Thyroid Cancer

Overview

A translocation fusing the PAX8-PPARG genes is present in follicular thyroid cancer and follicular variant of papillary thyroid carcinoma, and less frequently in follicular thyroid adenoma. In contrast in papillary thyroid cancer the RET gene is frequently involved in structural rearrangements with either PCT1, PCT3, or other genes. In the less common medullary thyroid cancer (3 to 4% of all thyroid cancers) approximately a quarter of these cases are familial - including MEN 2A (most common familial syndrome), MEN 2B, and familial non-MEN syndromes.

See also: Thyroid Cancer - clinical resources (31)

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (166)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
RET 10q11.2 PTC, MTC1, HSCR1, MEN2A, MEN2B, RET51, CDHF12, CDHR16, RET-ELE1 Fusion
Translocation
-RET-NTRK1 Rearangements in Papillary Thyroid Cancer
-RET-PTC1 Rearangements in Papillary Thyroid Cancer
-RET-PTC3 (RET-ELE1) Rearangements in Papillary Thyroid Cancer
-t(8,10) RET-HOOK Reaarangements in Papillary Thyroid Cancer
-RET mutations in Familial Medullary Thyroid Carcinoma
-RET mutations in Multiple Endocrine Neoplasia - type 2A
-RET mutations in Multiple Endocrine Neoplasia Type 2b
-RET Rearrangements Following Exposure to Ionizing Radiation
619
BRAF 7q34 NS7, BRAF1, RAFB1, B-RAF1 -BRAF and Thyroid Cancer
761
SLC5A5 19p13.11 NIS, TDH1 -SLC5A5 and Thyroid Cancer
253
CCDC6 10q21 H4, PTC, TPC, TST1, D10S170 Fusion
-RET-PTC1 Rearangements in Papillary Thyroid Cancer
-CCDC6 and Thyroid Cancer
216
NCOA4 10q11.2 RFG, ELE1, PTC3, ARA70 Fusion
-RET-PTC3 (RET-ELE1) Rearangements in Papillary Thyroid Cancer
148
PTEN 10q23.31 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN and Thyroid Cancer
143
NRAS 1p13.2 NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1 -NRAS and Thyroid Cancer
135
CTNNB1 3p22.1 CTNNB, MRD19, armadillo -CTNNB1 and Thyroid Cancer
123
KRAS 12p12.1 NS, NS3, CFC2, KRAS1, KRAS2, RASK2, KI-RAS, C-K-RAS, K-RAS2A, K-RAS2B, K-RAS4A, K-RAS4B -KRAS and Thyroid Cancer
97
NODAL 10q22.1 HTX5 -NODAL and Thyroid Cancer
91
HRAS 11p15.5 CTLO, HAMSV, HRAS1, RASH1, p21ras, C-H-RAS, H-RASIDX, C-BAS/HAS, C-HA-RAS1 -HRAS and Thyroid Cancer
87
PPARG 3p25 GLM1, CIMT1, NR1C3, PPARG1, PPARG2, PPARgamma Translocation
-PAX8-PPARG fusion in Folicular Thyroid Cancer
72
PAX8 2q13 Translocation
-PAX8-PPARG fusion in Folicular Thyroid Cancer
72
APC 5q21-q22 GS, DP2, DP3, BTPS2, DP2.5, PPP1R46 -APC and Thyroid Cancer (FAP Associated)
59
MEN1 11q13.1 MEAI, SCG2 -MEN1 and Thyroid Cancer
47
KIT 4q12 PBT, SCFR, C-Kit, CD117 -KIT and Thyroid Cancer
39
TPO 2p25 MSA, TPX, TDH2A -TPO and Thyroid Cancer
37
NTRK1 1q21-q22 MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA Fusion
-RET-NTRK1 Rearangements in Papillary Thyroid Cancer
36
CDKN1B 12p13.1-p12 KIP1, MEN4, CDKN4, MEN1B, P27KIP1 -CDKN1B and Thyroid Cancer
25
NKX2-1 14q13 BCH, BHC, NK-2, TEBP, TTF1, NKX2A, T/EBP, TITF1, TTF-1, NKX2.1 -NKX2-1 and Thyroid Cancer
-NKX2-1 (TITF1) and Thyroid Cancer
13
BIRC5 17q25 API4, EPR-1 -BIRC5 and Thyroid Cancer
21
GSTM1 1p13.3 MU, H-B, GST1, GTH4, GTM1, MU-1, GSTM1-1, GSTM1a-1a, GSTM1b-1b -GSTM1 and Thyroid Cancer
19
TIMP1 Xp11.3-p11.23 EPA, EPO, HCI, CLGI, TIMP -TIMP1 and Thyroid Cancer
19
GSTT1 22q11.23 -GSTT1 and Thyroid Cancer
18
SDHD 11q23.1 PGL, CBT1, CWS3, PGL1, QPs3, SDH4, cybS, CII-4 -SDHD and Thyroid Cancer
17
SLC2A1 1p34.2 PED, DYT9, GLUT, DYT17, DYT18, EIG12, GLUT1, HTLVR, GLUT-1, GLUT1DS -GLUT1 expression in Thyroid Cancers
16
MAPK1 22q11.21 ERK, p38, p40, p41, ERK2, ERT1, ERK-2, MAPK2, PRKM1, PRKM2, P42MAPK, p41mapk, p42-MAPK -MAPK1 and Thyroid Cancer
15
GSTP1 11q13.2 PI, DFN7, GST3, GSTP, FAEES3, HEL-S-22 -GSTP1 and Thyroid Cancer
14
RAP1A 1p13.3 RAP1, C21KG, G-22K, KREV1, KREV-1, SMGP21 -Thyroid Cancer and RAP1A
13
HMGA1 6p21 HMG-R, HMGIY, HMGA1A -HMGA1 and Thyroid Cancer
13
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 -NOTCH1 and Thyroid Cancer
12
AKT2 19q13.1-q13.2 PKBB, PRKBB, HIHGHH, PKBBETA, RAC-BETA -AKT2 and Thyroid Cancer
11
TERC 3q26 TR, hTR, TRC3, DKCA1, PFBMFT2, SCARNA19 -TERC and Thyroid Cancer
11
TTF1 9q34.13 TTF-1, TTF-I -TTF1 and Thyroid Cancer
11
ATM 11q22.3 AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1 -ATM and Thyroid Cancer
10
TGFBR2 3p22 AAT3, FAA3, LDS2, MFS2, RIIC, LDS1B, LDS2B, TAAD2, TGFR-2, TGFbeta-RII -TGFBR2 and Thyroid Cancer
10
PRKAR1A 17q24.2 CAR, CNC, CNC1, PKR1, TSE1, ADOHR, PPNAD1, PRKAR1, ACRDYS1 -PRKAR1A and Thyroid Cancer
10
