages 12, 7, and 20 years. The authors found one
other report of familial papillary carcinoma without polyposis coli, in
a father and daughter, aged 40 and 12, respectively, at discovery
(Lacour et al., 1973). The young age at occurrence and frequent
bilateral involvement are characteristic of hereditary cancers.

Stoffer et al. (1985, 1986) presented evidence for the existence of a
familial form of papillary carcinoma of the thyroid, possibly inherited
as an autosomal dominant. Four parents of patients with familial PACT
had colon cancer and 5 other family members died of intraabdominal
malignancy that was not further defined. Perkel et al. (1988) presented
evidence suggesting a familial susceptibility factor in
radiation-induced thyroid neoplasms.

Grossman et al. (1995) identified 13 families with 30 individuals
affected by familial nonmedullary thyroid cancer, which they abbreviated
FNMTC. In 14 of these affected individuals whom they personally treated,
13 had multifocal tumors, and 6 of these were bilateral. The incidence
of lymph node metastasis was 57%, as was the incidence of local
invasion. Recurrences occurred in 7 patients during follow-up. The
histologic diagnosis was papillary thyroid carcinoma in 13 of the 14
patients; in 1 patient it was Hurthle cell carcinoma.

Takami et al. (1996) identified 34 families in Japan with 72 individuals
affected by nonmedullary thyroid cancer: 17 men and 55 women. Pathologic
diagnosis was papillary carcinoma in 64 patients, follicular carcinoma
in 6, and anaplastic carcinoma in 2. From the findings in their study
they concluded that familial nonmedullary thyroid cancer behaves more
aggressively than sporadic nonmedullary thyroid cancer.

Canzian et al. (1998) noted that families with multiple cases of
nonmedullary thyroid cancer had been reported by Lote et al. (1980) and
Burgess et al. (1997). FNMTC may represent 3 to 7% of all thyroid
tumors. The tumors are usually multifocal, recur more frequently, and
show an earlier age at onset than in sporadic cases. These
characteristics are well exemplified by familial adenomatous
polyposis-associated thyroid carcinoma, which, in addition, has been
found to be a distinct morphologic entity, rather than the papillary
carcinoma that it had previously been believed to be (Harach et al.,
1994).

CLINICAL MANAGEMENT

Vascular endothelial growth factor (VEGF; 192240) is a potent stimulator
of endothelial cell proliferation that has been implicated in tumor
growth of thyroid carcinomas. Using the VEGF immunohistochemistry
staining score, Klein et al. (2001) correlated the level of VEGF
expression with the metastatic spread of 19 cases of thyroid papillary
carcinoma. The mean score +/- standard deviation was 5.74 +/- 2.59 for
all carcinomas. The mean score for metastatic papillary carcinoma was
8.25 +/- 1.13 vs 3.91 +/- 1.5 for nonmetastatic papillary cancers (P
less than .001). By discriminant analysis, they found a threshold value
of 6.0, with a sensitivity of 100% and a specificity of 87.5%. The
authors concluded that VEGF immunostaining score is a helpful marker for
metastasis spread in differentiated thyroid cancers. They proposed that
a value of 6 or more should be considered as high risk for metastasis
threat, prompting the physician to institute a tight follow-up of the
patient.

Baudin et al. (2003) studied the positive predictive value of serum
thyroglobulin (TG; 188450) level after thyroid hormone withdrawal,
measured during the first 6 to 12 months of follow-up in 256 consecutive
differentiated thyroid cancer patients. They confirmed that (131)I-total
body scan (TBS) has a limited interest for the follow-up of thyroid
cancer patients. They concluded that follow-up should rely on serum TG
level and prognostic parameters; however, initial serum TG may be
produced by thyroid tissues of various significance, an increase at 2
consecutive determinations indicating disease progression and a decrease
being related to late effects of therapy. The best positive predictive
value is obtained by the slope of serum TG levels.

Serum TG assays are sometimes unsatisfactory for monitoring thyroid
cancer because interference caused by anti-TG antibodies may reduce the
sensitivity of the tests during thyroid hormone therapy. Savagner et al.
(2002) developed a complementary method using real-time quantitative
RT-PCR based on the amplification of TG mRNA. Two different pairs of
primers were used for the determination of the frequency of 1 of the
variants of the alternative splicing of TG mRNA. The frequency of this
variant was as high in 40 patients as in 30 controls, accounting for
about 33% of the total TG mRNA. Using appropriate primers, the authors
observed that TG mRNA values in controls varied according to the volume
of thyroid tissue and the TSH concentration. The TG mRNA values allowed
the definition of a positive cutoff point at 1 pg/microg total RNA. This
cutoff point, tested on the group of patients treated for thyroid
cancer, produced fewer false negative results than those obtained with
serum TG assays.

Wagner et al. (2005) tested the preoperative sensitivity of RT-PCR for
TG and TSHR mRNA to detect thyroid cancer. TSHR and TG mRNA transcripts
were detected by RT-PCR assays previously determined to be specific for
cancer cells. There was 100% concordance between TSHR and TG mRNA RT-PCR
results. The authors concluded that the molecular detection of
circulating thyroid cancer cells by RT-PCR for TSHR/TG mRNA complements
fine-needle aspiration cytology in the preoperative differentiation of
benign from malignant thyroid disease, and that their combined use may
save unnecessary surgeries.

Carlomagno et al. (2002) showed that a pyrazolopyrimidine known as PP1
is a potent inhibitor of the RET kinase. Carlomagno et al. (2003) showed
that another compound of the same class, known as PP2, blocks the
enzymatic activity of the isolated RET kinase and RET/PTC1 oncoprotein
at IC50 (inhibitory concentration-50; the amount of drug required to
reduce activity in cell culture by 50%) in the nanomolar range. PP2
blocked in vivo phosphorylation and signaling of the RET/PTC1
oncoprotein. PP2 prevented serum-independent growth of
RET/PTC1-transformed NIH 3T3 fibroblasts and of TPC1 and FB2, 2 human
papillary thyroid carcinoma cell lines that carry spontaneous RET/PTC1
rearrangements. Growth in type I collagen (see 120150) gels efficiently
reflects invasive growth of malignant cells. PP2 blocked invasion of
type I collagen matrix by TPC1 cells. The authors concluded that
pyrazolopyrimidines hold promise for the treatment of human cancers
sustaining oncogenic activation of RET.

