RBCC Red Blood Cell Collection

TFG [Confidence: low (only semi-automatic identification from reviews)]
Protein TFG (TRK-fused gene protein)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt Q92734
ID TFG_HUMAN Reviewed; 400 AA.
AC Q92734; D3DN49; G5E9V1; Q15656; Q969I2;
DT 02-FEB-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-FEB-2009, sequence version 2.
DT 22-JAN-2014, entry version 118.
DE RecName: Full=Protein TFG;
DE AltName: Full=TRK-fused gene protein;
GN Name=TFG;
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] (ISOFORM 1).
RC TISSUE=Pancreas;
RX PubMed=9169129; DOI=10.1006/geno.1997.4625;
RA Mencinger M., Panagopoluos I., Andreasson P., Lassen C., Mitelman F.,
RA Aman P.;
RT "Characterization and chromosomal mapping of the human TFG gene
RT involved in thyroid carcinoma.";
RL Genomics 41:327-331(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
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 MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R.,
RA Buhay C.J., Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R.,
RA Gunaratne P., Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V.,
RA Hume J., Jackson A., Khan Z.M., Kovar-Smith C., Lewis L.R.,
RA Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D., Wei S.,
RA Wheeler D.A., Wright M.W., Worley K.C., Yuan Y., Zhang Z., Adams C.Q.,
RA Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clendenning J., Clerc-Blankenburg K.P., Chen R., Chen Z., Davis C.,
RA Delgado O., Dinh H.H., Dong W., Draper H., Ernst S., Fu G.,
RA Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., Hao B.,
RA Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., Jackson L.R.,
RA Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., Liu J.,
RA Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., Palmeiri A.,
RA Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J.,
RA Zhang X., Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H.,
RA Reinhardt R., Naylor S.L., Yang H., Olson M., Weinstock G.,
RA Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain, Placenta, 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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-193, AND CHROMOSOMAL TRANSLOCATION
RP WITH NTRK1.
RX PubMed=7565764;
RA Greco A., Mariani C., Miranda C., Lupas A., Pagliardini S., Pomati M.,
RA Pierotti M.A.;
RT "The DNA rearrangement that generates the TRK-T3 oncogene involves a
RT novel gene on chromosome 3 whose product has a potential coiled-coil
RT domain.";
RL Mol. Cell. Biol. 15:6118-6127(1995).
RN [9]
RP PROTEIN SEQUENCE OF 1-10; 15-22; 24-42 AND 48-57, ACETYLATION AT
RP MET-1, AND MASS SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RA Bienvenut W.V., Calvo F., Kolch W.;
RL Submitted (FEB-2008) to UniProtKB.
RN [10]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-197, AND MASS
RP 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 [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND MASS SPECTROMETRY.
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 [12]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-197, AND MASS
RP 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 [13]
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 [14]
RP VARIANT [LARGE SCALE ANALYSIS] SER-149.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [15]
RP VARIANT HMSNP LEU-285, AND CHARACTERIZATION OF VARIANT HMSNP LEU-285.
RX PubMed=22883144; DOI=10.1016/j.ajhg.2012.07.014;
RA Ishiura H., Sako W., Yoshida M., Kawarai T., Tanabe O., Goto J.,
RA Takahashi Y., Date H., Mitsui J., Ahsan B., Ichikawa Y., Iwata A.,
RA Yoshino H., Izumi Y., Fujita K., Maeda K., Goto S., Koizumi H.,
RA Morigaki R., Ikemura M., Yamauchi N., Murayama S., Nicholson G.A.,
RA Ito H., Sobue G., Nakagawa M., Kaji R., Tsuji S.;
RT "The TRK-fused gene is mutated in hereditary motor and sensory
RT neuropathy with proximal dominant involvement.";
RL Am. J. Hum. Genet. 91:320-329(2012).
CC -!- INTERACTION:
CC O15162:PLSCR1; NbExp=2; IntAct=EBI-357061, EBI-740019;
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q92734-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q92734-2; Sequence=VSP_047131;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
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 may be involved in
CC disease pathogenesis. A chromosomal aberration involving TFG is
CC found in thyroid papillary carcinomas. Translocation
CC t(1;3)(q21;q11) with NTRK1. The TFG sequence is fused to the 3'-
CC end of NTRK1 generating the TRKT3 (TRK-T3) fusion transcript.
CC -!- DISEASE: Hereditary motor and sensory neuropathy, proximal type
CC (HMSNP) [MIM:604484]: A neurodegenerative disorder characterized
CC by young adult onset of proximal muscle weakness and atrophy,