CHEK2 22q12.1 CDS1, CHK2, LFS2, RAD53, hCds1, HuCds1, PP1425 -CHEK2 and Thyroid Cancer
10
TPM3 1q21.2 TM3, TM5, TRK, CFTD, NEM1, TM-5, TM30, CAPM1, TM30nm, TPMsk3, hscp30, HEL-189, HEL-S-82p, OK/SW-cl.5 -TPM3 and Thyroid Cancer
9
MTHFR 1p36.22 -MTHFR and Thyroid Cancer
9
THRB 3p24.2 GRTH, PRTH, THR1, ERBA2, NR1A2, THRB1, THRB2, C-ERBA-2, C-ERBA-BETA -THRB and Thyroid Cancer
9
AKAP9 7q21-q22 LQT11, PRKA9, AKAP-9, CG-NAP, YOTIAO, AKAP350, AKAP450, PPP1R45, HYPERION, MU-RMS-40.16A -AKAP9 and Thyroid Cancer
8
GNAS 20q13.3 AHO, GSA, GSP, POH, GPSA, NESP, SCG6, SgVI, GNAS1, C20orf45 -GNAS and Thyroid Cancer
8
CITED1 Xq13.1 MSG1 -CITED1 and Thyroid Cancer
8
TPR 1q25 -TPR and Thyroid Cancer
8
IGF1R 15q26.3 IGFR, CD221, IGFIR, JTK13 -IGF1R and Thyroid Cancer
8
TERT 5p15.33 TP2, TRT, CMM9, EST2, TCS1, hTRT, DKCA2, DKCB4, hEST2, PFBMFT1 Prognostic
-TERT Promoter Mutations in Thyroid Cancer
8
CALCA 11p15.2 CT, KC, PCT, CGRP, CALC1, CGRP1, CGRP-I -CALCA and Thyroid Cancer
7
ITGB1 10p11.2 CD29, FNRB, MDF2, VLAB, GPIIA, MSK12, VLA-BETA -ITGB1 (CD29) and Thyroid Cancer
7
TRIM27 6p22 RFP, RNF76 -TRIM27 and Thyroid Cancer
7
GFRA1 10q26.11 GDNFR, RET1L, RETL1, TRNR1, GDNFRA, GFR-ALPHA-1 -GFRA1 and Thyroid Cancer
7
NAT2 8p22 AAC2, PNAT, NAT-2 -NAT2 and Thyroid Cancer
6
PTPRQ 12q21.2 DFNB84, DFNB84A, PTPGMC1, R-PTP-Q -PTPRQ and Thyroid Cancer
5
SLC5A8 12q23.1 AIT, SMCT, SMCT1 -SLC5A8 and Thyroid Cancer
5
HIF1A 14q23.2 HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA -HIF1A and Thyroid Cancer
5
IGF1 12q23.2 IGFI, IGF-I, IGF1A -IGF1 Expression in Thyroid Cancer
5
CD82 11p11.2 R2, 4F9, C33, IA4, ST6, GR15, KAI1, SAR2, TSPAN27 -CD82 and Thyroid Cancer
5
PTPRH 19q13.4 SAP1, R-PTP-H -PTPRH and Thyroid Cancer
5
PTPRJ 11p11.2 DEP1, SCC1, CD148, HPTPeta, R-PTP-ETA -PTPRJ and Thyroid Cancer
5
DUSP6 12q22-q23 HH19, MKP3, PYST1 -DUSP6 and Thyroid Cancer
5
CDK6 7q21-q22 MCPH12, PLSTIRE -CDK6 and Thyroid Cancer
5
TFG 3q12.2 TF6, HMSNP, SPG57, TRKT3 -TFG and Thyroid Cancer
5
MT1G 16q13 MT1, MT1K -MT1G and Thyroid Cancer
4
RBP3 10q11.2 IRBP, RBPI, RP66, D10S64, D10S65, D10S66 -RBP3 and Thyroid Cancer
4
AXL 19q13.1 ARK, UFO, JTK11, Tyro7 -AXL Expression in Thyroid Cancer
4
PIGS 17p13.2 -PIGS and Thyroid Cancer
4
CAV1 7q31.1 CGL3, PPH3, BSCL3, LCCNS, VIP21, MSTP085 -CAV1 and Thyroid Cancer
4
PITX2 4q25 RS, RGS, ARP1, Brx1, IDG2, IGDS, IHG2, PTX2, RIEG, IGDS2, IRID2, Otlx2, RIEG1 -PITX2 and Thyroid Cancer
4
SDHAF2 11q12.2 PGL2, SDH5, C11orf79 -SDHAF2 and Thyroid Cancer
3
SERPINA1 14q32.1 PI, A1A, AAT, PI1, A1AT, PRO2275, alpha1AT -SERPINA1 and Thyroid Cancer
3
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Thyroid Cancer
3
POLI 18q21.1 RAD30B, RAD3OB -POLI and Thyroid Cancer
3
MAP2K1 15q22.1-q22.33 CFC3, MEK1, MKK1, MAPKK1, PRKMK1 -MAP2K1 and Thyroid Cancer
3
HHEX 10q23.33 HEX, PRH, HMPH, PRHX, HOX11L-PEN -HHEX and Thyroid Cancer
3
CCK 3p22.1 -CCK and Thyroid Cancer
3
AURKB 17p13.1 AIK2, AIM1, ARK2, AurB, IPL1, STK5, AIM-1, STK12, PPP1R48, aurkb-sv1, aurkb-sv2 -AURKB and Thyroid Cancer
3
SLC34A2 4p15.2 NPTIIb, NAPI-3B, NAPI-IIb -SLC34A2 and Thyroid Cancer
3
GPC3 Xq26.1 SGB, DGSX, MXR7, SDYS, SGBS, OCI-5, SGBS1, GTR2-2 -GPC3 and Thyroid Cancer
3
ARAF Xp11.4-p11.2 PKS2, A-RAF, ARAF1, RAFA1 -ARAF and Thyroid Cancer
3
BUB1 2q14 BUB1A, BUB1L, hBUB1 -BUB1 and Thyroid Cancer
3
SSTR5 16p13.3 SS-5-R -SSTR5 and Thyroid Cancer
3
HLA-G 6p21.3 MHC-G -HLA-G and Thyroid Cancer
3
ZNF331 19q13.42 RITA, ZNF361, ZNF463 -ZNF331 and Thyroid Cancer
3
DAPK1 9q21.33 DAPK -DAPK1 and Thyroid Cancer
3
CA12 15q22 CAXII, HsT18816 -CA12 and Thyroid Cancer
3
BAG3 10q25.2-q26.2 BIS, MFM6, BAG-3, CAIR-1 -BAG3 and Thyroid Cancer
3
PDK1 2q31.1 -PDK1 and Thyroid Cancer
3
SSTR3 22q13.1 SS3R, SS3-R, SS-3-R, SSR-28 -SSTR3 and Thyroid Cancer
2
APEX1 14q11.2 APE, APX, APE1, APEN, APEX, HAP1, REF1 -APEX1 and Thyroid Cancer
2
CCL5 17q12 SISd, eoCP, SCYA5, RANTES, TCP228, D17S136E, SIS-delta -CCL5 and Thyroid Cancer
2
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2, RHEPDGFRA -PDGFRA and Thyroid Cancer
2
CTSB 8p22 APPS, CPSB -CTSB and Thyroid Cancer
2
POT1 7q31.33 CMM10, HPOT1 -POT1 and Thyroid Cancer
2
OLAH 10p13 SAST, AURA1, THEDC1 -OLAH and Thyroid Cancer
2
KAT5 11q13.1 TIP, ESA1, PLIP, TIP60, cPLA2, HTATIP, ZC2HC5, HTATIP1 -KAT5 and Thyroid Cancer
2
DAPK2 15q22.31 DRP1, DRP-1 -DAPK2 and Thyroid Cancer
2
RAD52 12p13-p12.2 -RAD52 and Thyroid Cancer
2
PCM1 8p22-p21.3 PTC4, RET/PCM-1 -PCM1 and Thyroid Cancer
2
CEACAM6 19q13.2 NCA, CEAL, CD66c -CEACAM6 and Thyroid Cancer
2