Fortunati et al. (2004) evaluated the action of valproic acid, a potent
anticonvulsant reported to inhibit histone deacetylase, on cultured
thyroid cancer cells. NPA (papillary or poorly differentiated) and ARO
(anaplastic) cells were treated with increasing valproic acid
concentrations. Expression of mRNA and cell localization pattern for the
sodium-iodide symporter (NIS; 601843), as well as iodine-125 uptake,
were evaluated before and after treatment. Valproic acid induced NIS
gene expression, NIS membrane localization, and iodide accumulation in
NPA cells, and it was effective at clinically safe doses in the
therapeutic range. In ARO cells, only induction of NIS mRNA was
observed, and was not followed by any change in iodide uptake. The
authors concluded that valproic acid is effective at restoring the
ability of NPA cells to accumulate iodide.

CYTOGENETICS

- Oncogenic Rearrangements in Papillary Thyroid Carcinoma

Pierotti et al. (1996) indicated that oncogenic rearrangements of the
RET gene are found in about 35% of cases of papillary thyroid carcinoma;
rearrangements involving the NTRK1 gene are involved in about 15% of
cases. The RET and NTRK1 genes encode membrane receptor-like proteins
with tyrosine kinase activity. Their expression is strictly regulated
and confined to subsets of neural crest-derived cells. The oncogenic
rearrangements cause deletion of the N-terminal domain and fusion of the
remaining tyrosine kinase domain of the receptor genes with the 5-prime
end of different unrelated genes, designated activating genes. Since all
the activating genes are ubiquitously expressed and also contain a
dimerization domain, each RET and NTRK1 rearrangement produces chimeric
mRNAs and proteins in the thyroid cells in which rearrangements occur.
Moreover, the fusion products express an intrinsic and constitutive
tyrosine kinase activity.

Among 329 thyroid lesions analyzed cytogenetically, Frau et al. (2008)
identified 9 nodules with trisomy 17 as the only chromosomal change. All
9 cases were noninvasive, exhibited follicular growth pattern, and
showed PTC-specific nuclear changes focally defined within the nodule.
Frau et al. (2008) concluded that isolated trisomy 17 is associated with
focal papillary carcinoma changes in follicular-patterned thyroid
nodules and may be a marker for this poorly characterized subset of
thyroid lesions.

- RET Fusion Genes

In the case of the chimeric gene PTC1, RET is fused to the H4 gene
(CCDC6; 601985), which, like RET, is located on chromosome 10 and
becomes fused with RET through an intrachromosomal rearrangement. The
chimeric gene PTC3 results from a structural rearrangement between RET
with the ELE1 gene (NCOA4; 601984) on chromosome 10, and the chimeric
gene PTC2 is generated through fusion of RET with the PRKAR1A gene
(188830) on chromosome 17.

Corvi et al. (2000) identified a rearrangement involving the RET
tyrosine kinase domain and the 5-prime portion of PCM1 (600299) on
chromosome 8p22-p21. Immunohistochemistry using an antibody specific for
the C-terminal portion of PCM1 showed that the protein level was
drastically decreased and its subcellular localization altered in
papillary thyroid tumor tissue with respect to normal thyroid.

By RT-PCR screening of PTCs of 2 patients exposed to radioactive fallout
after the Chernobyl nuclear power plant disaster, followed by 5-prime
RACE, Klugbauer et al. (1998) identified a novel RET rearrangement,
PTC5, involving fusion of the RET tyrosine kinase domain to RFG5
(GOLGA5; 606918) on chromosome 14q.

Klugbauer and Rabes (1999) identified 2 novel types of RET
rearrangements, which they termed PTC6 and PTC7. In PTC6, RET is fused
to the N-terminal part of transcriptional intermediary factor-1-alpha
(TIF1A; 603406) on chromosome 7q32-q34, and in PTC7, RET is fused to a
C-terminal part of TIF1-gamma (TIF1G; 605769) on chromosome 1p13.

Herrmann et al. (1991) found clonal abnormalities on cytogenetic
analysis in 9 out of 26 papillary thyroid cancers and 5 follicular
thyroid cancers. In the former group, the abnormalities included loss of
the Y chromosome, addition of an extra chromosome 5, or inversion in
chromosome 10, inv(10)(q11.2q21.2). Using DNA probes specific for
chromosomes 1, 3, 10, 16, and 17, they carried out RFLP analyses of 12
papillary cancers. No loss of heterozygosity (LOH) was observed for loci
mapped to chromosome 10. Jenkins et al. (1990) likewise found the
inv(10)(q11.2q21) with breakpoints where RET and another sequence of
unknown function, D10S170 (H4; 601985), are located. Among 18 cases of
papillary thyroid carcinoma, Pierotti et al. (1992) identified 5 with
the identical abnormality. They reported the cytogenetic and molecular
characterization of 4 of these tumors and demonstrated that the
cytogenetic inversion provided the structural basis for the D10S170/RET
fusion, leading to the generation of the chimeric transforming sequence
which they referred to as RET/PTC. Santoro et al. (1992) found the
activated form of the RET oncogene in 33 (19%) of 177 papillary
carcinomas and in none of 109 thyroid tumors of other histotypes.

Bongarzone et al. (1994) examined tumors from a series of 52 patients
with papillary thyroid carcinomas and identified 10 cases of RET fusion
with the D10S170 locus (also known as H4) resulting in the generation of
the RET/PTC1 oncogene, 2 cases with the gene encoding the regulatory
subunit RI-alpha of protein kinase A (PRKAR1A; 188830), and 6 cases with
a newly discovered gene they called ELE1 (601984) located on chromosome
10 and leading to the formation of the RET/PTC3 oncogene. The RET/PTC3
hybrid gene was expressed in all 6 cases and was associated with the
synthesis of 2 constitutively phosphorylated isoforms of the oncoprotein
(p75 and p80). The chromosome 10 localization of both RET and ELE1 and
the detection, in all cases, of a sequence reciprocal to that generating
the oncogenic rearrangements, strongly suggested that RET/PTC3 formation
is a consequence of an intrachromosomal inversion of chromosome 10. The
RET/PTC3 hybrid oncogene was observed in both sporadic and
radiation-associated post-Chernobyl papillary thyroid carcinomas.

Bongarzone et al. (1997) examined the genomic regions containing the
ELE1/RET breakpoints in 6 sporadic and 3 post-Chernobyl tumors in 2
papillary carcinomas of different origins. Notably, in all sporadic
tumors and in 1 post-Chernobyl tumor, the ELE1/RET recombination
corresponded with short sequences of homology (3 to 7 bp) between the 2
rearranging genes. In addition, they observed an interesting
distribution of the post-Chernobyl breakpoints in the ELE1 break cluster
region (bcr) located within an Alu element, or between 2 closely
situated elements, and always in AT-rich regions.