CC muscle cramps, and fasciculations, with later onset of distal
CC sensory impairment. The disorder is slowly progressive and
CC clinically resembles amyotrophic lateral sclerosis. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/TFGID281.html";
CC -----------------------------------------------------------------------
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DR EMBL; Y07968; CAA69264.1; -; mRNA.
DR EMBL; AK093456; BAG52721.1; -; mRNA.
DR EMBL; BT007428; AAP36096.1; -; mRNA.
DR EMBL; CR456781; CAG33062.1; -; mRNA.
DR EMBL; AC068763; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471052; EAW79813.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79814.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79815.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79816.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79817.1; -; Genomic_DNA.
DR EMBL; BC001483; AAH01483.1; -; mRNA.
DR EMBL; BC009241; AAH09241.1; -; mRNA.
DR EMBL; BC023599; AAH23599.1; -; mRNA.
DR EMBL; X85960; CAA59936.1; ALT_TERM; mRNA.
DR RefSeq; NP_001007566.1; NM_001007565.2.
DR RefSeq; NP_001182407.1; NM_001195478.1.
DR RefSeq; NP_001182408.1; NM_001195479.1.
DR RefSeq; NP_006061.2; NM_006070.5.
DR RefSeq; XP_005247122.1; XM_005247065.1.
DR RefSeq; XP_005247123.1; XM_005247066.1.
DR UniGene; Hs.518123; -.
DR ProteinModelPortal; Q92734; -.
DR SMR; Q92734; 9-89.
DR IntAct; Q92734; 21.
DR MINT; MINT-1156489; -.
DR STRING; 9606.ENSP00000240851; -.
DR PhosphoSite; Q92734; -.
DR DMDM; 223634676; -.
DR PaxDb; Q92734; -.
DR PRIDE; Q92734; -.
DR DNASU; 10342; -.
DR Ensembl; ENST00000240851; ENSP00000240851; ENSG00000114354.
DR Ensembl; ENST00000418917; ENSP00000397182; ENSG00000114354.
DR Ensembl; ENST00000476228; ENSP00000417952; ENSG00000114354.
DR Ensembl; ENST00000490574; ENSP00000419960; ENSG00000114354.
DR GeneID; 10342; -.
DR KEGG; hsa:10342; -.
DR UCSC; uc003dug.3; human.
DR CTD; 10342; -.
DR GeneCards; GC03P100428; -.
DR H-InvDB; HIX0003505; -.
DR HGNC; HGNC:11758; TFG.
DR HPA; HPA019473; -.
DR MIM; 188550; phenotype.
DR MIM; 602498; gene.
DR MIM; 604484; phenotype.
DR neXtProt; NX_Q92734; -.
DR Orphanet; 209916; Extraskeletal myxoid chondrosarcoma.
DR Orphanet; 90117; Hereditary motor and sensory neuropathy, Okinawa type.
DR Orphanet; 146; Papillary or follicular thyroid carcinoma.
DR Orphanet; 320406; Spastic paraplegia-optic atrophy-neuropathy syndrome.
DR PharmGKB; PA36473; -.
DR eggNOG; NOG85275; -.
DR HOGENOM; HOG000132915; -.
DR HOVERGEN; HBG009087; -.
DR InParanoid; Q92734; -.
DR KO; K09292; -.
DR OMA; IQYSAGY; -.
DR OrthoDB; EOG7TXKJH; -.
DR PhylomeDB; Q92734; -.
DR SignaLink; Q92734; -.
DR ChiTaRS; TFG; human.
DR GeneWiki; TFG_(gene); -.
DR GenomeRNAi; 10342; -.
DR NextBio; 18907; -.
DR PRO; PR:Q92734; -.
DR ArrayExpress; Q92734; -.
DR Bgee; Q92734; -.
DR CleanEx; HS_TFG; -.
DR Genevestigator; Q92734; -.
DR GO; GO:0005737; C:cytoplasm; NAS:UniProtKB.
DR GO; GO:0004871; F:signal transducer activity; IMP:UniProtKB.
DR GO; GO:0008219; P:cell death; IEA:UniProtKB-KW.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IMP:UniProtKB.
DR InterPro; IPR000270; OPR_PB1.
DR Pfam; PF00564; PB1; 1.
DR SMART; SM00666; PB1; 1.
PE 1: Evidence at protein level;
KW Acetylation; Alternative splicing; Chromosomal rearrangement;
KW Coiled coil; Complete proteome; Direct protein sequencing;
KW Disease mutation; Neurodegeneration; Neuropathy; Phosphoprotein;
KW Polymorphism; Proto-oncogene; Reference proteome.
FT CHAIN 1 400 Protein TFG.
FT /FTId=PRO_0000072500.
FT COILED 97 124 Potential.
FT SITE 193 194 Breakpoint for translocation to form TRK-
FT T3.
FT MOD_RES 1 1 N-acetylmethionine.
FT MOD_RES 197 197 Phosphoserine.
FT VAR_SEQ 237 240 Missing (in isoform 2).
FT /FTId=VSP_047131.
FT VARIANT 43 43 V -> F (in dbSNP:rs15245).
FT /FTId=VAR_059731.
FT VARIANT 149 149 A -> S (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035668.
FT VARIANT 211 211 A -> V (in dbSNP:rs430945).
FT /FTId=VAR_054322.
FT VARIANT 285 285 P -> L (in HMSNP; results in
FT mislocalization and TARDBP-inclusion-body
FT formation in cultured cells).
FT /FTId=VAR_068917.
FT VARIANT 364 364 T -> P (in dbSNP:rs6772054).
FT /FTId=VAR_054323.
FT CONFLICT 13 13 I -> V (in Ref. 1; CAA69264 and 8;
FT CAA59936).
SQ SEQUENCE 400 AA; 43448 MW; D8A559D0F7314D1F CRC64;
MNGQLDLSGK LIIKAQLGED IRRIPIHNED ITYDELVLMM QRVFRGKLLS NDEVTIKYKD
EDGDLITIFD SSDLSFAIQC SRILKLTLFV NGQPRPLESS QVKYLRRELI ELRNKVNRLL
DSLEPPGEPG PSTNIPENDT VDGREEKSAS DSSGKQSTQV MAASMSAFDP LKNQDEINKN
VMSAFGLTDD QVSGPPSAPA EDRSGTPDSI ASSSSAAHPP GVQPQQPPYT GAQTQAGQIE
GQMYQQYQQQ AGYGAQQPQA PPQQPQQYGI QYSASYSQQT GPQQPQQFQG YGQQPTSQAP
APAFSGQPQQ LPAQPPQQYQ ASNYPAQTYT AQTSQPTNYT VAPASQPGMA PSQPGAYQPR
PGFTSLPGST MTPPPSGPNP YARNRPPFGQ GYTQPGPGYR
//

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.

