Background
Common genetic determinants of thyroid cancer subtypes
Chromosomal location | DbSNP identification No. | Gene | Gene function | Cancer type | Tested population | Literature |
---|---|---|---|---|---|---|
1p31.3 | rs334725 |
NFIA
| Nuclear transcription factor | PTC, FTC | Icelandic, American, Dutch, Spanish | Gudmundsson et al., 2012 |
1q42.2 | rs12129938 |
PCNXL2
| Correlated with tumorigenesis of colorectal carcinomas | DTC | Icelandic, American, Spanish, Dutch | Gudmundsson et al., 2017 |
2q35 | rs966423, rs6759952 |
DIRC3
| lincRNA | PTC, FTC | Icelandic, American, Dutch, Spanish, Polish | Gudmundsson et al., 2012, Liyanarachchi et al., 2013 |
DTC | Italian, Polish, Spanish, English | Köhler et al., 2013 | ||||
3q25.32 | rs7617304 |
RARRES1
| Membrane protein gene responsive to retinoid acid | DTC | Italian | Köhler et al., 2013 |
3q26.2 | rs6793295 | LRCC34 near TERC (missense) | RNA telomerase | PTC, FTC | Icelandic, American, Spanish, Dutch | Gudmundsson et al., 2017 |
4q34.3 | rs17739370 TT variant |
NEIL3
| DNA repair, BER | DTC | Italian | Cipollini et al., 2016 |
5q22.1 | rs73227498 | NREP and EPB41L4A | Intergenic region | PTC, FTC | Icelandic, American, Spanish, Dutch | Gudmundsson et al., 2017 |
5 | rs13184587 | ARSB intron | Intron of lysosomal sulfatase | DTC | Italian | Figlioli et al., 2014 |
7q21 | rs10238549, rs7800391 |
IMMP2L
| Processing of signal peptides in mitochondrial membrane | DTC | Italian | Köhler et al., 2013 |
8p12 | rs2439302 |
NRG1
| membrane glycoprotein, signaling mediator | PTC, FTC | Icelandic, American, Dutch, Spanish | Gudmundsson et al., 2012 |
8q24 | rs6983267 | ncRNA | N/A | PTC | English | Jones et al., 2012 |
9q3.3 | rs10781500 |
SNAPC4
| Large subunit of the DNAP complex | DTC | Italian | Köhler et al., 2013 |
9q22.33 | rs965513, rs1867277 (5’UTR region), rs71369530 | Proximity to FOXE1 | Deregulation of thyroid morphogenesis | PTC | Icelandic, Caucasian, Asian, Cuban, English, Belarussian, French Polynesian | Jones et al., 2012, Gudmundsson et al., 2009, Liyanarachchi et al., 2013, Damiola et al., 2014, Wang et al., 2016, Pereda et al., 2015, Maillard et al., 2015 |
10q24.33 | rs7902587 | near OBFC1 | Stimulator of DNA replication initiation factor | PTC, FTC | Icelandic, American, Spanish, Dutch | Gudmundsson et al., 2017 |
11 | rs1801516 |
ATM
| Cell-cycle checkpoint, response to DNA damage | DTC | Cuban women after multiple pregnancies, French Polynesian | Pereda et al., 2015, Maillard et al., 2015 |
13 | rs1220597 | SPATA13 intron | Regulation of cell migration and adhesion, guanine nucleotide exchange factor | DTC | Italian | Figlioli et al., 2014 |
14q13.3 | rs116909374 |
NKX2–1
| Thyroid-specific transcription factor | PTC, FTC | Icelandic, American, Dutch, Spanish, Polish | Gudmundsson et al., 2012, Liyanarachchi et al., 2013 |
14q13.3 | rs944289 | Close to NKX2–1 | Thyroid-specific transcription factor | PTC, FTC | Icelandic, Cuban, English, American, Polish, French Polynesian | Jones et al., 2012, Gudmundsson et al., 2009, Liyanarachchi et al., 2013, Pereda et al., 2015, Maillard et al., 2015 |
14 | 241(Thr > Met) |
XRCC3
| DNA repair, homologous recombination | DTC | Chinese, Iranian, Caucasian Portuguese | Wang et al., 2015, Fayaz et al., 2014, Bastos et al., 2009 |
14 | rs10136427 |
BATF