- NTRK1 Fusion Genes

In about 15% of cases of papillary thyroid carcinoma, the NTRK1
protooncogene (191315) is activated through fusion with neighboring
genes TPM3 (191030) and TPR (189940) on chromosome 1q, and TFG (602498)
on chromosome 3.

- AKAP9/BRAF Fusion Gene

Ciampi et al. (2005) reported an AKAP9 (600409)-BRAF (164757) fusion
that was preferentially found in radiation-induced papillary carcinomas
developing after a short latency, whereas BRAF point mutations were
absent in this group. Ciampi et al. (2005) concluded that in thyroid
cancer, radiation activates components of the MAPK pathway primarily
through chromosomal paracentric inversions, whereas in sporadic forms of
the disease, effectors along the same pathway are activated
predominantly by point mutations.

HETEROGENEITY

Lesueur et al. (1999) performed a linkage analysis on 56 informative
kindreds collected through an international consortium on NMTC. Linkage
analysis using both parametric and nonparametric methods excluded MNG1,
TCO, and RET as major genes of susceptibility to NMTC and demonstrated
that this trait is characterized by genetic heterogeneity.

MAPPING

In a genomewide association study of 192 Icelandic individuals with
thyroid cancer and 37,196 controls, Gudmundsson et al. (2009) identified
associations with SNPs on chromosomes 9q22.33 and 14q13.3, respectively.
The findings were replicated in 2 cohorts of European descent (342 and
90 thyroid cancer cases, respectively). Overall, the strongest
association signals were observed for dbSNP rs965513 on 9q22.33 (odds
ratio of 1.75; p = 1.7 x 10(-27)) and dbSNP rs944289 on 14q13.3 (odds
ratio of 1.37; p = 2.0 x 10(-9)). The gene nearest the 9q22.33 locus is
thyroid transcription factor-2 (FOXE1; 602617) and thyroid transcription
factor-1 (NKX2-1; 600635) is among the genes located at the 14q13.3
locus. Both variants contributed to an increased risk of both papillary
and follicular thyroid cancer. Approximately 3.7% of individuals were
homozygous for both variants, and their estimated risk of thyroid cancer
was 5.7-fold greater than that of noncarriers. In large sample set from
the general Icelandic population, both risk alleles were associated with
low concentrations of TSH, and the 9q22.33 allele was associated with
low concentration of T4 and high concentration of T3.

In an association study of the 9q22 locus and thyroid-related phenotypes
identified by electronic selection algorithms of medical records, Denny
et al. (2011) found no significant association with thyroid cancer.

Jendrzejewski et al. (2012) found that dbSNP rs944289 is located in a
CEBP-alpha (CEBPA; 116897)/CEBP-beta (189965)-binding element in the
5-prime UTR of PTCSC3 (614821), a noncoding gene. They presented
evidence suggesting that the risk allele of dbSNP rs944289 decreases
PTCSC3 promoter activation by reducing CEBP-alpha and CEBP-beta binding
affinity compared with the nonrisk allele and thereby predisposes to
papillary thyroid carcinoma.

Takahashi et al. (2010) conducted a genomewide association study
employing Belarusian patients with papillary thyroid cancer (PTC) aged
18 years or younger at the time of the Chernobyl accident and
age-matched Belarusian control subjects. Two series of genome scans were
performed using independent sample sets, and association with
radiation-related PTC was evaluated. Metaanalysis combining the 2
studies identified 4 SNPs at chromosome 9q22.33 showing significant
associations with the disease. The association was further reinforced by
a validation analysis using one of these SNP markers, dbSNP rs965513,
with another set of samples. dbSNP rs965513 is located 57 kb upstream to
FOXE1 (602617), a thyroid-specific transcription factor with pivotal
roles in thyroid morphogenesis and was reported as the strongest genetic
risk marker of sporadic PTC in European populations. Of interest, no
association was obtained between radiation-related PTC and dbSNP
rs944289 at 14p13.3, which showed the second strongest association with
sporadic PTC in Europeans. The authors suggested that the complex
pathway underlying the pathogenesis may be partly shared by the 2
etiologic forms of PTC, but their genetic components do not completely
overlap each other, suggesting the presence of other unknown
etiology-specific genetic determinants in radiation-related PTC.

POPULATION GENETICS

The world's highest incidence of thyroid cancer has been reported among
females in New Caledonia, a French overseas territory in the Pacific
located between Australia and Fiji. Chua et al. (2000) investigated the
prevalence and distribution of RET/PTC 1, 2, and 3 in papillary thyroid
carcinoma from the New Caledonian population and compared the pattern
with that of an Australian population. Fresh-frozen and
paraffin-embedded papillary carcinomas from 27 New Caledonian and 20
Australian patients were examined for RET rearrangements by RT-PCR with
primers flanking the chimeric region, followed by hybridization with
radioactive probes. RET/PTC was present in 70% of the New Caledonian and
in 85% of the Australian samples. Multiple rearrangements were detected
and confirmed by sequencing in 19 cases, 4 of which had 3 types of
rearrangements in the same tumor. The authors concluded that this study
demonstrates a high prevalence of RET/PTC in New Caledonian and
Australian papillary carcinoma. The findings of multiple RET/PTC in the
same tumor suggested that some thyroid neoplasms may indeed by
polyclonal.

Hrafnkelsson et al. (2001) studied the incidence of thyroid cancer in
the relatives of Icelandic individuals in whom a diagnosis of
nonmedullary thyroid cancer was made in the period 1955 to 1994. They
identified 712 cases. The relative risk for thyroid cancer in all
relatives was 3.83 for male relatives and 2.08 for female. The risk was
highest in the male relatives of male probands (6.52) and lowest in the
female relatives of female probands (2.02). For first-degree relatives
the risk ratios were 4.10 for male relatives and 1.93 for female
relatives.

Abubaker et al. (2008) studied the relationship of genetic alterations
in the PIK3CA gene with various clinicopathologic characteristics of PTC
in a Middle Eastern population. PIK3CA amplification was seen in 265
(53.1%) of 499 PTC cases analyzed, and PIK3CA gene mutations in 4 (1.9%)
of 207 PTC. N2-RAS mutations were found in 16 (6%) of 265 PTC, and BRAF
mutations in 153 (51.7%) of 296 PTC. NRAS mutations were associated with
an early stage and lower incidence of extrathyroidal extension, whereas
BRAF mutations were associated with metastasis and poor disease-free
survival in PTCs. Abubaker et al. (2008) noted that the frequency of
PIK3CA amplification was higher than that observed in Western and Asian
populations, and remained higher after the amplification cutoff was
raised to 10 or more.