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10. Chua, E. L.; Wu, W. M.; Tran, K. T.; McCarthy, S. W.; Lauer, C.
S.; Dubourdieu, D.; Packham, N.; O'Brien, C. J.; Turtle, J. R.; Dong,
Q.: Prevalence and distribution of ret/ptc 1, 2, and 3 in papillary
thyroid carcinoma in New Caledonia and Australia. J. Clin. Endocr.
Metab. 85: 2733-2739, 2000.

11. Ciampi, R.; Knauf, J. A.; Kerler, R.; Gandhi, M.; Zhu, Z.; Nikiforova,
M. N.; Rabes, H. M.; Fagin, J. A.; Nikiforov, Y. E.: Oncogenic AKAP9-BRAF
fusion is a novel mechanism of MAPK pathway activation in thyroid
cancer. J. Clin. Invest. 115: 94-101, 2005.

12. Corvi, R.; Berger, N.; Balczon, R.; Romeo, G.: RET/PCM-1: a novel
fusion gene in papillary thyroid carcinoma. Oncogene 19: 4236-4242,
2000.

13. Denny, J. C.; Crawford, D. C.; Ritchie, M. D.; Bielinski, S. J.;
Basford, M. A.; Bradford, Y.; Chai, H. S.; Bastarache, L.; Zuvich,
R.; Peissig, P.; Carrell, D.; Ramirez, A. H.; and 22 others: Variants
near FOXE1 are associated with hypothyroidism and other thyroid conditions:
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J. Hum. Genet. 89: 529-542, 2011.

14. Elisei, R.; Romei, C.; Vorontsova, T.; Cosci, B.; Veremeychik,
V.; Kuchinskaya, E.; Basolo, F.; Demidchik, E. P.; Miccoli, P.; Pinchera,
A.; Pacini, F.: RET/PTC rearrangements in thyroid nodules: studies
in irradiated and not irradiated, malignant and benign thyroid lesions
in children and adults. J. Clin. Endocr. Metab. 86: 3211-3216, 2001.

15. Fenton, C. L.; Lukes, Y.; Nicholson, D.; Dinauer, C. A.; Francis,
G. L.; Tuttle, R. M.: The ret/PTC mutations are common in sporadic
papillary thyroid carcinoma of children and young adults. J. Clin.
Endocr. Metab. 85: 1170-1175, 2000.

16. Finn, S. P.; Smyth, P.; O'Leary, J.; Sweeney, E. C.; Sheils, O.
: Ret/PTC chimeric transcripts in an Irish cohort of sporadic papillary
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17. Flannigan, G. M.; Clifford, R. P.; Winslet, M.; Lawrence, D. A.
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18. Fortunati, N.; Catalano, M. G.; Arena, K.; Brignardello, E.; Piovesan,
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19. Frau, D. V.; Lai, M. L.; Caria, P.; Dettori, T.; Coni, P.; Faa,
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20. Grossman, R. F.; Tu, S.-H.; Duh, Q.-Y.; Siperstein, A. E.; Novosolov,
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21. Gudmundsson, J.; Sulem, P.; Gudbjartsson, D. F.; Jonasson, J.
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22. Harach, H. R.; Williams, G. T.; Williams, E. D.: Familial adenomatous
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23. Herrmann, M. A.; Hay, I. D.; Bartelt, D. H., Jr.; Ritland, S.
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24. Hrafnkelsson, J.; Tulinius, H.; Jonasson, J. G.; Olafsdottir,
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25. Jendrzejewski, J.; He, H.; Radomska, H. S.; Li, W.; Tomsic, J.;
Liyanarachchi, S.; Davuluri, R. V.; Nagy, R.; de la Chapelle, A.:
The polymorphism rs944289 predisposes to papillary thyroid carcinoma
through a large intergenic noncoding RNA gene of tumor suppressor
type. Proc. Nat. Acad. Sci. 109: 8646-8651, 2012.

26. Jenkins, R. B.; Hay, I. D.; Herath, J. F.; Schultz, C. G.; Spurbeck,
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of cytogenetic abnormalities in sporadic nonmedullary thyroid carcinoma. Cancer 66:
1213-1220, 1990.

27. Kimura, E. T.; Nikiforova, M. N.; Zhu, Z.; Knauf, J. A.; Nikiforov,
Y. E.; Fagin, J. A.: High prevalence of BRAF mutations in thyroid
cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF
signaling pathway in papillary thyroid carcinoma. Cancer Res. 63:
1454-1457, 2003.

28. Klein, M.; Vignaud, J.-M.; Hennequin, V.; Toussaint, B.; Bresler,
L.; Plenat, F.; Leclere, J.; Duprez, A.; Weryha, G.: Increased expression
of the vascular endothelial growth factor is a pejorative prognosis
marker in papillary thyroid carcinoma. J. Clin. Endocr. Metab. 86:
656-658, 2001.