| Transcription factor, negative regulator of AP-1/ATF transcriptional events | DTC | Italian, Polish, Spanish | Figlioli et al., 2014 |
15q22.33 | rs2289261, rs56062135 |
SMAD3
| Transcriptional modulator | PTC, FTC | Icelandic, American, Spanish, Dutch | Gudmundsson et al., 2017 |
20 | rs7267944 |
DHX35
| RNA helicases | DTC | Italian, Polish, Spanish | Figlioli et al., 2014 |
Papillary thyroid Cancer (PTC)
Gene | Localization | Gene function | Mutation | Defect in cancer | Clinical correlation | Literature |
---|---|---|---|---|---|---|
Gene | ||||||
BRAF
| 7q34 | Serine/threonine kinase, response to cell growth factors | B-type Raf Kinase (chr 7) 2 Missense mutation V600E (T < A 1799), rs113488022 | Constitutive activation of MAPK pathway | Positive correlation with age, marker of TCV subtype | TCGA, Kimbrell et al., 2015, Lu et al., 2016, Gandolfi et al., 2013, Kim et al., 2006, Guerra et al., 2012, Sun et al., 2016, Gertz et al., 2016, Iyer et al., 2015, Lee et al., 2016 |
CHEK2
| 22q12.1 | Cell cycle checkpoint kinase | IVS2 + 1G > A, 1100delC or del5395, missense mutation I157T | DNA repair mechanism dysfunctions | Positive correlation with cancer aggressiveness | Siolek et al., 2015, Wójcicka et al., 2014, Kaczmarek-Ryś et al., 2015 |
DLL4
| 15q15.1 | Notch signaling mediator | Patient specific mutations | Promotes angiogenesis | Correlated with presence of lymph node metastases | Le Pennec et al., 2015 |
EIF1AX
| Xp22.12 | Translation initiation factor, transfer of Met-tRNAf | Hotspot at A113_splice site intron 5/exon 6 | Potential driver mutation | N/A | TCGA, Forbes 2011, Martin 2013, Karanamurthy 2016 |
FOXE1
| 9q22.33 | Transcription factor | rs965513 AA, AG; rs944289; c.821C > A, p.P54Q; c.943A > C p.K95Q; c.994C > T, p.L112F | Deregulation of thyroid morphogenesis | Thyroid cancer susceptibility marker | Mond et al., 2015, Gudmundsson et al., 2009, Penna-Martinez et al., 2014 |
PIK3CA
| 3q26.32 | PI3K/AKT/mTOR pathway effector | E545A | Mutation of helical domain | N/A | Lee et al., 2016 |
PTEN
| 10q23.31 | PI3K/AKT/mTOR pathway effector | N/A | Produces a truncated protein | N/A | Xing et al., 2013 |
RAS
| 11p15.5, 1p13.2, 12p12.1 | Signal transduction | H-Ras (chr11), N-Ras (chr1), K-Ras (chr12) | Preferential activation of PI3K-AKT pathway | Positive correlation with cancer aggressiveness | Rossi et al., 2015, Gertz et al., 2016, Abubaker et al., 2008, Zou et al., 2014 |
TERT promoter | 5p15.33 | Telomerase reverse transcriptase | C > T 1295228 and 1,295,250 C > A at 1295250 | Gain of immortality | Positive correlation with cancer aggressiveness | Bae et al., 2016, Liu et al., 2014, Liu et al., 2013, Sun et al., 2016 |
Chromosomal Abberations | ||||||
RET
| 10q11.21 | Tyrosine kinase transmembrane receptor | Rearrangements: RET/PTC1, RET/PTC2, RET/PTC3, RET/PTC4. RET/PTC5, RET/PTC6, RET/PTC7, RET/PTC8, RET/PTC9, PCM1-RET, EKLS-RET, FKBP-RET, RET-ANK3, TBL1XR1-RET, AKAP13-RET, ERC1-RET, HOOK3-RET, SPECC1L-RET, ACBD5-RET, ΔRFP-RET | Downstream signaling of MAPK and PI3K pathways, evasion of apoptosis | Common in pediatric PTC, common co-occurrence with BRAF mutation | TCGA, Gertz et al., 2016, Rossi et al., 2015, Hamatani et al., 2014, Corvi et al., 2000, Ciampi et al., 2007, Klugbauer et al., 1998, Salassidis et al., 2000, Saenko et al., 2003, Nakata et al., 1999, Hamatani et al., 2014, Bongarzone et al., 1993, Grieco et al., 1990 |