CDKN1C 11p15.4 BWS, WBS, p57, BWCR, KIP2, p57Kip2 -CDKN1C and Thyroid Cancer
2
PIK3CB 3q22.3 PI3K, PIK3C1, P110BETA, PI3KBETA -PIK3CB and Thyroid Cancer
2
EPHB4 7q22 HTK, MYK1, TYRO11 -EPHB4 and Thyroid Cancer
2
FTCDNL1 2q33.1 FONG -FONG and Thyroid Cancer
2
RASAL1 12q23-q24 RASAL -RASAL1 and Thyroid Cancer
2
HIPK2 7q34 PRO0593 -HIPK2 and Thyroid Cancer
2
SPRY2 13q31.1 hSPRY2 -SPRY2 and Thyroid Cancer
2
PTTG1 5q35.1 EAP1, PTTG, HPTTG, TUTR1 -PTTG1 and Thyroid Cancer
2
MAP3K8 10p11.23 COT, EST, ESTF, TPL2, AURA2, MEKK8, Tpl-2, c-COT -MAP3K8 and Thyroid Cancer
2
MSH3 5q14.1 DUP, MRP1 -MSH3 and Thyroid Cancer
2
HOOK3 8p11.21 HK3 Translocation
-t(8,10) RET-HOOK Reaarangements in Papillary Thyroid Cancer
2
CASP9 1p36.21 MCH6, APAF3, APAF-3, PPP1R56, ICE-LAP6 -CASP9 and Thyroid Cancer
2
FGF7 15q21.2 KGF, HBGF-7 -FGF7 and Thyroid Cancer
2
SSTR1 14q13 SS1R, SS1-R, SRIF-2, SS-1-R -SSTR1 and Thyroid Cancer
2
PTMS 12p13 ParaT -PTMS and Thyroid Cancer
2
IKBKB 8p11.2 IKK2, IKKB, IMD15, NFKBIKB, IKK-beta -IKBKB and Thyroid Cancer
2
PMS2 7p22.1 MLH4, PMSL2, HNPCC4, PMS2CL -PMS2 and Thyroid Cancer
2
CASP7 10q25 MCH3, CMH-1, LICE2, CASP-7, ICE-LAP3 -CASP7 and Thyroid Cancer
2
GOLGA5 14q32.12 RFG5, GOLIM5, ret-II -GOLGA5 and Thyroid Cancer
2
CBX7 22q13.1 -CBX7 and Thyroid Cancer
2
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Thyroid Cancer
2
IGFBP5 2q35 IBP5 -IGFBP5 and Thyroid Cancer
2
NOTCH4 6p21.3 INT3 -NOTCH4 and Thyroid Cancer
2
CTSL 9q21.33 MEP, CATL, CTSL1 -CTSL1 and Thyroid Cancer
2
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Thyroid Cancer
2
HDAC4 2q37.3 HD4, AHO3, BDMR, HDACA, HA6116, HDAC-4, HDAC-A -HDAC4 and Thyroid Cancer
2
CD63 12q12-q13 MLA1, ME491, LAMP-3, OMA81H, TSPAN30 -CD63 and Thyroid Cancer
2
RXRB 6p21.3 NR2B2, DAUDI6, RCoR-1, H-2RIIBP -RXRB and Thyroid Cancer
2
KTN1 14q22.1 CG1, KNT, MU-RMS-40.19 -KTN1 and Thyroid Cancer
1
GRASP 12q13.13 TAMALIN -GRASP and Thyroid Cancer
1
FOXO1 13q14.1 FKH1, FKHR, FOXO1A -FOXO1 and Thyroid Cancer
1
MMP13 11q22.2 CLG3, MDST, MANDP1, MMP-13 -MMP13 and Thyroid Cancer
1
HDAC6 Xp11.23 HD6, JM21, CPBHM, PPP1R90 -HDAC6 and Thyroid Cancer
1
RXRG 1q22-q23 RXRC, NR2B3 -RXRG and Thyroid Cancer
1
CASR 3q13 CAR, FHH, FIH, HHC, EIG8, HHC1, NSHPT, PCAR1, GPRC2A, HYPOC1 -CASR and Thyroid Cancer
1
IL1A 2q14 IL1, IL-1A, IL1F1, IL1-ALPHA -IL1A and Thyroid Cancer
1
SIRT3 11p15.5 SIR2L3 -SIRT3 and Thyroid Cancer
1
PRKCA 17q22-q23.2 AAG6, PKCA, PRKACA, PKC-alpha -PRKCA and Thyroid Cancer
1
PYGM 11q13.1 -PYGM and Thyroid Cancer
1
CEACAM7 19q13.2 CGM2 -CEACAM7 and Thyroid Cancer
1
C2orf40 2q12.2 ECRG4 -C2orf40 and Thyroid Cancer
1
ERC1 12p13.3 ELKS, Cast2, ERC-1, RAB6IP2 -ERC1 and Thyroid Cancer
1
ST5 11p15.4 HTS1, p126, DENND2B -ST5 and Thyroid Cancer
1
KLLN 10q23 CWS4, KILLIN -KLLN and Thyroid Cancer
1
CYP2D6 22q13.1 CPD6, CYP2D, CYP2DL1, CYPIID6, P450C2D, P450DB1, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, P450-DB1 -CYP2D6 and Thyroid Cancer
1
RASSF2 20p13 CENP-34, RASFADIN Methylation
Epigenetics
-Inactivation of RASSF2 in thyroid cancer
1
IDO1 8p12-p11 IDO, INDO, IDO-1 -IDO1 and Thyroid Cancer
1
TSPO 22q13.31 DBI, IBP, MBR, PBR, PBS, BPBS, BZRP, PKBS, PTBR, mDRC, pk18 -TSPO and Thyroid Cancer
1
MYCL 1p34.2 LMYC, L-Myc, MYCL1, bHLHe38 -MYCL and Thyroid Cancer
1
G6PD Xq28 G6PD1 -G6PD and Thyroid Cancer
1
ASAH1 8p22 AC, PHP, ASAH, PHP32, ACDase, SMAPME -ASAH1 and Thyroid Cancer
1
ATG5 6q21 ASP, APG5, APG5L, hAPG5, APG5-LIKE -ATG5 and Thyroid Cancer
1
PTPRC 1q31-q32 LCA, LY5, B220, CD45, L-CA, T200, CD45R, GP180 -PTPRC and Thyroid Cancer
1
CEACAM3 19q13.2 CEA, CGM1, W264, W282, CD66D -CEACAM3 and Thyroid Cancer
1
DLL4 15q14 hdelta2 -DLL4 and Thyroid Cancer
1
FOXP1 3p14.1 MFH, QRF1, 12CC4, hFKH1B, HSPC215 -FOXP1 and Thyroid Cancer
1
SPARC 5q31.3-q32 ON -SPARC and Thyroid Cancer
1
MAD2L1 4q27 MAD2, HSMAD2 -MAD2L1 and Thyroid Cancer
1
IL11 19q13.3-q13.4 AGIF, IL-11 -IL11 and Thyroid Cancer
1
PTHLH 12p12.1-p11.2 HHM, PLP, BDE2, PTHR, PTHRP -PTHLH and Thyroid Cancer
1
GPX3 5q33.1 GPx-P, GSHPx-3, GSHPx-P -GPX3 and Thyroid Cancer
1
CA9 9p13.3 MN, CAIX -CA9 and Thyroid Cancer
1
GAGE1 Xp11.23 CT4.1, GAGE-1 -GAGE1 and Thyroid Cancer
1
CD24 6q21 CD24A -CD24 and Thyroid Cancer
1
CEACAM4 19q13.2 NCA, CGM7, CGM7_HUMAN -CEACAM4 and Thyroid Cancer
1
CCKBR 11p15.4 GASR, CCK-B, CCK2R -CCKBR and Thyroid Cancer
LIMK1 7q11.23 LIMK, LIMK-1 -LIMK1 and Thyroid Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Recurrent Chromosome Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.