29. Klugbauer, S.; Demidchik, E. P.; Lengfelder, E.; Rabes, H. M.
: Detection of a novel type of RET rearrangement (PTC5) in thyroid
carcinomas after Chernobyl and analysis of the involved RET-fused
gene RFG5. Cancer Res. 58: 198-203, 1998.

30. Klugbauer, S.; Rabes, H. M.: The transcription coactivator HTIF1
and a related protein are fused to the RET receptor tyrosine kinase
in childhood papillary thyroid carcinomas. Oncogene 18: 4388-4393,
1999.

31. Lacour, J.; Vignalou, J.; Perez, R.; Gerard-Marchant, R.: Epithelioma
papillaire du corps thyroide; a propos de deux cas familiaux. Nouv.
Presse Med. 2: 2249-2252, 1973.

32. Learoyd, D. L.; Messina, M.; Zedenius, J.; Guinea, A. I.; Delbridge,
L. W.; Robinson, B. G.: RET/PTC and RET tyrosine kinase expression
in adult papillary thyroid carcinomas. J. Clin. Endocr. Metab. 83:
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
from 2 families with associated lymphocytic thyroiditis harbouring
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,
S.: Clinical implication of hot spot BRAF mutation, V599E, in papillary
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
the blood of thyroid cancer patients. J. Clin. Endocr. Metab. 87:
635-639, 2002.

43. Stoffer, S. S.; Bach, J. V.; Van Dyke, D. L.; Szpunar, W.; Weiss,
L.: Familial papillary carcinoma of the thyroid (FPCT): is it autosomal
dominant? (Abstract) Am. J. Hum. Genet. 37: A40 only, 1985.

44. Stoffer, S. S.; Van Dyke, D. L.; Bach, J. V.; Szpunar, W.; Weiss,
L.: Familial papillary carcinoma of the thyroid. Am. J. Med. Genet. 25:
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.

49. Vriens, M. R.; Suh, I.; Moses, W.; Kebebew, E.: Clinical features
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
cytology: diagnostic synergy for detecting thyroid cancer. J. Clin.
Endocr. Metab. 90: 1921-1924, 2005.

51. Xing, M.; Tufano, R. P.; Tufaro, A. P.; Basaria, S.; Ewertz, M.;
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 602498
*RECORD*
*FIELD* NO
602498
*FIELD* TI
*602498 TRK-FUSED GENE; TFG
TRKT3 ONCOGENE, INCLUDED;;
TFG/NTRK1 FUSION GENE, INCLUDED;;
read moreTFG/NR4A3 FUSION GENE, INCLUDED
*FIELD* TX

CLONING

Mencinger et al. (1997) identified the complete TFG gene by searching
for ESTs that were similar to the N-terminal regions of EWS (133450) and
FUS (137070). TFG encodes a predicted 400-amino acid protein with a
putative N-terminal coiled-coil region. On Northern blots, the 2.2-kb
TFG mRNA was expressed in all tissues tested. Greco et al. (1995) stated
that a coiled-coil structure and ubiquitous expression are features
shared by all NTRK1-activating genes as well as genes that activate
other tyrosine kinase protooncogenes.

By PCR-based cloning of a cDNA library from a fetal brain, Ishiura et
al. (2012) identified 4 TFG isoforms generated by alternative splicing.
TFG was ubiquitously expressed, including in the spinal cord and dorsal
root ganglia. Immunohistochemical studies showed fine granular
immunostaining of TFG in the cytoplasm of motor neurons in the spinal
cord of neurologically normal human controls.

GENE STRUCTURE

Ishiura et al. (2012) demonstrated that the TFG gene contains 8 exons;
they also identified a new exon, 7b, which is included in some of the
transcripts.

MAPPING

Greco et al. (1995) localized the TFG gene to chromosome 3 by PCR of a
hybrid panel. Mencinger et al. (1997) mapped the TFG gene to 3q11-q12 by
fluorescence in situ hybridization.

CYTOGENETICS

- TFG/NTRK1 Fusion Gene

Greco et al. (1995) stated that approximately 50% of papillary thyroid
carcinomas (188550) are associated with rearrangements of the RET
(164761) and NTRK1 (191315) transmembrane receptor tyrosine kinase
protooncogenes. The rearrangements juxtapose the tyrosine kinase domain
to 5-prime sequences from unrelated loci, yielding chimeric proteins
with ectopic, constitutive tyrosine kinase activity. In one tumor, Greco
et al. (1995) found a chimeric oncogene, which they designated TRKT3, in
which 1,412 nucleotides of the NTRK1 gene were fused to 598 nucleotides
from the TFG gene. Greco et al. (1995) determined that the TRKT3
oncogene encodes a predicted 592-amino acid chimeric protein that forms
multimeric complexes in vivo.

- TFG/NR4A3 Fusion Gene

Hisaoka et al. (2004) identified an NR4A3 (600542)/TFG fusion gene in an
extraskeletal myxoid chondrosarcoma (EMC; 612237) derived from a
Japanese patient. The fusion occurred between exon 6 of the TFG gene and
exon 3 of the NR4A3 gene. Hisaoka et al. (2004) used the symbol NOR1 for
the NR4A3 gene.