GENOTYPE/PHENOTYPE CORRELATIONS

Sugg et al. (1998) examined the expression of RET/PTC-1, -2, and -3 in
human thyroid microcarcinomas and clinically evident PTC to determine
its role in early-stage versus developed PTC and to examine the
diversity of RET/PTC in multifocal disease. Thirty-nine occult papillary
thyroid microcarcinomas from 21 patients were analyzed. Of the 30 tumors
(77%) positive for RET/PTC rearrangements, 12 were positive for
RET/PTC1, 3 for RET/PTC2, 6 for RET/PTC3, and 9 for multiple RET/PTC
oncogenes. In clinically evident tumors, 47% had RET/PTC rearrangements.
Immunohistochemistry demonstrated close correlation with RT-PCR-derived
findings. The authors concluded that RET/PTC expression is highly
prevalent in microcarcinomas and occurs more frequently than in
clinically evident PTC (P less than 0.005). Multifocal disease,
identified in 17 of the 21 patients, exhibited identical RET/PTC
rearrangements within multiple tumors in only 2 patients; the other 15
patients had diverse rearrangements in individual tumors. The authors
inferred that RET/PTC oncogene rearrangements may play a role in
early-stage papillary thyroid carcinogenesis, but seem to be less
important in determining progression to clinically evident disease. In
multifocal disease, the diversity of RET/PTC profiles, in the majority
of cases, suggested to Sugg et al. (1998) that individual tumors arise
independently in a background of genetic or environmental
susceptibility.

By RT-PCR, Learoyd et al. (1998) analyzed the 3 main RET/PTC
rearrangements and RET tyrosine kinase domain sequence expression in a
prospective study of 50 adult PTCs. The genetic findings were correlated
with the MACIS clinical prognostic score and with individual clinical
parameters. Three of the patients had been exposed to radiation in
childhood or adolescence. Four of the PTCs contained RET/PTC1, confirmed
by sequencing, and none contained RET/PTC2 or RET/PTC3. The prevalence
of RET rearrangements was 8% overall, but in the subgroup of 3
radiation-exposed patients it was 66.6%. Interestingly, RET tyrosine
kinase domain mRNA was detectable in 70% of PTCs using RET exon 12/13
primers, and was detectable in 24% of PTCs using RET exon 15/17 primers.
RT-PCR for calcitonin and RET extracellular domain, however, was
negative. There was no association between the presence or absence of
RET/PTC in any patient's tumor and clinical parameters. Learoyd et al.
(1998) concluded that RET/PTC1 is the predominant rearrangement in PTCs
from adults with a history of external irradiation in childhood.

Finn et al. (2003) assessed the prevalence of the common RET chimeric
transcripts RET/PTC1 and RET/PTC3 in a group of sporadic PTCs and
correlated them with tumor morphology. Thyroid follicular cells were
laser capture microdissected from sections of 28 archival PTCs. Total
RNA was extracted and analyzed for expression of glyceraldehyde
3-phosphate dehydrogenase (138400), RET/PTC1, and RET/PTC3 using TaqMan
PCR. Ret/PTC rearrangements were detected in 60% of PTCs. Specifically,
transcripts of RET/PTC1 and RET/PTC3 were detected in 43% and 18% of
PTCs, respectively. Ret/PTC3 was detected in only follicular variant
subtype (60%) and was not detected in classic PTC. One case of tall cell
variant demonstrated chimeric expression of both RET/PTC1 and RET/PTC3
transcripts within the same tumor.

A sharp increase in the incidence of pediatric PTC was documented after
the Chernobyl power plant explosion. An increased prevalence of
rearrangements of the RET protooncogene (RET/PTC rearrangements) had
been reported in Belarussian post-Chernobyl papillary carcinomas arising
between 1990 and 1995. Thomas et al. (1999) analyzed 67 post-Chernobyl
pediatric PTCs arising in 1995 to 1997 for RET/PTC activation; 28 were
from Ukraine and 39 were from Belarus. The study, conducted by a
combined immunohistochemistry and RT-PCR approach, demonstrated a high
frequency (60.7% of the Ukrainian and 51.3% of the Belarussian cases) of
RET/PTC activation. A strong correlation was observed between the
solid-follicular subtype of PTC and the RET/PTC3 isoform: 19 of 24 (79%)
RET/PTC-positive solid-follicular carcinomas harbored a RET/PTC3
rearrangement, whereas only 5 had a RET/PTC1 rearrangement. The authors
concluded that these results support the concept that RET/PTC activation
played a central role in the pathogenesis of PTCs in both Ukraine and
Belarus after the Chernobyl accident.

Fenton et al. (2000) examined spontaneous PTC from 33 patients (23
females and 10 males) with a median age of 18 years (range, 6-21 years)
and a median follow-up of 3.5 years (range, 0-13.4 years). RET/PTC
mutations were identified in 15 tumors (45%), including 8 PTC1 (53%), 2
PTC2 (13%), 2 PTC3 (13%), and 3 (20%) combined PTC mutations (PTC1 and
PTC2). This distribution is significantly different from that reported
for children with radiation-induced PTC. There was no correlation
between the presence or type of RET/PTC mutation and patient age, tumor
size, focality, extent of disease at diagnosis, or recurrence. The
authors concluded that RET/PTC mutations are (1) common in sporadic
childhood PTC, (2) predominantly PTC1, (3) frequently multiple, and (4)
of different distribution than that reported for children with
radiation-induced PTC.