Abnormal expression | ||||||
ATP5E
| 20q13.32 | ATPase subunit 5E | Down-regulation | Disruption of ATP synthesis in mitochondria | Potential PTC biomarker | Hurtado-Lopez et al., 2015 |
MUC1
| 1q22 | Proliferation and signaling of epithelial cells | Overexpression | Leads to propagation of tumorigenesis and metastasis | Poor outcome marker | Renaud et al., 2014 |
TMPRSS4
| 11q23.3 | Serine protease | Overexpression | Migration and metastasis of cancer cells | Malignant tumors | Kebebew et al., 2005, Jarzab et al., 2005, Guan et al., 2015 |
YY1
| 14q32.2 | Transcription factor | Overexpression | Leads to increased cell proliferation | Positive correlation with age | Arribas et al., 2015 |
Regulation Of Expression | ||||||
micro RNA | Xp11.3 | Regulation of expression of affiliated genes | let-7 miRNA overexpression | Disruption of regulatory pathways (e.g. DNA damage response, stress response), propagation of cancer growth and expansion through down/up-regulation of target genes | N/A | Salajegheh et al., 2016, Yoruker et al., 2016, Lee et al., 2013, Zhang et al., 2010, Lei et al., 2016, Hong et al., 2016, Samsonov et al., 2016, Hu et al., 2017 |
9p21.3 | miR-31 overexpression | |||||
8q24.3 | miR-146b overexpression | |||||
19q13.41 | miR-151-5p overexpression | |||||
10q24.32 | miR-221 overexpression | |||||
Xp11.3 | miR-222 overexpression | |||||
17q23.1 | miR-21 down-regulation | |||||
9q34.3 | miR-126 down-regulation | |||||
19p13.12 | miR-20b | |||||
Xq26.2 | miR-639 |
Genetic alterations in kinases
BRAF
PIK3CA
RET proto-oncogene
Gene fusions
RET/PTC gene fusions
KAZN–C1ORF196
Mutations of DNA-repair genes
CHEK2
Alterations in cell signaling pathways
RAS
MUC1
Deregulation of protease expression
TMPRSS4
Mutations in transcription regulators
EIF1AX
FOXE1
TERT promoter
Regulatory RNAs
Up-regulation | Localization | Sample origin | Down-regulation | Localization | Sample origin |
---|---|---|---|---|---|
let-7 | 19q13.41 | serum | miR-15a | 13q14.2 | tumor tissue |
miR-31 | 9p21.3 | miR-16 | 13q14.2, 3q25.33 | ||
miR-151-5p | 8q24.3 | miR-21 | 17q23.1 | serum | |
miR-146b | 10q24.32 | plasma, tumor tissue | miR-126 | 9q34.3 | tumor tissue |
miR-221 | Xp11.3 | miR-940 | 16p13.3 | ||
miR-222 | Xp11.3 | ||||
miR-639 | 19p13.12 | tumor tissue |
Follicular thyroid carcinoma (FTC)
Gene | Localization | Gene function | Mutation | Defect in cancer | Clinial correlation | Literature |
---|---|---|---|---|---|---|
Gene | ||||||
ARNT
| 1q21.3 | N/A | CNV | unknown | N/A | Świerniak et al., 2016 |
CHEK2
| 22q12.1 | protein kinase | SNV, (C29,108,001A) | gain of immortality | N/A | Świerniak et al., 2016, Wójcicka et al., 2014 |
COL1A1
| 17q21.33 | pro-alpha1 chain of type I collagen | indel, chr17: 48275120 | unknown | N/A | Świerniak et al., 2016 |
COX6/DERL2
| COX6/A1: 12q24.31, COX6/A2: 16p11.2, DERL2: 17p13.2 | N/A | translocation | unknown | N/A | Świerniak et al., 2016 |
FBXW7
| 4q31.3 | subunit of ubiquitin protein ligase complex called SCFs | CNV | unknown | N/A | Świerniak et al., 2016 |
FOXO4
| Xq13.1 | suppressor of transcription | SNV, (C70,321,204 T) | Deregulation of transcription, alters protein structure | N/A | Świerniak et al., 2016 |
IDH1
| 2q34 | catalyzes the oxidative decarboxylation of isocitrate to 2-oxoglutarate | LOH | unknown | N/A | Świerniak et al., 2016 |