MOLECULAR GENETICS

In affected members of 4 Japanese families with proximal hereditary
motor and sensory neuropathy (HMSNP; 604484), Ishiura et al. (2012)
identified a heterozygous mutation in the TFG gene (P285L; 602498.0001).
Two of the families were from the Kansai region (Maeda et al., 2007) and
2 were from Okinawa. The mutation was found by exome capture of the
candidate region identified by linkage analysis. Expression of the
mutant TFG protein resulted in mislocalization and TDP43 (TARDBP;
605078)-inclusion-body formation in cultured cells. These findings
suggested a pathogenic link to amyotrophic lateral sclerosis (ALS;
105400), in which TDP43 inclusions are found, and suggested that
alteration of vesicle trafficking or RNA-mediated mechanisms might be
involved in motor neuron degeneration in HMSNP.

Lee et al. (2013) identified a heterozygous P285L mutation in the TFG
gene in affected members of a Korean family with HMSNP. The mutation,
which was found by whole-exome sequencing and confirmed by Sanger
sequencing, segregated with the disorder in the family and was not found
in several large control databases. TFG levels in patient peripheral
nerves were similar to those in controls. The phenotype was
characterized by young adult onset of proximal muscle weakness, with
cramping and fasciculations, and distal sensory impairment. Some of the
patients had hand tremor early in the disease course, and MRI showed
fatty infiltration in proximal muscles of the lower limbs.

*FIELD* AV
.0001
HEREDITARY MOTOR AND SENSORY NEUROPATHY, PROXIMAL TYPE
TFG, PRO285LEU

In affected members of 4 Japanese families with proximal hereditary
motor and sensory neuropathy (HMSNP; 604484), Ishiura et al. (2012)
identified a heterozygous 854C-T transition in the TFG gene, resulting
in a pro285-to-leu (P285L) substitution at a highly conserved residue in
the P/Q-rich domain in the C-terminal region. The mutation was not
observed in 964 Japanese control chromosomes or in several exome
databases. Two of the families were from the Kansai region and 2 were
from Okinawa, and haplotype analysis suggested 2 independent origins of
the mutation. The disorder was characterized clinically by young adult
onset of proximal muscle weakness and atrophy, muscle cramps, and
fasciculations, with later onset of distal sensory impairment.
Neuropathologic examination of 1 patient showed TFG-immunopositive
inclusion bodies in the motor neurons of the facial, hypoglossal, and
abducens nuclei, and the spinal cord, as well as in the sensory neurons
of the dorsal root ganglia. Inclusions were not found in glial cells.
The TFG-immunopositive inclusions colocalized with ubiquitin deposition.
In addition, phosphorylated TDP43 (605078)-positive inclusions were
identified in motor and sensory neurons in the spinal cord; some
inclusions were positive for both TFG and TDP43. There was also
fragmentation of the Golgi apparatus in HMSNP motor neurons. Expression
of the mutant TFG protein resulted in mislocalization and
TDP43-inclusion-body formation in cultured cells. These findings
suggested a pathogenic link to amyotrophic lateral sclerosis (ALS;
105400), in which TDP43 inclusions are found, and suggested that
alteration of vesicle trafficking or RNA-mediated mechanisms might be
involved in motor neuron degeneration in HMSNP.

Lee et al. (2013) identified a heterozygous P285L mutation in the TFG
gene in affected members of a Korean family with HMSNP. The mutation,
which was found by whole-exome sequencing and confirmed by Sanger
sequencing, segregated with the disorder in the family and was not found
in several large control databases. TFG levels in patient peripheral
nerves were similar to those in controls. The phenotype was
characterized by young adult onset of proximal muscle weakness with
cramping and fasciculations, and distal sensory impairment. Some of the
patients had hand tremor early in the disease course, and MRI showed
fatty replacement in proximal muscles of the lower limbs.

*FIELD* RF
1. Greco, A.; Mariani, C.; Miranda, C.; Lupas, A.; Pagliardini, S.;
Pomati, M.; Pierotti, M. A.: The DNA rearrangement that generates
the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product
has a potential coiled-coil domain. Molec. Cell Biol. 15: 6118-6127,
1995.

2. Hisaoka, M.; Ishida, T.; Imamura, T.; Hashimoto, H.: TFG is a
novel fusion partner of NOR1 in extraskeletal myxoid chondrosarcoma. Genes
Chromosomes Cancer 40: 325-328, 2004.

3. Ishiura, H.; Sako, W.; Yoshida, M.; Kawarai, T.; Tanabe, O.; Goto,
J.; Takahashi, Y.; Date, H.; Mitsui, J.; Ahsan, B.; Ichikawa, Y.;
Iwata, A.; and 16 others: The TRK-fused gene is mutated in hereditary
motor and sensory neuropathy with proximal dominant involvement. Am.
J. Hum. Genet. 91: 320-329, 2012.

4. Lee, S.-S.; Lee, H. J.; Park, J.-M.; Hong, Y. B.; Park, K.-D.;
Yoo, J. H.; Koo, H.; Jung, S.-C.; Park, H. S.; Lee, J. H.; Lee, M.
G.; Hyun, Y. S.; Nakhro, K.; Chung, K. W.; Choi, B.-O.: Proximal
dominant hereditary motor and sensory neuropathy with proximal dominance
association with mutation in the TRK-fused gene. JAMA Neurol. 70:
607-615, 2013.