Familial Thyroid Cancer (1 links)

    Nosé V
    Familial thyroid cancer: a review.
    Mod Pathol. 2011; 24 Suppl 2:S19-33 [PubMed] Related Publications
    Thyroid carcinomas can be sporadic or familial. Familial syndromes are classified into familial medullary thyroid carcinoma (FMTC), derived from calcitonin-producing C cells, and familial non-medullary thyroid carcinoma, derived from follicular cells. The familial form of medullary thyroid carcinoma (MTC) is usually a component of multiple endocrine neoplasia (MEN) IIA or IIB, or presents as pure FMTC syndrome. The histopathological features of tumors in patients with MEN syndromes are similar to those of sporadic tumors, with the exception of bilaterality and multiplicity of tumors. The genetic events in the familial C-cell-derived tumors are well known, and genotype-phenotype correlations well established. In contrast, the case for a familial predisposition of non-medullary thyroid carcinoma is only now beginning to emerge. Although, the majority of papillary and follicular thyroid carcinomas are sporadic, the familial forms are rare and can be divided into two groups. The first includes familial syndromes characterized by a predominance of non-thyroidal tumors, such as familial adenomatous polyposis and PTEN-hamartoma tumor syndrome, within others. The second group includes familial syndromes characterized by predominance of papillary thyroid carcinoma (PTC), such as pure familial PTC (fPTC), fPTC associated with papillary renal cell carcinoma, and fPTC with multinodular goiter. Some characteristic morphologic findings should alert the pathologist of a possible familial cancer syndrome, which may lead to further molecular genetics evaluation.

    Khan A, Smellie J, Nutting C, et al.
    Familial nonmedullary thyroid cancer: a review of the genetics.
    Thyroid. 2010; 20(7):795-801 [PubMed] Related Publications
    OBJECTIVE: Thyroid cancer, the commonest of endocrine malignancies, continues to increase in incidence with over 19,000 new cases diagnosed in the European Union per year. Although nonmedullary thyroid cancer (NMTC) is mostly sporadic, evidence for a familial form, which is not associated with other Mendelian cancer syndromes (e.g., familial adenomatous polyposis and Cowden's syndrome), is well documented and thought to cause more aggressive disease. Just over a decade ago, the search for a genetic susceptibility locus for familial NMTC (FNMTC) began. This review details the genetic studies conducted thus far in the search for potential genes for FNMTC.
    DESIGN: An electronic PubMed search was performed from the English literature for genetics of FNMTC and genetics of familial papillary thyroid carcinoma (subdivision of FNMTC). The references from the selected papers were reviewed to identify further studies not found in the original search criteria.
    MAIN OUTCOME: Six potential regions for harboring an FNMTC gene have been identified: MNG1 (14q32), TCO (19p13.2), fPTC/PRN (1q21), NMTC1 (2q21), FTEN (8p23.1-p22), and the telomere-telomerase complex. Important genes reported to have been excluded are RET, TRK, MET, APC, PTEN, and TSHR.
    CONCLUSION: The genetics of FNMTC is an exciting field in medical research that has the potential to permit individualized management of thyroid cancer. Studies thus far have been on small family groups using varying criteria for the diagnosis of FNMTC. Results have been contradictory and further large-scale genetic studies utilizing emerging molecular screening tests are warranted to elucidate the underlying genetic basis of FNMTC.

Latest Publications

Liu Y, Li H, Zhang J, Gao X
Potassium Iodate Differently Regulates the Proliferation, Migration, and Invasion of Human Thyroid Cancer Cells via Modulating miR-146a.
Cancer Invest. 2017; 35(2):122-128 [PubMed] Related Publications
The effects of different doses of potassium iodate (KIO3) on the malignancy of thyroid cancer were investigated. Results showed that the proliferation, migration, and invasion of SW579 thyroid cancer cells were improved by 10(-6) M KIO3, which was associated with microRNA(miR)-146a deficit; 10(-2) M KIO3 significantly enhanced miR-146a level and suppressed SW579 cell proliferation, migration, and invasion. The diverse effects of KIO3 on SW579 cells were associated with the expression changes in miR-146a targets, Bcl-2, Bax, and caspase-3. Our study concludes that different doses of KIO3 have counteracting effects on the malignancy of thyroid cancer through modulating miR-146a level.

Kern B, Coppin L, Romanet P, et al.
Multiple HABP2 variants in familial papillary thyroid carcinoma: Contribution of a group of "thyroid-checked" controls.
Eur J Med Genet. 2017; 60(3):178-184 [PubMed] Related Publications
A heterozygous germline variant in the HABP2 gene c.1601G > A (p.Gly534Glu), which negatively impacts its tumor suppressive activity in vitro, has been described in 4-14% of kindreds of European-American ancestry with familial papillary thyroid carcinoma (fPTC). But it is also found in ≈4% of Europeans and European/Americans from public databases that, however, did not provide information on the thyroid function of the controls. To get unbiased results, we decided to compare HABP2 genotypes of patients with fPTC with those of "thyroid-checked" controls. A control group consisting of 136 European patients who were thyroidectomised for medullary thyroid carcinoma and devoid of any histologically detectable PTC or follicular-deriving carcinoma was built. In parallel we recruited 20 patients with fPTC from eleven independent European kindreds. The entire coding region of HABP2 was analyzed by Sanger sequencing the germline DNAs of patients. Nucleotide variants were searched for by Snap Shot analysis in the controls. Two variants, c.1601G > A (p.Gly534Glu) and c.364C > T (p.Arg122Trp), were found in 2 and 3 patients at the heterozygous level respectively (minor allele frequency (MAF): 5.0% and 7.5%, respectively). In controls, the MAF was either similar for the c.1601G > A HABP2 variant (2.94%, ns) or significantly lower for the c.364C > T variant (0.73%, p = 0.016). The Arg122 residue lies in the EGF-3 domain of HABP2 which is important for its activation but, however, superposition of the predicted 3D structures of the wild type and mutated proteins suggests that this variant is tolerated at the protein level. In conclusion, our data do not support the pathogenicity of the HABP2 c.1601G > A variant but highlight the existence of a new one that should be more extensively searched for in fPTC patients and its pathogenicity more carefully evaluated.