Elisei et al. (2001) evaluated the pattern of RET/PTC activation in
thyroid tumors from different groups of patients (exposed or not exposed
to radiation, children or adults, with benign or malignant tumors). They
studied 154 patients, 65 with benign nodules and 89 with papillary
thyroid cancer. In the last group, 25 were Belarus children exposed to
the post-Chernobyl radioactive fallout, 17 were Italian adults exposed
to external radiotherapy for benign diseases, and 47 were Italian
subjects (25 children and 22 adults) with no history of radiation
exposure. Among patients with benign thyroid nodules, 21 were Belarus
subjects (18 children and 3 adults) exposed to the post-Chernobyl
radioactive fallout, 8 were Italian adults exposed to external radiation
on the head and neck, and 36 were Italian adults with naturally
occurring benign nodules. The overall frequency of RET/PTC
rearrangements in papillary thyroid cancer was 55%. The highest
frequency was found in post-Chernobyl children and was significantly
higher (P = 0.02) than that found in Italian children not exposed to
radiation, but not significantly higher than that found in adults
exposed to external radiation. No difference of RET/PTC rearrangements
was found between samples from irradiated (external x-ray) or
nonirradiated adult patients, as well as between children and adults
with naturally occurring thyroid cancer. RET/PTC rearrangements were
also found in 52.4% of post-Chernobyl benign nodules, in 37.5% of benign
nodules exposed to external radiation and in 13.9% of naturally
occurring nodules (P = 0.005, between benign post-Chernobyl nodules and
naturally occurring nodules). The relative frequency of RET/PTC1 and
RET/PTC3 in rearranged benign tumors showed no major difference. The
authors concluded that the presence of RET/PTC rearrangements in thyroid
tumors is not restricted to the malignant phenotype, is not higher in
radiation-induced tumors compared with those naturally occurring, is not
different after exposure to radioiodine or external radiation, and is
not dependent on young age.

Mechler et al. (2001) reported 6 cases of familial PTC associated with
lymphocytic thyroiditis in 2 unrelated families. PTC was diagnosed on
classic nuclear and architectural criteria, and was bilateral in 5
cases. Architecture was equally distributed between typical PTC and its
follicular variant. Lymphocytic thyroiditis was present in variable
degrees, including, in 4 cases, oncocytic metaplasia. By use of RT-PCR,
Mechler et al. (2001) demonstrated RET/PTC rearrangement in the
carcinomatous areas of patients of both families: PTC1 in family 1, PTC3
in family 2, and a RET/PTC rearrangement in nonmalignant thyroid tissue
with lymphocytic thyroiditis in family 2. The findings suggested that
the molecular event at the origin of the PTCs was particular to each of
the studied families, and confirmed that RET protooncogene activating
rearrangement is an early event in the thyroid tumorigenic process and
that it may occur in association with lymphocytic thyroiditis.

Zhu et al. (2006) analyzed 65 papillary carcinomas for RET1/PTC1 and
RET/PTC3 using 5 different detection methods. The results suggested that
broad variability in the reported prevalence of RET1/PTC arrangement is
at least in part a result of the use of different detection methods and
tumor genetic heterogeneity.

MOLECULAR GENETICS

Kimura et al. (2003) identified a val600-to-glu (V600E; 164757.0001)
mutation in the BRAF gene in 28 (35.8%) of 78 cases of PTC; it was not
found in any of the other types of differentiated follicular neoplasms
arising from the same cell type (0 of 46). RET/PTC mutations and RAS
(see 190020) mutations were each identified in 16.4% of PTCs, but there
was no overlap in the 3 mutations. Kimura et al. (2003) concluded that
thyroid cell transformation to papillary cancer takes place through
constitutive activation of effectors along the RET/PTC-RAS-BRAF
signaling pathway.

Namba et al. (2003) determined the frequency of BRAF mutations in
thyroid cancer and their correlation with clinicopathologic parameters.
The V600E mutation was found in 4 of 6 cell lines and 51 (24.6%) of 207
thyroid tumors. Examination of 126 patients with papillary thyroid
cancer showed that BRAF mutation correlated significantly with distant
metastasis (P = 0.033) and clinical stage (P = 0.049). The authors
concluded that activating mutation of the BRAF gene could be a
potentially useful marker of prognosis of patients with advanced thyroid
cancers.

Xing et al. (2004) detected the V600E mutation in the BRAF gene in
thyroid cytologic specimens from fine-needle aspiration biopsy (FNAB).
Prospective analysis showed that 50% of the nodules that proved to be
PTCs on surgical histopathology were correctly diagnosed by BRAF
mutation analysis on FNAB specimens; there were no false-positive
findings.

*FIELD* SA
Flannigan et al. (1983)
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16. Finn, S. P.; Smyth, P.; O'Leary, J.; Sweeney, E. C.; Sheils, O.
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26. Jenkins, R. B.; Hay, I. D.; Herath, J. F.; Schultz, C. G.; Spurbeck,
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27. Kimura, E. T.; Nikiforova, M. N.; Zhu, Z.; Knauf, J. A.; Nikiforov,
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28. Klein, M.; Vignaud, J.-M.; Hennequin, V.; Toussaint, B.; Bresler,
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656-658, 2001.

29. Klugbauer, S.; Demidchik, E. P.; Lengfelder, E.; Rabes, H. M.
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gene RFG5. Cancer Res. 58: 198-203, 1998.

30. Klugbauer, S.; Rabes, H. M.: The transcription coactivator HTIF1
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1999.

31. Lacour, J.; Vignalou, J.; Perez, R.; Gerard-Marchant, R.: Epithelioma
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32. Learoyd, D. L.; Messina, M.; Zedenius, J.; Guinea, A. I.; Delbridge,
L. W.; Robinson, B. G.: RET/PTC and RET tyrosine kinase expression
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3631-3635, 1998.

33. Lesueur, F.; Stark, M.; Tocco, T.; Ayadi, H.; Delisle, M. J.;
Goldgar, D. E.; Schlumberger, M.; Romeo, G.; Canzian, F.: Genetic
heterogeneity in familial nonmedullary thyroid carcinoma: exclusion
of linkage to RET, MNG1, and TCO in 56 families. J. Clin. Endocr.
Metab. 84: 2157-2162, 1999.

34. Lote, K.; Andersen, K.; Nordal, E.; Brennhovd, I. O.: Familial
occurrence of papillary thyroid carcinoma. Cancer 46: 1291-1297,
1980.

35. Mechler, C.; Bounacer, A.; Suarez, H.; Frison, M. S.; Magois,
C.; Aillet, G.; Gaulier, A.: Papillary thyroid carcinoma: 6 cases
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RET/PTC rearrangements. Brit. J. Cancer 85: 1831-1837, 2001.

36. Namba, H.; Nakashima, M.; Hayashi, T.; Hayashida, N.; Maeda, S.;
Rogounovitch, T. I.; Ohtsuru, A.; Saenko, V. A.; Kanematsu, T.; Yamashita,
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thyroid cancers. J. Clin. Endocr. Metab. 88: 4393-4397, 2003.