5. Maeda, K.; Kaji, R.; Yasuno, K.; Jambaldorj, J.; Nodera, H.; Takashima,
H.; Nakagawa, M.; Makino, S.; Tamiya, G.: Refinement of a locus for
autosomal dominant hereditary motor and sensory neuropathy with proximal
dominancy (HMSN-P) and genetic heterogeneity. J. Hum. Genet. 52:
907-914, 2007.

6. Mencinger, M.; Panagopoulos, I.; Andreasson, P.; Lassen, C.; Mitelman,
F.; Aman, P.: Characterization and chromosomal mapping of the human
TFG gene involved in thyroid carcinoma. Genomics 41: 327-331, 1997.

*FIELD* CN
Cassandra L. Kniffin - updated: 9/5/2013
Cassandra L. Kniffin - updated: 9/12/2012

*FIELD* CD
Rebekah S. Rasooly: 4/6/1998

*FIELD* ED
carol: 09/06/2013
tpirozzi: 9/6/2013
ckniffin: 9/5/2013
carol: 9/12/2012
ckniffin: 9/12/2012
carol: 8/20/2008
ckniffin: 8/14/2008
alopez: 6/14/1999
alopez: 4/9/1998
alopez: 4/6/1998

MIM 604484
*RECORD*
*FIELD* NO
604484
*FIELD* TI
#604484 HEREDITARY MOTOR AND SENSORY NEUROPATHY, PROXIMAL TYPE; HMSNP
;;NEUROPATHY, HEREDITARY MOTOR AND SENSORY, OKINAWA TYPE; HMSNO
read more*FIELD* TX
A number sign (#) is used with this entry because proximal hereditary
motor and sensory neuropathy (HMSNP) is caused by heterozygous mutation
in the TFG gene (602498) on chromosome 3q.

DESCRIPTION

HMSNP is an autosomal dominant neurodegenerative disorder characterized
by young adult onset of proximal muscle weakness and atrophy, muscle
cramps, and fasciculations, with later onset of distal sensory
impairment. The disorder is slowly progressive and clinically resembles
amyotrophic lateral sclerosis (ALS; 105400) (summary by Ishiura et al.,
2012).

CLINICAL FEATURES

Takashima et al. (1997) reported an autosomal dominant form of
hereditary motor and sensory neuropathy with dominant proximal
involvement (HMSNP). There were 23 patients from 8 families, all from
Okinawa, Japan. The characteristics of the disorder included adult-onset
proximal neurogenic atrophy, sensory involvement, painful muscle cramps,
fasciculations, areflexia, and high incidences of elevated creatine
kinase levels, hyperlipidemia, and diabetes mellitus. The clinical
features resembled those of Kennedy syndrome (313200), although the mode
of inheritance was different (autosomal dominant, not X-linked), and
HMSNP had been reported only in Okinawa, Japan. Neuropathologic analysis
revealed decreased numbers of anterior horn cells and marked loss of
myelinated fibers in the posterior funiculus.

Maeda et al. (2007) reported 2 large families from a small mountain
village in the Kansai area of mainland Japan with an autosomal dominant
phenotype similar to HMSN-P. The families consisted of 5 to 6
generations with a total of at least 40 affected individuals. The
average age at onset was 37.5 years. Features included gradual
progression of proximal muscle weakness and atrophy, painful muscle
cramps, fasciculations, areflexia, and distal sensory loss. Pathology
showed loss of axons in the peripheral nerves, as well as loss of
anterior horn and dorsal root ganglion cells. Fujita et al. (2011)
reported the neuropathologic findings of 1 of the patients reported by
Maeda et al. (2007) who died of pneumonia at age 67 years. The disorder
in this patient had progressed, and he was bedridden with bulbar
weakness and dysphagia. He also had extensor plantar responses,
areflexia, and distal sensory impairment. There was marked atrophy of
the spinal cord roots, neuronal loss and gliosis in brainstem nuclei,
severe neuronal loss in the anterior horns of the spinal cord, and loss
of myelinated fibers in the corticospinal and spinocerebellar tracts and
posterior column. The sural nerve showed decreased numbers of myelinated
fibers. Immunohistochemistry revealed ubiquitin- and optineurin (OPTN;
602432)-positive neuronal inclusions. However, TDP43 (TARDBP;
605078)-positive inclusions were not observed. The findings indicated
that the disorder has features in common with motor neuron diseases,
such as spinal muscular atrophy and ALS, and Fujita et al. (2011)
proposed that it be considered a familial motor neuron disease with
sensory neuronopathy rather than a form of HMSN.

Maeda et al. (2007) reported 3 adult brothers with HMSNP. They lived in
Brazil, but their parents were from Okinawa, Japan. Each presented in
the early forties with proximal muscle weakness affecting the upper and
lower limbs, muscle cramps, and fasciculations. Although only 1 reported
distal sensory impairment, all had decreased reflexes and decreased
sensory nerve action potentials. EMG showed neurogenic changes, and
serum creatine kinase was increased. One of the patients had been
diagnosed with spinal muscular atrophy, and Maeda et al. (2007) noted
that the phenotype also resembled ALS. Since individuals have emigrated
from Okinawa to South America since 1908, neurologists in such places
should be aware of this hereditary neuropathy.