JAK3
| 19p13.11 | Protein kinase | intronic region | unknown | N/A | Świerniak et al., 2016 |
KAZN-C1ORF196
| KAZN: 1p36.21, C1ORF196: 1p36.21 | unknown | Gene fusion | unknown | N/A | Salajegheh et al., 2016 |
KTN1
| 14q22.3 | membrane protein involved in organelle motility | deletion in chr14:56139994 | unknown | N/A | Świerniak et al., 2016 |
MITF
| 3p13 | transcription regulator | insertion, chr3:69987750 | unknown | N/A | Świerniak et al., 2016 |
NCOA2
| 8q13.3 | epigenetic modifier | chr8 position 71,053,835 A > C | unknown | N/A | Świerniak et al., 2016 |
PAX8/PPARG
|
PAX8: 2q14.1, PPARG: 3p25.2
| N/A | t(2;3)(q13;p25) translocation | competitor inhibitor of PPARγ/ transcription factor similar to endogenous PPARγ | N/A | Lacroix et al., 2005, Giordano et al., 2006 |
PIK3CA
|
3q26.32
| catalytic subunit of phosphatidylinositol 3-kinase | CNV (gain) | unknown | N/A | Hou et al., 2007 |
TMPRSS4
| 11q23.3 | serine protease | overexpression | Promotes cancer cells proliferation, invasion and metastasis | positive correlation with staging of tumor nodes metastasis | Guan et al.,2015 |
TERT promoter | 5p15.33 | telomerase reverse transcriptase | C228T (rs35809415), C250A, C250T(rs1020948523) | unknown | presence of metastases | Bae et al., 2016 |
USP6
| 17p13.2 | ubiquitin Specific Peptidase | CNV | unknown | N/A | Świerniak et al., 2016 |
WRN
| 8p12 | repair od double stranded breaks | LOH | unknown | N/A | Świerniak et al., 2016 |
Regulation of expression | ||||||
miR-199a-5p | 19p13.2 | regulator of CTFG in healthy cells | Micro RNA | Disruption of regulatory pathways, propagation of cancer | Downregulation during tumorigenesis | Sun et al., 2016 |
Anaplastic thyroid carcinoma (ATC)
Gene | Localization | Gene function | Mutation | Defect in cancer | Physiological effect | Literature |
---|---|---|---|---|---|---|
Chromosomal Abberation | ||||||
KAZN-CIORF196 | 1p36.21, 1p36.21 | N/A | Gene fusion | potential role in progression and development of tumors | Le Pennec et al., 2015 | |
Gene | ||||||
ARID1A, ARID1B, ARD2, ARID5B, SMARCB1, PBRM1, ATRX
| 1p36.11, 6q25.3, N/A, N/A, 22q11.23, 3p21.1, Xq21.1 | components of the SWI/SNF complex, responsible for the chromatin remodeling | N/A | mutation in one of the complex components leads to dysfunction of the whole complex | N/A | Landa et al., 2016, Latteyer et al., 2016 |
ALK
| 2p23.1 | anaplastic lymphoma kinase | D1203H | hallmark of anaplastic tumors | N/A | Bonhomme et al., 2017, Latteyer et al., 2016 |
ATM
| 11q22.3 | cell-cycle checkpoint, response to DNA damage | E2039K | higher mutation burden, consistent with the lack of checkpoint function | N/A | Landa et al.,2016, Kunstman et al.,2015 |
BRAF rs113488022
| 7q34 | serine/threonine kinase, response to cell growth factors | V600E | constitutive activation of MAPK pathway | N/A | Santarpia et al., 2008, Guerra et al., 2013, Kasaian et al., 2015, Landa et al., 2016, Latteyer et al., 2016 |
DAXX
| 6p21.32 | transcription repressor binding the sumoylated transcription factors | S641X | potential driver mutation | correlates with non-thyroidal malignancies | Kunstman et al., 2015 |
EIF1AX
| Xp22.12 | translation initiation factor, transfer of met-trnaf | Splice site 1 bp upstream of ex6 (C > G), G9R (C > G), P2R(G > C) | potential driver mutation | N/A | Kunstman et al., 2015, Landa et al., 2016 |