Crescenzi A, Fulciniti F, Bongiovanni M, et al.
Detecting N-RAS Q61R Mutated Thyroid Neoplasias by Immunohistochemistry.
Endocr Pathol. 2017; 28(1):71-74 [PubMed] Related Publications
Recently, the immunohistochemistry (IHC) for N-RAS Q61R has been developed and commercialized for clinical practice. Here, we investigated the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia. A series of 24 consecutive thyroid lesions undergone surgery following indeterminate cytology were enrolled. Paraffin sections were stained for IHC using the rabbit monoclonal anti-human N-RAS Q61R, clone SP174. N-RAS mutations in codon 61 were also investigated by automated sequencing. At histology, 12 cases of follicular carcinoma, cytologically defined as follicular lesions, 1 papillary cancer, 7 follicular adenomas, and 4 hyperplastic nodules were found. Of these, 4 showed a positive IHC for anti N-RAS antibody where N-RAS expression was detected mainly at cytoplasmic level with similar intensity of reaction. The remaining cases had negative IHC. A 100% concordance between IHC and molecular analysis for N-RAS Q61R was observed. In conclusion, this study shows high reliability of IHC to identify N-RAS Q61R mutated thyroid lesions with high cost-effectiveness. These data indicate the reliability of IHC to identify N-RAS Q61R mutated thyroid neoplasia and suggest to adopt this approach for a more accurate management of patients, when indicated.

Wang YL, Gong WG, Yuan QL
Effects of miR-27a upregulation on thyroid cancer cells migration, invasion, and angiogenesis.
Genet Mol Res. 2016; 15(4) [PubMed] Related Publications
Thyroid cancer is the most common type of endocrine tumor. MicroRNAs (miRNAs) play a critical role in a variety of diseases, especially cancer occurrence and progression. However, the specific mechanism by which miRNAs trigger disease states has not been fully elucidated. This study aims to investigate the role of miR-27a in thyroid cancer cells. A wound healing assay was adopted to examine cell migration. A transwell assay was applied to assess cell invasion. A thyroid cancer xenograft model was established using BALB/c nude mice. Western blot was performed to quantify iNOS expression. Tumor tissue blood vessel density was evaluated via immunohistochemistry assays. The results indicated that miR-27a downregulation inhibited thyroid cancer cell migration, while upregulation of miR-27a promoted thyroid cancer cell migration (P < 0.05). Furthermore, reduction in miR-27a expression suppressed thyroid cancer cell invasion (P < 0.05). In the nude mouse model of thyroid cancer xenograft, upregulation of miR-27 induced iNOS expression in pathological tumor tissues, whereas miR-27a inhibition resulted in the opposite effect (P < 0.05). CD105 level was also significantly increased during miR-27a upregulation, and was declined when miR-27a was inhibited (P < 0.05). In conclusion, miR-27a upregulation in thyroid cancer cells affects tumor cell migration, invasion, and angiogenesis by targeting downstream genes. Therefore, miR27a may act as a biomarker of thyroid cancer.

Qiu W, Yang Z, Fan Y, Zheng Q
ZNRF3 is downregulated in papillary thyroid carcinoma and suppresses the proliferation and invasion of papillary thyroid cancer cells.
Tumour Biol. 2016; 37(9):12665-12672 [PubMed] Related Publications
Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that has emerged as an important regulator of cancer development; however, its cancer-related function remains controversial. Here, we investigated the possible role of ZNRF3 in thyroid carcinoma (TC). We found that ZNRF3 is downregulated in papillary thyroid carcinoma (PTC) compared to normal thyroid tissues and inversely correlated with the degree of cell differentiation. Overexpression of ZNRF3 significantly suppressed cell malignant behaviors, including cell proliferation, migration, and invasion in vitro, as well as tumor growth in vivo. Consistent with recent studies showing that ZNRF3 is involved in the Wnt/β-catenin pathway, ZNRF3 overexpression negatively regulated β-catenin activation, modulating PTC cell behaviors. Clinical specimens revealed a significant inverse correlation between ZNRF3 and β-catenin mRNA levels. Taken together, these results provide insight into a potential tumor suppressor role of ZNRF3 in PTC progression, and may have potential clinical relevance for the prognosis and treatment of PTC.

Samsonov R, Burdakov V, Shtam T, et al.
Plasma exosomal miR-21 and miR-181a differentiates follicular from papillary thyroid cancer.
Tumour Biol. 2016; 37(9):12011-12021 [PubMed] Related Publications
Thyroid cancer (TC) is the most common endocrine malignancy and its incidence has increased over the last few decades. As has been revealed by a number of studies, TC tissue's micro-RNA (miRNA) profile may reflect histological features and the clinical behavior of tumor. However, alteration of the miRNA profile of plasma exosomes associated with TC development has to date not been explored. We isolated exosomes from plasma and assayed their characteristics using laser diffraction particle size analysis, atomic force microscopy, and western blotting. Next, we profiled cancer-associated miRNAs in plasma exosomes obtained from papillary TC patients, before and after surgical removal of the tumor. The diagnostic value of selected miRNAs was evaluated in a large cohort of patients displaying different statuses of thyroid nodule disease. MiRNA assessment was performed by RT-qPCR. In total, 60 patients with different types of thyroid nodal pathology were included in the study. Our results revealed that the development of papillary TC is associated with specific changes in exosomal miRNA profiles; this phenomenon can be used for differential diagnostics. MiRNA-31 was found to be over-represented in the plasma exosomes of patients with papillary TC vs. benign tumors, while miRNA-21 helped to distinguish between benign tumors and follicular TC. MiRNA-21 and MiRNA-181a-5p were found to be expressed reciprocally in the exosomes of patients with papillary and follicular TC, and their comparative assessment may help to distinguish between these types of TC with 100 % sensitivity and 77 % specificity.

Lopez-Campistrous A, Adewuyi EE, Benesch MG, et al.
PDGFRα Regulates Follicular Cell Differentiation Driving Treatment Resistance and Disease Recurrence in Papillary Thyroid Cancer.
EBioMedicine. 2016; 12:86-97 [PubMed] Free Access to Full Article Related Publications
Dedifferentiation of follicular cells is a central event in resistance to radioactive iodine and patient mortality in papillary thyroid carcinoma (PTC). We reveal that platelet derived growth factor receptor alpha (PDGFRα) specifically drives dedifferentiation in PTC by disrupting the transcriptional activity of thyroid transcription factor-1 (TTF1). PDGFRα activation dephosphorylates TTF1 consequently shifting the localization of this transcription factor from the nucleus to the cytoplasm. TTF1 is required for follicular cell development and disrupting its function abrogates thyroglobulin production and sodium iodide transport. PDGFRα also promotes a more invasive and migratory cell phenotype with a dramatic increase in xenograft tumor formation. In patient tumors we confirm that nuclear TTF1 expression is inversely proportional to PDGFRα levels. Patients exhibiting PDGFRα at time of diagnosis are three times more likely to exhibit nodal metastases and are 18 times more likely to recur within 5years than those patients lacking PDGFRα expression. Moreover, high levels of PDGFRα and low levels of nuclear TTF1 predict resistance to radioactive iodine therapy. We demonstrate in SCID xenografts that focused PDGFRα blockade restores iodide transport and decreases tumor burden by >50%. Focused PDGFRα inhibitors, combined with radioactive iodine, represent an additional avenue for treating patients with aggressive variants of PTC.