Patroclo et al. (2009) reported 4 Brazilian brothers with HMSNP. Their
grandparents had immigrated to Brazil from Okinawa, Japan. All had onset
after age 30 years of muscle cramps and weakness affecting the upper and
lower proximal muscles. There was slow progression, resulting in
muscular atrophy of affected muscles. Other features included areflexia,
distal sensory impairment, myotonia in the hands, fasciculations, and
dysphagia. Two patients were wheelchair-bound in their late fifties. EMG
showed neurogenic changes, and all had electrophysiologic evidence of an
axonal motor and sensory polyneuropathy. Laboratory studies showed
increased serum creatine kinase and variable dyslipidemia. Sural nerve
biopsy of 2 patients showed reduction of nerve fibers, focal thickening
of the myelin sheath, and abnormal mitochondria. Muscle biopsy of 1
patient showed neurogenic atrophy. Their deceased father was reportedly
affected, consistent with autosomal dominant inheritance.

Ishiura et al. (2012) reported 2 new families from Okinawa, Japan, with
HMSNP. Affected individuals had features similar to those reported by
Takashima et al. (1997) and Maeda et al. (2007). The initial stage of
the disorder was characterized by painful muscle cramps and
fasciculations. Although some patients reported the painful cramps in
their twenties, most had onset of motor weakness in the early forties.
There was slowly progressive, predominantly proximal weakness and
atrophy with diminished tendon reflexes in the lower extremities.
Sensory impairment was generally mild. Laboratory studies showed mildly
increased serum creatine kinase, and electrophysiologic studies showed a
decreased number of motor units with abundant positive sharp waves,
fibrillation, and fasciculation potentials. Sensory-nerve action
potentials of the sural nerve were lost in the later stage of the
disease. Neuropathologic examination of 1 patient (Fujita et al., 2011)
showed TFG-immunopositive inclusion bodies in the motor neurons of the
facial, hypoglossal, and abducens nuclei, and the spinal cord, as well
as in the sensory neurons of the dorsal root ganglia. Inclusions were
not found in glial cells. The TFG-immunopositive inclusions colocalized
with ubiquitin deposition. In addition, phosphorylated TDP43-positive
inclusions were identified in some motor and sensory neurons in the
spinal cord; some inclusions were positive for both TFG and TDP43. There
was also fragmentation of the Golgi apparatus in HMSNP motor neurons.

Lee et al. (2013) reported a large Korean family with autosomal dominant
HMSNP. Affected individuals had adult onset (range, 27-48 years) of
proximal muscle weakness, with cramping and fasciculations, and distal
sensory impairment. Some of the patients had hand tremor early in the
disease course, and MRI showed fatty infiltration in proximal muscles of
the lower limbs. Laboratory studies showed hyperlipidemia and mildly
increased serum creatine kinase. Sural nerve biopsy showed absence of
large myelinated fibers, irregular thickness of myelin, and regenerating
axonal clusters. Endoneural blood vessels of 2 patients showed swollen
vesicular endothelial cells and narrowed lumens. Bulbar signs and pes
cavus were not present.

MAPPING

Takashima et al. (1997) mapped the disease locus to a 41-cM region on
chromosome 3p14.1-q13 with a maximum lod score of 4.04 and 3.10 for
D3S1284 and D3S1591, respectively. The presence of a common allele of
marker D3S1591 and the geographic specificity of the disease suggested
linkage disequilibrium and a single founder. To further narrow the
localization, Takashima et al. (1999) used the linkage disequilibrium
method. They showed that the locus maps to a 3.1-cM interval bracketed
by D3S1591 and D3S1281. Using 9 marker loci jointly, they demonstrated a
lod score of 4.93. Consequently, they concluded that the locus almost
certainly lies on chromosome 3q13.1.

By linkage analysis of 2 large families from Kansai, Japan, Maeda et al.
(2007) identified a candidate region on chromosome 3q13.1 (maximum
2-point lod score of 8.44) that overlapped with the locus identified by
Takashima et al. (1999). The findings indicated that the causative gene
likely resides in a 7.3-Mb interval between D3S1488i and D3S1083i. The
disease haplotype shared among all affected members of the Kansai
kindreds differed from that of the Okinawa kindred, suggesting allelic
heterogeneity. Kansai is located about 1,200 km from Okinawa, and there
is no record of migration or affinal connection between the 2 areas.

MOLECULAR GENETICS

In affected members of 4 Japanese families with proximal hereditary
motor and sensory neuropathy, Ishiura et al. (2012) identified a
heterozygous mutation in the TFG gene (P285L; 602498.0001). Two of the
families were from the Kansai region (Maeda et al., 2007) and 2 were
from Okinawa. Haplotype analysis suggested 2 independent origins of the
mutation. The mutation was found by exome capture of the candidate
region identified by linkage analysis. Expression of the mutant TFG
protein resulted in mislocalization and TDP43-inclusion-body formation
in cultured cells. These findings suggested a pathogenic link to ALS, in
which TDP43 inclusions are found, and suggested that alteration of
vesicle trafficking or RNA-mediated mechanisms might be involved in
motor neuron degeneration in HMSNP.

Lee et al. (2013) identified a heterozygous P285L mutation in the TFG
gene in affected members of a Korean family with HMSNP. The mutation,
which was found by whole-exome sequencing and confirmed by Sanger
sequencing, segregated with the disorder in the family and was not found
in several large control databases. TFG levels in patient peripheral
nerves were similar to controls.

*FIELD* RF
1. Fujita, K.; Yoshida, M.; Sako, W.; Maeda, K.; Hashizume, Y.; Goto,
S.; Sobue, G.; Izumi, Y.; Kaji, R.: Brainstem and spinal cord motor
neuron involvement with optineurin inclusions in proximal-dominant
hereditary motor and sensory neuropathy. (Letter) J. Neurol. Neurosurg.
Psychiat. 82: 1402-1403, 2011.