37. Perkel, V. S.; Gail, M. H.; Lubin, J.; Pee, D. Y.; Weinstein,
R.; Shore-Freedman, E.; Schneider, A. B.: Radiation-induced thyroid
neoplasms: evidence for familial susceptibility factors. J. Clin.
Endocr. Metab. 66: 1316-1322, 1988.

38. Phade, V. R.; Lawrence, W. R.; Max, M. H.: Familial papillary
carcinoma of the thyroid. Arch. Surg. 116: 836-837, 1981.

39. Pierotti, M. A.; Bongarzone, I.; Borello, M. G.; Greco, A.; Pilotti,
S.; Sozzi, G.: Cytogenetics and molecular genetics of the carcinomas
arising from thyroid epithelial follicular cells. Genes Chromosomes
Cancer 16: 1-14, 1996.

40. Pierotti, M. A.; Santoro, M.; Jenkins, R. B.; Sozzi, G.; Bongarzone,
I.; Grieco, M.; Monzini, N.; Miozzo, M.; Herrmann, M. A.; Fusco, A.;
Hay, I. D.; Della Porta, G.; Vecchio, G.: Characterization of an
inversion on the long arm of chromosome 10 juxtaposing D10S170 and
RET and creating the oncogenic sequence RET/PTC. Proc. Nat. Acad.
Sci. 89: 1616-1620, 1992.

41. Santoro, M.; Carlomagno, F.; Hay, I. D.; Herrmann, M. A.; Grieco,
M.; Melillo, R.; Pierotti, M. A.; Bongarzone, I.; Della Porta, G.;
Berger, N.; Peix, J. L.; Paulin, C.; Fabien, N.; Vecchio, G.; Jenkins,
R. B.; Fusco, A.: Ret oncogene activation in human thyroid neoplasms
is restricted to the papillary cancer subtype. J. Clin. Invest. 89:
1517-1522, 1992.

42. Savagner, F.; Rodien, P.; Reynier, P.; Rohmer, V.; Bigorgne, J.-C.;
Malthiery, Y.: Analysis of Tg transcripts by real-time RT-PCR in
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635-639, 2002.

43. Stoffer, S. S.; Bach, J. V.; Van Dyke, D. L.; Szpunar, W.; Weiss,
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44. Stoffer, S. S.; Van Dyke, D. L.; Bach, J. V.; Szpunar, W.; Weiss,
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775-782, 1986.

45. Sugg, S. L.; Ezzat, S.; Rosen, I. B.; Freeman, J. L.; Asa, S.
L.: Distinct multiple RET/PTC gene rearrangements in multifocal papillary
thyroid neoplasia. J. Clin. Endocr. Metab. 83: 4116-4122, 1998.

46. Takahashi, M.; Saenko, V. A.; Rogounovitch, T. I.; Kawaguchi,
T.; Drozd, V. M.; Takigawa-Imamura, H.; Akulevich, N. M.; Ratanajaraya,
C.; Mitsutake, N.; Takamura, N.; Danilova, L. I.; Lushchik, M. L.;
Demidchik, Y. E.; Heath, S.; Yamada, R.; Lathrop, M.; Matsuda, F.;
Yamashita, S.: The FOXE1 locus is a major genetic determinant for
radiation-related thyroid carcinoma in Chernobyl. Hum. Molec. Genet. 19:
2516-2523, 2010.

47. Takami, H.; Ozaki, O.; Ito, K.: Familial nonmedullary thyroid
cancer: an emerging entity that warrants aggressive treatment. (Letter) Arch.
Surg. 131: 676 only, 1996.

48. Thomas, G. A.; Bunnell, H.; Cook, H. A.; Williams, E. D.; Nerovnya,
A.; Cherstvoy, E. D.; Tronko, N. D.; Bogdanova, T. I.; Chiappetta,
G.; Viglietto, G.; Pentimalli, F.; Salvatore, G.; Fusco, A.; Santoro,
M.; Vecchio, G.: High prevalence of RET/PTC rearrangements in Ukrainian
and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong
correlation between RET/PTC3 and the solid-follicular variant. J.
Clin. Endocr. Metab. 84: 4232-4238, 1999.

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and genetic predisposition to hereditary nonmedullary thyroid cancer. Thyroid 19:
1343-1349, 2009.

50. Wagner, K.; Arciaga, R.; Siperstein, A.; Milas, M.; Warshawsky,
I.; Reddy, S. S. K.; Gupta, M. K.: Thyrotropin receptor/thyroglobulin
messenger ribonucleic acid in peripheral blood and fine-needle aspiration
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Endocr. Metab. 90: 1921-1924, 2005.

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Rosenbaum, E.; Byrne, P. J.; Wang, J.; Sidransky, D.; Ladenson, P.
W.: Detection of BRAF mutation on fine needle aspiration biopsy specimens:
a new diagnostic tool for papillary thyroid cancer. J. Clin. Endocr.
Metab. 89: 2867-2872, 2004.

52. Zhu, Z.; Ciampi, R.; Nikiforova, M. N.; Gandhi, M.; Nikiforov,
Y. E.: Prevalence of RET/PTC rearrangements in thyroid papillary
carcinomas: effects of the detection methods and genetic heterogeneity. J.
Clin. Endocr. Metab. 91: 3603-3610, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEOPLASIA:
Papillary carcinoma of thyroid;
Reported colon and other abdominal cancer in relatives

LABORATORY ABNORMALITIES:
Frequent inv(10)(q11.2q21) producing chimeric transforming sequence
RET/PTC

MISCELLANEOUS:
Age of onset earlier in familial cases than in sporadic cases

MOLECULAR BASIS:
Caused by fusion of the RET protooncogene (164761) with TIF1G (605769),
D10S170 (601985), ELE1 (601984), and PRKAR1A (188830)

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/12/2002

*FIELD* CN
George E. Tiller - updated: 08/08/2013
Matthew B. Gross - updated: 9/13/2012
Marla J. F. O'Neill - updated: 10/28/2011
Cassandra L. Kniffin - updated: 6/8/2009
John A. Phillips, III - updated: 5/11/2009
John A. Phillips, III - updated: 4/24/2009
John A. Phillips, III - updated: 1/7/2008
John A. Phillips, III - updated: 7/24/2006
John A. Phillips, III - updated: 4/4/2006
John A. Phillips, III - updated: 7/11/2005
Marla J. F. O'Neill - updated: 2/2/2005
John A. Phillips, III - updated: 9/30/2003
John A. Phillips, III - updated: 9/11/2003
Victor A. McKusick - updated: 10/8/2002
Victor A. McKusick - updated: 5/31/2002
Paul J. Converse - updated: 5/8/2002
Michael J. Wright - updated: 4/26/2002
John A. Phillips, III - updated: 2/28/2002
Victor A. McKusick - updated: 8/30/2001
John A. Phillips, III - updated: 7/26/2001
Paul J. Converse - updated: 3/26/2001
John A. Phillips, III - updated: 3/7/2001
John A. Phillips, III - updated: 11/10/2000
John A. Phillips, III - updated: 3/7/2000
Victor A. McKusick - updated: 11/4/1999
John A. Phillips, III - updated: 3/25/1999
John A. Phillips, III - updated: 3/24/1999
Victor A. McKusick - updated: 9/4/1997