Vidinov K, Nikolova D
Familial Papillary Thyroid Carcinoma (FPTC): a Retrospective Analysis in a Sample of the Bulgarian Population for a 10-Year Period.
Endocr Pathol. 2017; 28(1):54-59 [PubMed] Related Publications
In recent years, there are numerous reports indicating the presence of familial papillary carcinoma. Unfortunately, no genetic defect can be linked directly to the disease. In this study, we set the goal to make a retrospective analysis of the cases with papillary carcinoma in the Department of Endocrine Surgery for the past 10 years, to compare the characteristics of sporadic and familial forms of the disease and to find families with hereditary papillary carcinoma. The study included 810 patients treated for thyroid cancer in the Department of Endocrine Surgery, USBALE "Acad. Iv. Penchev" Hospital, between January 1, 2006 and December 31, 2015. We used chi square test to determine statistical significant difference. The data analysis and interpretation was performed on SPSS 20.0. Both groups had similar demographic distribution. We found that 587 patients have sporadic papillary carcinoma, while 147 have a relative with thyroid pathology in the first degree of kinship. In 8 patients, there was a blood relative with thyroid cancer. When we compared the two groups, we found statistically significant difference only in tumor size. There was no significant difference in aggressiveness of the thyroid cancer (multifocality and lymph node metastasis). When analyzing the results, we identified 147 patients with a family history of thyroid disease (20%). In 8 patients (5.44%), we found at least one relative with papillary thyroid carcinoma. However, our study does not demonstrate any difference in the aggressiveness of familial and sporadic papillary thyroid carcinoma.

Huang JK, Ma L, Song WH, et al.
MALAT1 promotes the proliferation and invasion of thyroid cancer cells via regulating the expression of IQGAP1.
Biomed Pharmacother. 2016; 83:1-7 [PubMed] Related Publications
BACKGROUND: Increasing evidence indicated that metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) acted as a key regulator in the proliferation and invasion of several cancers. However, the function of MALAT1 in the development of thyroid cancer has not been experimentally established.
METHODS: The expression of MALAT1 and IQGAP1 in thyroid cancer tissues and cells were detected by quantitative real-time PCR and western blot. The effects of MALAT1 and IQGAP1 on the cell proliferation and invasion of thyroid cancer cells were detected with a 3-(4,5-dimethylthiazol)-2,5-diphenyl tetrazolium 4 (MTT) assay and a Transwell assay, respectively. FTC-133 or SW1736 transfected with si-MALAT1 or pcDNA-MALAT1 were injected subcutaneously into 4-week-olds BALB/c mice to examine the impact of MALAT1 on the tumor development of thyroid cancer in vivo.
RESULTS: In this study, we discovered the higher level of MALAT-1 and expression of IQGAP1 in thyroid cancer tissues and in thyroid cancer cells compared to that in the control. MTT and Transwell assay showed that the proliferation and invasion of FTC-133 cells with MALAT-1 knockdown were inhibited. Moreover, MALAT-1 could upregulate the expression of IQGAP1 in thyroid cancer cells. In addition, IQGAP1 knockdown reversed the decreasing cell proliferation and invasion of thyroid cancer induced by MALAT-1 overexpression. Finally, the study in vivo verified that MALAT-1 promoted the tumor growth of thyroid cancer.
CONCLUSION: Our study indicated that MALAT1 promoted the proliferation and invasion of thyroid cancer cells via regulating the expression of IQGAP1.

Boaventura P, Batista R, Pestana A, et al.
TERT promoter mutations: a genetic signature of benign and malignant thyroid tumours occurring in the context of tinea capitis irradiation.
Eur J Endocrinol. 2017; 176(1):49-55 [PubMed] Related Publications
OBJECTIVE: The aim of this study is to evaluate the frequency and molecular characteristics of TERTp mutations in thyroid adenomas and carcinomas occurring in the low-dose radiation exposure tinea capitis setting.
DESIGN AND METHODS: Twenty-seven patients with 34 well-differentiated thyroid carcinomas and 28 patients with 29 follicular adenomas diagnosed in a Portuguese tinea capitis cohort were studied. Blood samples were obtained from all the patients. Screening for TERTp mutations was performed by PCR amplification followed by Sanger sequencing. A series of 33 sporadic thyroid adenomas was used as control.
RESULTS: TERTp mutations were detected in six of the 28 patients with adenoma (21.4%) and in four of the 27 patients with carcinoma (14.8%). Three tumours (two carcinomas and one adenoma) had the tandem mutation -124/-125 GG>AA (30.0%), whereas the remaining seven had the -124G > A. The 20.7% frequency of TERTp mutations in adenomas contrasts with the absence of mutations in the adenomas from the control group and from most series on record, whereas the one found in carcinomas (11.8%) is similar to those reported in the literature for sporadic carcinomas.
CONCLUSION: TERTp mutations, including the tandem mutation -124/-125 GG>AA not described previously in thyroid tumours, appear to represent a genetic signature for thyroid tumours in patients submitted to low-dose X-ray irradiation. The high frequency of TERTp mutations in the adenomas of our cohort contrasts with their absence in sporadically occurring, as well as in adenomas of the Chernobyl series.

Nasirden A, Saito T, Fukumura Y, et al.
In Japanese patients with papillary thyroid carcinoma, TERT promoter mutation is associated with poor prognosis, in contrast to BRAF (V600E) mutation.
Virchows Arch. 2016; 469(6):687-696 [PubMed] Related Publications
The prognostic value of BRAF (V600E) and TERT promoter mutation in papillary thyroid carcinoma (PTC) is controversial. We examined alterations in BRAF (V600E) and TERT promoter by PCR-direct sequencing in PTC of 144 Japanese patients. Alternative lengthening of telomeres was examined as another mechanism of telomere maintenance by immunohistochemical staining for ATRX and DAXX. Of the clinicopathological characteristics, regional lymph node metastasis, extra-thyroid extension, multifocality/intrathyroidal spread, and advanced stage (III/V) were associated with shorter disease-free survival rate (DFSR). TERT promoter mutation was found in eight patients (6 %), and this was significantly associated with total thyroidectomy, multifocality/intrathyroidal spread, lymph node metastasis and advanced stage. The BRAF (V600E) mutation was found in 53 patients (38.2 %) but was not associated with any clinicopathological factors. TERT mutations were not correlated with BRAF (V600E) mutation status. TERT mutation-positive tumors (TERT+) showed lower DFSR than BRAF (V600E) -mutation-positive tumors (BRAF (V600E) +), and TERT+/BRAF (V600E) + tumors showed lower DFSR than BRAF (V600E) + tumors. No cases showed loss of ATRX/DAXX expression by immunohistochemistry. TERT promoter mutations showed a lower prevalence in our series and appeared to be associated with aggressive behavior. In PTCs, telomerase activation by TERT promoter mutation might be more important than alternative lengthening of telomeres.

Zhang H, Gao B, Shi B
Identification of Differentially Expressed Kinase and Screening Potential Anticancer Drugs in Papillary Thyroid Carcinoma.
Dis Markers. 2016; 2016:2832980 [PubMed] Free Access to Full Article Related Publications
Aim. We aim to identify protein kinases involved in the pathophysiology of papillary thyroid carcinoma (PTC) in order to provide potential therapeutic targets for kinase inhibitors and unfold possible molecular mechanisms. Materials and Methods. The gene expression profile of GSE27155 was analyzed to identify differentially expressed genes and mapped onto human protein kinases database. Correlation of kinases with PTC was addressed by systematic literature search, GO and KEGG pathway analysis. Results. The functional enrichment analysis indicated that "mitogen-activated protein kinases pathway" expression was extremely enriched, followed by "neurotrophin signaling pathway," "focal adhesion," and "GnRH signaling pathway." MAPK, SRC, PDGFRa, ErbB, and EGFR were significantly regulated to correct these pathways. Kinases investigated by the literature on carcinoma were considered to be potential novel molecular therapeutic target in PTC and application of corresponding kinase inhibitors could be possible therapeutic tool. Conclusion. SRC, MAPK, and EGFR were the most important differentially expressed kinases in PTC. Combined inhibitors may have high efficacy in PTC treatment by targeting these kinases.