ERBB2
| 17q12 | downstream enhancer of kinase-mediated signaling pathways | D387N | potential driver mutation | N/A | Kunstman et al., 2015 |
D873N, A763T | N/A | Bonhomme et al., 2017 | ||||
HECTD1 rs769574276
| 14q12 | ubiquitin protein ligase | L547 V | impairment of ubiquitynylated proteins degradation | N/A | Kunstman et al., 2015 |
KMT2A, KMT2C, KMT2D (MLL2), SETD2
| 11q23.3, 7q36.1, 12q13.12, 3p21.31 | histone methyltransferases, epigenetic modifiers | N/A, KMT2D: Q1892Q (rs753626919), R5389W | impairment of epigenetic mechanisms, potential driver mutation | N/A, KMT2D: correlates with non-thyroidal malignancies | Landa et al., 2016, Kunstman et al., 2015 |
MET
| 7q31.2 | tyrosine-protein kinase met | I166T | proto-oncogene | N/A | Bonhomme et al., 2017 |
mTOR
| 1p36.22 | response element = to stress, possessing kinase activity | R164Q (rs573705289), M2327I | potential driver mutation | correlates with non-thyroidal malignancies | Kunstman et al., 2015 |
NF1
| 17q11.2 | neurofibromatosis related gene | P2696L (rs778799019), R2496X (rs752162999) | potential driver mutation | correlates with non-thyroidal malignancies | Kunstman et al., 2015, Landa et al., 2016, Latteyer et al., 2016 |
NOTCH1–4 (NOTCH2 in Kunstman) | 1p12 | transmembrane receptors | NOTCH2: S361F (rs587735797), R1393H | potential driver mutation | correlates with non-thyroidal malignancies | Kunstman et al., 2015, Landa et al., 2016 |
PIK3CA
| 3q26.32 | PI3K/AKT/mTOR pathway effector | E542K (rs121913273), E545K (rs104886003) | mutation of helical domain | N/A | Landa et al., 2016, Kunstman et al., 2015, Hou et al., 2007 |
PTEN
| 10q23.31 | PI3K/AKT/mTOR pathway effector | N/A | truncated protein | N/A | Landa et al., 2016, Hou et al., 2007 |
RAS
| 11p15.5, 1p13.2, 12p12.1 | signal transduction | N/A | preferential activation of PI3K-AKT pathway | N/A | Santarpia et al., 2008, Guerra et al., 2013, Landa et al., 2016, Latteyer et al., 2016, Hou et al., 2007 |
TERT promoter | 5p15.33 | telomerase reverse transcriptase | C228T (rs35809415), C250T (rs1020948523) | gain of immortality | shorter survival | Bae et al., 2016, Landa et al., 2016 |
TMPRSS4
| 11q23.3 | serine protease | N/A | promotes proliferation | positive correlation with tumor grade | Guan et al., 2015 |
TP53
| 17p13.1 | tumor suppressor protein | Y163C (rs148924904) | gain of immortality | N/A | Kasaian et al., 2015, Landa et al., 2016, Bonhomme et al., 2017 |
USH2A
| 1q41 | uscherin, extracellular matrix binding protein interacting with collagen and fibronectin | I2189V (rs542406401), D798V (rs148431156), E571K(C > T), L1727F(G > A) | missense mutations | N/A | Kunstman et al., 2015 |
CREBBP
| 16p13.3 | histone acetyltransferase | N/A | epigenetic modifier | N/A | Landa et al., 2016 |
EP300, BCOR, BCL6
| 22q13.2, Xp11.4, 3q27.3 | epigenetic modifiers | N/A | abnormal protein modifications | N/A | Landa et al., 2016 |
CTNNB1
| 3p22.1 | cytoskeletal anchor, adhesive junctions | Q108H | unknown | N/A | Kunstman et al., 2015, Landa et al., 2016 |
MSH2
| 2p21 | DNA mismatch repair | N/A | gain of mutation phenotype | N/A | Landa et al., 2016, Kunstman et al., 2015 |
MSH5
| 6p21.33 | A199V (C > T) | N/A | |||
MSH6
| 2p16.3 | D736H (G > C) | N/A | |||
MLH1
| 3p22.2 | I19M (C > G), I68M (rs780141938), Q60X (C > T) | N/A | |||
MLH3
| 14q24.3 | L264 V (G > C) | N/A |