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
alopez: 08/08/2013
mgross: 9/13/2012
terry: 10/28/2011
terry: 3/18/2011
alopez: 11/23/2010
alopez: 11/22/2010
wwang: 9/29/2009
terry: 9/10/2009
alopez: 7/28/2009
wwang: 6/17/2009
ckniffin: 6/8/2009
alopez: 5/11/2009
alopez: 4/24/2009
alopez: 2/24/2009
carol: 12/22/2008
carol: 12/15/2008
carol: 1/7/2008
alopez: 7/24/2006
alopez: 4/4/2006
alopez: 7/11/2005
terry: 6/28/2005
tkritzer: 2/3/2005
terry: 2/2/2005
alopez: 1/11/2005
wwang: 1/11/2005
carol: 7/12/2004
alopez: 9/30/2003
alopez: 9/11/2003
carol: 10/16/2002
tkritzer: 10/14/2002
terry: 10/8/2002
alopez: 6/18/2002
terry: 5/31/2002
mgross: 5/8/2002
alopez: 4/26/2002
alopez: 2/28/2002
mgross: 8/31/2001
terry: 8/30/2001
mgross: 7/26/2001
mgross: 3/26/2001
alopez: 3/7/2001
carol: 2/14/2001
alopez: 2/14/2001
mgross: 11/20/2000
terry: 11/10/2000
mgross: 3/7/2000
terry: 2/28/2000
carol: 11/9/1999
terry: 11/4/1999
carol: 6/29/1999
mgross: 4/7/1999
mgross: 3/25/1999
mgross: 3/24/1999
carol: 3/15/1999
terry: 3/11/1999
dkim: 9/22/1998
alopez: 4/6/1998
dholmes: 9/30/1997
terry: 9/11/1997
mark: 9/10/1997
terry: 9/4/1997
mark: 10/3/1996
terry: 9/17/1996
mark: 10/16/1995
mimadm: 5/10/1995
carol: 10/5/1992
carol: 8/28/1992
carol: 5/29/1992
carol: 3/27/1992

MIM 601985
*RECORD*
*FIELD* NO
601985
*FIELD* TI
*601985 COILED-COIL DOMAIN-CONTAINING PROTEIN 6; CCDC6
;;H4 GENE;;
D10S170;;
TRANSFORMING SEQUENCE, THYROID 1; TST1
read morePTC1 CHIMERIC ONCOGENE, INCLUDED;;
H4/RET FUSION GENE, INCLUDED;;
H4/PDGFRB FUSION GENE, INCLUDED
*FIELD* TX

CLONING

From 5 thyroid papillary carcinomas (188550) and 2 of their respective
lymph node metastases, Fusco et al. (1987) isolated a novel oncogene by
demonstrating transforming activity using DNA transfection analysis on
NIH 3T3 cells. Radice et al. (1988) found a TaqI polymorphism in a probe
prepared from a genomic lambda phage library constructed with a tertiary
NIH 3T3 transfectant obtained by transfection with a human thyroid
papillary carcinoma DNA (Fusco et al., 1987). Grieco et al. (1990)
demonstrated that the oncogene, which they called PTC, is a novel,
rearranged form of the RET protooncogene fused to a then-unknown
nucleotide sequence, which they called H4.

MAPPING

Using a panel of rodent-human cell hybrid DNA and by in situ
hybridization, Fusco et al. (1987) mapped the PTC chimeric oncogene to
chromosome 10q. Radice et al. (1989) refined the assignment to 10q11-q12
by in situ hybridization.

GENE FUNCTION

Tong et al. (1997) found that the PTC1 oncoprotein forms a dimer in
vivo, and the leucine zipper in the N-terminal region of H4 is
responsible for this dimerization. Dimerization is essential for
tyrosine hyperphosphorylation and the transforming activity of the PTC1
oncogene.

Merolla et al. (2007) found that treatment of human cells with the
DNA-damaging agent etoposide or with ionizing radiation led to ATM
(607585)-mediated phosphorylation of H4 at thr434, which stabilized H4
in the nucleus. ATM-deficient lymphoblasts showed cytoplasmic H4
localization, and ionizing radiation failed to induce H4 thr434
phosphorylation. Inhibition of ATM interfered with H4 apoptotic
activity, and expression of H4 with a thr434-to-ala mutation protected
cells from genotoxic stress-induced apoptosis. Furthermore, silencing of
H4 increased cell survival and allowed DNA synthesis and mitotic
progression in irradiated human cell lines. Merolla et al. (2007)
concluded that H4 is involved in the ATM-mediated cellular response to
DNA damage and that impaired H4 function may have a role in thyroid
carcinogenesis.

- H4/RET Fusion Gene

The PTC1 chimeric oncogene (RET/PTC1), which is detected only in
papillary thyroid carcinoma (188550), is generated by the fusion of the
tyrosine kinase domain of the RET protooncogene (164761) to the 5-prime
terminal region of another gene, H4 (Donghi et al., 1989; Grieco et al.,
1990; Sozzi et al., 1991). PTC1 oncogene occurs in as many as 30% of
papillary thyroid carcinomas. The fusion gene is formed through
intrachromosomal 'illegitimate' recombination involving an inversion of
10q (Pierotti et al., 1992). The RET protooncogene encodes a
receptor-type tyrosine kinase, whose receptor is glial cell line-derived
neurotrophic factor (600837). Tong et al., (1995) showed that the
putative leucine zipper in the N-terminal region of H4 can mediate
oligomerization of the PTC1 oncogene in vitro. Tong et al. (1997)
demonstrated that the PTC1 oncogene forms a dimer in vivo, and the
leucine zipper is responsible for this dimerization. Constitutive
dimerization of the PTC1 oncogene appears to be essential for PTC1
transforming activity and constitutive oligomerization acquired by
rearrangement or by point mutations may be a general mechanism for the
activation of receptor tyrosine kinase oncogenes. See 601984 for
discussion of the PTC3 chimeric oncogene.