Zhang R, Hardin H, Huang W, et al.
MALAT1 Long Non-coding RNA Expression in Thyroid Tissues: Analysis by In Situ Hybridization and Real-Time PCR.
Endocr Pathol. 2017; 28(1):7-12 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Long non-coding RNAs (lncRNAs) are important for transcription and for epigenetic or posttranscriptional regulation of gene expression and may contribute to carcinogenesis. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), an lncRNA involved in the regulation of the cell cycle, cell proliferation, and cell migration, is known to be deregulated in multiple cancers. Here, we analyzed the expression of MALAT1 on 195 cases of benign and malignant thyroid neoplasms by using tissue microarrays for RNA in situ hybridization (ISH) and real-time PCR. MALAT1 is highly expressed in normal thyroid (NT) tissues and thyroid tumors, with increased expression during progression from NT to papillary thyroid carcinomas (PTCs) but is downregulated in poorly differentiated thyroid cancers (PDCs) and anaplastic thyroid carcinomas (ATCs) compared to NT. Induction of epithelial to mesenchymal transition (EMT) by transforming growth factor (TGF)-beta in a PTC cell line (TPC1) led to increased MALAT1 expression, supporting a role for MALAT1 in EMT in thyroid tumors. This is the first ISH study of MALAT1 expression in thyroid tissues. It also provides the first piece of evidence suggesting MALAT1 downregulation in certain thyroid malignancies. Our findings support the notion that ATCs may be molecularly distinct from low-grade thyroid malignancies and suggest that MALAT1 may function both as an oncogene and as a tumor suppressor in different types of thyroid tumors.

Oh EJ, Lee S, Bae JS, et al.
TERT Promoter Mutation in an Aggressive Cribriform Morular Variant of Papillary Thyroid Carcinoma.
Endocr Pathol. 2017; 28(1):49-53 [PubMed] Related Publications
The cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is a rare thyroid neoplasm characterized by unique morphologic findings and association with familial adenomatous polyposis. The biologic behavior of this variant has been reported to behave similarly to classic PTC. We report a rare sporadic case of CMV-PTC occurring in a 45-year-old female with multiple lymph nodes and bone metastases, which were detected after total thyroidectomy and radioactive iodine remnant ablation. Molecular analyses of primary thyroid and metastatic tumor tissues revealed a telomerase reverse transcriptase (TERT) promoter mutation, but absence of BRAF, KRAS, NRAS, HRAS, and PIK3CA mutations. Over a 4-year follow-up period, structurally identifiable bone metastases were persistent, but serial post-operative serum thyroglobulin levels remained undetectable in the absence of thyroglobulin antibody. The literature was reviewed. This is the first case of aggressive CMV-PTC showing TERT promoter mutation. TERT promoter mutations may help in predicting aggressive clinical behavior in CMV-PTC. Postoperative serum thyroglobulin measurement may have no impact on clinical decision-making in this type of tumor.

Riesco-Eizaguirre G, Santisteban P
ENDOCRINE TUMOURS: Advances in the molecular pathogenesis of thyroid cancer: lessons from the cancer genome.
Eur J Endocrinol. 2016; 175(5):R203-17 [PubMed] Related Publications
Thyroid cancer is the most common endocrine malignancy giving rise to one of the most indolent solid cancers, but also one of the most lethal. In recent years, systematic studies of the cancer genome, most importantly those derived from The Cancer Genome Altas (TCGA), have catalogued aberrations in the DNA, chromatin, and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Cancer genomics is therefore providing new information on cancer development and behavior, as well as new insights into genetic alterations and molecular pathways. From this genomic perspective, we will review the main advances concerning some essential aspects of the molecular pathogenesis of thyroid cancer such as mutational mechanisms, new cancer genes implicated in tumor initiation and progression, the role of non-coding RNA, and the advent of new susceptibility genes in thyroid cancer predisposition. This look across these genomic and cellular alterations results in the reshaping of the multistep development of thyroid tumors and offers new tools and opportunities for further research and clinical development of novel treatment strategies.

Cai LL, Liu GY, Tzeng CM
Genome-wide DNA methylation profiling and its involved molecular pathways from one individual with thyroid malignant/benign tumor and hyperplasia: A case report.
Medicine (Baltimore). 2016; 95(35):e4695 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
BACKGROUND: During development, methylation permanently changes gene activity, while aberrant gene methylation is key to human tumorigenesis. Gene methylation is an epigenetic event leading to gene silencing and some tumor suppressor genes that are aberrantly methylated in both thyroid cancer and benign thyroid tumor, suggesting a role for methylation in early thyroid tumorigenesis. Specific gene methylation occurs in certain types of thyroid cancer and depends on particular signaling pathways. Most reports rely on data from varied samples that vary tremendously with respect to methylation.
RESULTS: We observed that hyperplastic/malignant (H/M) thyroid tissue and benign/manligant (B/M) tissue had the most profoundly methylated loci compared to hyperplastic/benign (H/B) tissue. These loci are mapped to 863 genes (|Δβ value| > 0.15) in B/M and 1082 genes (|Δβ value| > 0.15) in H/M. After bioinformatic analysis, these genes were found to be involved in T-cell receptor signaling pathway (B/M) and Jak-Stat signaling pathways (H/M).
CONCLUSION: Our study offers the most comprehensive DNA methylation data for thyroid disease to date, using 1 patient with 3 tissue types and high-resolution 450K arrays. Our data may lay the foundation for future identification of novel epigenetic targets or diagnosis of thyroid cancer.

Chu YH, Lloyd RV
Medullary Thyroid Carcinoma: Recent Advances Including MicroRNA Expression.
Endocr Pathol. 2016; 27(4):312-324 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine tumor arising from the C cells in the thyroid and accounts for about 5 % of all thyroid cancers. MTC exhibits more aggressive behavior than follicular tumors, with the majority of cases presenting with lymph node metastasis. It is particularly common among patients carrying germline RET mutations with almost 100 % penetrance. Because activating RET mutations occur in over 90 % of hereditary and 40 % of sporadic MTC, clinical trials of several RET-targeting multikinase inhibitors (MKIs) have resulted in FDA approval of vandetanib and cabozantinib for the treatment of MTC. Nevertheless, in light of significant individual differences in tumor behavior and treatment responses, there has been a persistent need for research efforts to decipher the molecular events within RET-driven or non-RET-driven tumors. Recently, the gene regulatory roles of microRNAs (miRNAs) in MTC have been studied extensively. Multiple miRNA deregulations have been discovered in MTC with potential prognostic and therapeutic implications. This review provides an overview of the basic pathology of MTC and an update on recent investigational progress.