2. Ishiura, H.; Sako, W.; Yoshida, M.; Kawarai, T.; Tanabe, O.; Goto,
J.; Takahashi, Y.; Date, H.; Mitsui, J.; Ahsan, B.; Ichikawa, Y.;
Iwata, A.; and 16 others: The TRK-fused gene is mutated in hereditary
motor and sensory neuropathy with proximal dominant involvement. Am.
J. Hum. Genet. 91: 320-329, 2012.

3. Lee, S.-S.; Lee, H. J.; Park, J.-M.; Hong, Y. B.; Park, K.-D.;
Yoo, J. H.; Koo, H.; Jung, S.-C.; Park, H. S.; Lee, J. H.; Lee, M.
G.; Hyun, Y. S.; Nakhro, K.; Chung, K. W.; Choi, B.-O.: Proximal
dominant hereditary motor and sensory neuropathy with proximal dominance
association with mutation in the TRK-fused gene. JAMA Neurol. 70:
607-615, 2013.

4. Maeda, K.; Kaji, R.; Yasuno, K.; Jambaldorj, J.; Nodera, H.; Takashima,
H.; Nakagawa, M.; Makino, S.; Tamiya, G.: Refinement of a locus for
autosomal dominant hereditary motor and sensory neuropathy with proximal
dominancy (HMSN-P) and genetic heterogeneity. J. Hum. Genet. 52:
907-914, 2007.

5. Maeda, K.; Sugiura, M.; Kato, H.; Sanada, M.; Kawai, H.; Yasuda,
H.: Hereditary motor and sensory neuropathy (proximal dominant form,
HMSN-P) among Brazilians of Japanese ancestry. Clin. Neurol. Neurosurg. 109:
830-832, 2007.

6. Patroclo, C. B.; Lino, A. M. M.; Marchiori, P. E.; Brotto, M. W.
I.; Hirata, M. T. A.: Autosomal dominant HMSN with proximal involvement:
new Brazilian cases. Arq. Neuropsiquiatr. 67: 892-896, 2009.

7. Takashima, H.; Nakagawa, M.; Nakahara, K.; Suehara, M.; Matsuzaki,
T.; Higuchi, I.; Higa, H.; Arimura, K.; Iwamasa, T.; Izumo, S.; Osame,
M.: A new type of hereditary motor and sensory neuropathy linked
to chromosome 3. Ann. Neurol. 41: 771-780, 1997.

8. Takashima, H.; Nakagawa, M.; Suehara, M.; Saito, M.; Saito, A.;
Kanzato, N.; Matsuzaki, T.; Hirata, K.; Terwilliger, J. D.; Osame,
M.: Gene for hereditary motor and sensory neuropathy (proximal dominant
form) mapped to 3q13.1. Neuromusc. Disord. 9: 368-371, 1999.

*FIELD* CS
INHERITANCE:
Autosomal dominant

MUSCLE, SOFT TISSUE:
Muscle weakness and atrophy, proximal;
Painful muscle cramps;
Fasciculations;
Neurogenic changes seen on EMG and biopsy;
Fatty replacement in hip muscles and proximal muscles of the lower
limb seen on MRI

NEUROLOGIC:
[Central nervous system];
Gait disturbance;
Bulbar symptoms may occur (less common);
Hand tremor (in some patients);
Loss of anterior horn cells;
Loss of dorsal root ganglion cells;
Loss of myelinated fibers in spinal cord roots;
Gliosis;
TFG- and TDP43-positive intraneuronal inclusions in some sensory and
motor spinal cord neurons;
[Peripheral nervous system];
Axonal motor and sensory neuropathy;
Distal sensory loss;
Hypo- or areflexia;
Mild loss of touch and temperature;
More severe loss of position and vibration;
Tetraplegia in advanced disease;
Loss of peripheral nerve axons;
Loss of myelinated fibers;
Axonal degeneration seen on nerve conduction studies

LABORATORY ABNORMALITIES:
Mildly increased serum creatine kinase;
Hyperlipidemia

MISCELLANEOUS:
Adult onset (27 to 48 years);
Slow progression;
Some patients may become bedridden 10 to 20 years after onset;
Prevalent among individuals of Japanese descent

MOLECULAR BASIS:
Caused by mutation in the TRK-fused gene (TFG, 602498.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 9/5/2013
Cassandra L. Kniffin - updated: 9/12/2012

*FIELD* CD
Cassandra L. Kniffin: 12/28/2007

*FIELD* ED
joanna: 09/24/2013
ckniffin: 9/5/2013
joanna: 9/28/2012
ckniffin: 9/12/2012
ckniffin: 12/28/2007

*FIELD* CN
Cassandra L. Kniffin - updated: 9/5/2013
Cassandra L. Kniffin - updated: 9/12/2012
Cassandra L. Kniffin - updated: 12/28/2007

*FIELD* CD
Victor A. McKusick: 1/31/2000

*FIELD* ED
carol: 10/22/2013
carol: 9/6/2013
tpirozzi: 9/6/2013
ckniffin: 9/5/2013
carol: 9/12/2012
ckniffin: 9/12/2012
wwang: 1/22/2008
ckniffin: 12/28/2007
joanna: 3/19/2004
terry: 10/4/2000
mgross: 1/31/2000