Nikiforova et al. (2000) asked whether, despite the great linear
distance (30 mg) between RET and H4, recombination might be promoted by
their proximity in the nucleus. Nikiforova et al. (2000) used 2-color
FISH and 3-dimensional microscopy to map the positions of the RET and H4
loci within interphase nuclei. At least one pair of RET and H4 was
juxtaposed in 35% of normal human thyroid cells and in 21% of peripheral
blood lymphocytes, but only in 6% of normal mammary epithelial cells.
Nikiforova et al. (2000) suggested that spatial contiguity of RET and H4
may provide a structural basis for generation of RET/PTC1 rearrangement
by allowing a single radiation track to produce a double-strand break in
each gene at the same site in the nucleus.

- H4/PDGFRB Fusion Gene

Kulkarni et al. (2000) described fusion of H4/D10S170 5-prime to the
platelet-derived growth factor receptor-beta gene (PDGFRB; 173410) in
BCR-ABL-negative myeloproliferative disorders (131440) with a
t(5;10)(q33;q21) translocation.

*FIELD* RF
1. Donghi, R.; Sozzi, G.; Pierotti, M. A.; Biunno, I.; Miozzo, M.;
Fusco, A.; Grieco, M.; Santoro, M.; Vecchio, G.; Spurr, N. K.; Della
Porta, G.: The oncogene associated with human papillary thyroid carcinoma
(PTC) is assigned to chromosome 10 q11-q12 in the same region as multiple
endocrine neoplasia type 2A (MEN2A). Oncogene 4: 521-523, 1989.

2. Fusco, A.; Grieco, M.; Santoro, M.; Berlingieri, M. T.; Pilotti,
S.; Pierotti, M. A.; Della Porta, G.; Vecchio, G.: A new oncogene
in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 328:
170-172, 1987.

3. Grieco, M.; Santoro, M.; Berlingieri, M. T.; Melillo, R. M.; Donghi,
R.; Bongarzone, I.; Pierotti, M. A.; Della Porta, G.; Fusco, A.; Vecchio,
G.: PTC is a novel rearranged form of the ret proto-oncogene and
is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:
557-563, 1990.

4. Kulkarni, S.; Heath, C.; Parker, S.; Chase, A.; Iqbal, S.; Pocock,
C. F.; Kaeda, J.; Cwynarski, K.; Goldman, J. M.; Cross, N. C. P.:
Fusion of H4/D10S170 to the platelet-derived growth factor receptor
beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21). Cancer
Res. 60: 3592-3598, 2000.

5. Merolla, F.; Pentimalli, F.; Pacelli, R.; Vecchio, G.; Fusco, A.;
Grieco, M.; Celetti, A.: Involvement of H4(D10S170) protein in ATM-dependent
response to DNA damage. Oncogene 26: 6167-6175, 2007.

6. Nikiforova, M. N.; Stringer, J. R.; Blough, R.; Medvedovic, M.;
Fagin, J. A.; Nikiforov, Y. E.: Proximity of chromosomal loci that
participate in radiation-induced rearrangements in human cells. Science 290:
138-141, 2000.

7. Pierotti, M. A.; Santoro, M.; Jenkins, R. B.; Sozzi, G.; Bongarzone,
I.; Grieco, M.; Monzini, N.; Miozzo, M.; Herrmann, M. A.; Fusco, A.;
Hay, I. D.; Della Porta, G.; Vecchio, G.: Characterization of an
inversion on the long arm of chromosome 10 juxtaposing D10S170 and
RET and creating the oncogenic sequence RET/PTC. Proc. Nat. Acad.
Sci. 89: 1616-1620, 1992.

8. Radice, P.; Donghi, R.; Pierotti, M. A.; Longoni, A.; Fusco, A.;
Grieco, M.; Santoro, M.; Vecchio, G.; Della Porta, G.: RFLP for TaqI
of the human thyroid papillary carcinoma (PTC) oncogene. Nucleic
Acids Res. 16: 9062 only, 1988.

9. Radice, P.; Donghi, R.; Sozzi, G.; Pierotti, M. A.; Miozzo, M.;
Longoni, A.; Mondini, P.; Fusco, A.; Grieco, M.; Santoro, M.; Vecchio,
G.; Spurr, N. K.; Della Porta, G.: DNA sequences linked to the human
papillary thyroid carcinoma (PTC) oncogene map to chromosome 10q11-q12
and identify TaqI and HincII RFLPs. (Abstract) Cytogenet. Cell Genet. 51:
1062 only, 1989.

10. Sozzi, G.; Pierotti, M. A.; Miozzo, M.; Donghi, R.; Radice, P.;
De Benedetti, V.; Grieco, M.; Santoro, M.; Fusco, A.; Vecchio, G.;
Mathew, C. G. P.; Ponder, B. A. J.; Spurr, N. K.: Refined localization
to contiguous regions on chromosome 10q of the two genes (H4 and RET)
that form the oncogenic sequence PTC. Oncogene 6: 339-342, 1991.

11. Tong, Q.; Li, Y.; Smanik, P. A.; Fithian, L. J.; Xing, S.; Mazzaferri,
E. L.; Jhiang, S. M.: Characterization of the promoter region and
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with the ret proto-oncogene. Oncogene 10: 1781-1787, 1995.

12. Tong, Q.; Xing, S.; Jhiang, S. M.: Leucine zipper-mediated dimerization
is essential for the PTC1 oncogenic activity. J. Biol. Chem. 272:
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13. Tong, Q.; Xing, S.; Jhiang, S. M.: Leucine zipper-mediated dimerization
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*FIELD* CN
Patricia A. Hartz - updated: 5/1/2008
Victor A. McKusick - updated: 9/25/2002
Ada Hamosh - updated: 10/19/2000

*FIELD* CD
Victor A. McKusick: 9/10/1997

*FIELD* ED
alopez: 10/06/2010
terry: 9/29/2010
carol: 2/11/2009
carol: 12/19/2008
carol: 12/11/2008
mgross: 5/1/2008
mgross: 5/22/2007
carol: 2/7/2006
carol: 9/26/2002
tkritzer: 9/25/2002
alopez: 10/20/2000
terry: 10/19/2000
carol: 6/29/1999
dholmes: 9/30/1997
mark: 9/11/1997
terry: 9/11/1997
mark: 9/10/1997