Estrada-Florez AP, Bohórquez ME, Sahasrabudhe R, et al.
Clinical features of Hispanic thyroid cancer cases and the role of known genetic variants on disease risk.
Medicine (Baltimore). 2016; 95(32):e4148 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Thyroid cancer (TC) is the second most common cancer among Hispanic women. Recent genome-wide association (GWA) and candidate studies identified 6 single nucleotide polymorphisms (SNPs; rs966423, rs2439302, rs965513, rs6983267, rs944289, and rs116909374), associated with increased TC risk in Europeans but their effects on disease risk have not been comprehensively tested in Hispanics. In this study, we aimed to describe the main clinicopathological manifestations and to evaluate the effects of known SNPs on TC risk and on clinicopathological manifestations in a Hispanic population.We analyzed 281 nonmedullary TC cases and 1146 cancer-free controls recruited in a multicenter population-based study in Colombia. SNPs were genotyped by Kompetitive allele specific polymerase chain reaction (KASP) technique. Association between genetic variants and TC risk was assessed by computing odds ratios (OR) and confidence intervals (CIs).Consistent with published data in U.S. Hispanics, our cases had a high prevalence of large tumors (>2 cm, 43%) and a high female/male ratio (5:1). We detected significant associations between TC risk and rs965513A (OR = 1.41), rs944289T (OR = 1.26), rs116909374A (OR = 1.96), rs2439302G (OR = 1.19), and rs6983267G (OR = 1.18). Cases carried more risk alleles than controls (5.16 vs. 4.78, P = 4.8 × 10). Individuals with ≥6 risk alleles had >6-fold increased TC risk (OR = 6.33, P = 4.0 × 10) compared to individuals with ≤2 risk alleles. rs944289T and rs116909374A were strongly associated with follicular histology (ORs = 1.61 and 3.33, respectively); rs2439302G with large tumors (OR = 1.50); and rs965513A with regional disease (OR = 1.92).To our knowledge, this is the first study of known TC risk variants in South American Hispanics and suggests that they increase TC susceptibility in this population and can identify patients at higher risk of severe disease.

GallegosVargas J, SanchezRoldan J, RonquilloSanchez M, et al.
Gene Expression of CYP1A1 and its Possible Clinical Application in Thyroid Cancer Cases.
Asian Pac J Cancer Prev. 2016; 17(7):3477-82 [PubMed] Related Publications
BACKGROUND: Thyroid cancer is the most common endocrine malignancy, and exact causes remain unknown. The role of CYP450 1A1 (CYP1A1) in cancer initiation and progression has been investigated. The aim of this work was to analyze, for the first time, CYP1A1 gene expression and its relationship with several clinicopathological factors in Mexican patients diagnosed with thyroid cancer.
MATERIALS AND METHODS: Realtime PCR analysis was conducted on 32 sets of thyroid tumors and benign pathologies. Expression levels were tested for correlations with clinical and pathological data. All statistical analysis were performed using GraphPad Prism version 3.0 software.
RESULTS: We found that female gender was associated with thyroid cancer risk (P<0.05). A positive relationship was identified between CYP1A1 mRNA levels and the presence of chronic disease, alcohol use, tumor size, metastasis and an advanced clinical stage (P<0.05).
CONCLUSIONS: The results suggest that CYP1A1 gene expression could be used as a marker for thyroid cancer.

Gong L, Xu Y, Hu YQ, et al.
hTERT gene polymorphism correlates with the risk and the prognosis of thyroid cancer.
Cancer Biomark. 2016; 17(2):195-204 [PubMed] Related Publications
OBJECTIVES: The study explored the association between rs10069690C/T and rs2736100G/T of human telomerase reverse transcriptase (hTERT) gene, and the prognosis of thyroid cancer.
METHODS: The study had 452 thyroid cancer patients recruited as case group who hospitalized in Jingzhou Central Hospital from January 2001 to June 2004 and 452 healthy people recruited as control group at the same area. The hTERT gene polymorphisms at rs10069690 C/T and rs2736100 G/T were tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The association between patients' life quality and hTERT gene polymorphisms six months after surgery was evaluated based on the Cancer patients' quality of life index rating scale.
RESULTS: There were statistical differences in genotype and allele frequencies of rs10069690 C/T between the case group and control group (both P < 0.05). An association between rs10069690C/T polymorphism and an increased risk of thyroid cancer was shown by logistic regression analysis (CT vs. CC, OR = 1.333, 95%CI = 1.006-1.766, P = 0.045; TT vs. CC, OR = 1.910, 95%CI = 1.084-3.367, P = 0.023; CT + TT vs. CC, OR = 2.246, 95%CI = 1.078-1.840, P = 0.006; T vs. C, OR = 1.376, 95%CI = 1.104-1.715, P = 0.004). Genotype frequency of rs2736100G/T between the two groups had no statistical differences (P > 0.05). After stratification according to age, T stage, tumor size and tumor node metastasis (TNM) stage, the distribution frequencies of CC genotype and CT + TT genotype of rs10069690C/T showed significant difference (P < 0.05). The life quality of patients with CC genotype was better than that of patients with CT $+$ TT genotype. The results of Cox regression model multifactor analysis showed that age, T stage, tumor size and rs10069690C/T were independent risk factors of thyroid cancer prognosis.
CONCLUSIONS: hTERT gene polymorphism at rs10069690C/T is associated with the risk and prognosis of thyroid cancer, but hTERT gene polymorphism at rs2736100G/T is not.

Karagiannis AK, Girio-Fragkoulakis C, Nakouti T
Procalcitonin: A New Biomarker for Medullary Thyroid Cancer? A Systematic Review.
Anticancer Res. 2016; 36(8):3803-10 [PubMed] Related Publications
Medullary thyroid cancer (MTC) is a rare but aggressive thyroid malignancy. The gold-standard biomarker for its diagnosis and follow-up is calcitonin (CT); however, it has a variable half-life dependent on its circadian variability. It has been suggested that a more stable hormone, procalcitonin (PCT), may overcome these problems and its introduction to routine practice may give more accurate results in the diagnosis and follow-up of MTC. We systematically reviewed Pubmed, Scopus, Biosis Previews and Embase databases up to March 2016. A total of 15 out of 184 articles were retrieved and analyzed. Of these 15 studies, 3 were case reports. In these 15 studies, the values of CT and PCT were assessed in both patients with MTC and patients that were either healthy volunteers or with benign/malignant thyroid nodular disease or with bacterial infection. Our search suggests that PCT seems to be a useful biomarker for the diagnosis and follow-up of MTC when used in conjunction with CT, particularly in a small proportion of tumors that are CT-negative or secrete low levels of CT. So far, there has not been enough data to suggest a specific threshold for normal PCT. However, most studies indicate a value of 0.1 ng/ml as an acceptable cut-off in everyday clinical practice. At present, CT should continue to be the primary biomarker in MTC with the addition of PCT in some patient groups. Nevertheless, larger patient series need to be conducted in order to provide safer and more accurate results.

Park VY, Kim EK, Moon HJ, et al.
The thyroid imaging reporting and data system on US, but not the BRAFV600E mutation in fine-needle aspirates, is associated with lateral lymph node metastasis in PTC.
Medicine (Baltimore). 2016; 95(29):e4292 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
The majority of patients with papillary thyroid carcinoma (PTC) have an excellent prognosis, but some show poorer outcomes and would benefit from adjunctive prognostic tools. The B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutation, either based on both its presence or its quantitative measurement, and ultrasound (US) features may serve as a prognostic marker. The aim of this study was to investigate (1) the association between clinical-pathologic prognostic factors and the BRAF mutation found in fine-needle aspirates, based on both its presence and its corresponding cycle threshold (Ct) value, and (2) the association between prognostic factors and suspicious US features classified by the thyroid imaging reporting and data system (TIRADS) in PTC.Two-hundred fifty-eight consecutive patients with PTC > 1 cm and who underwent preoperative US-guided fine-needle aspiration were included in this retrospective study. Clinical-pathologic variables were compared between patients with and without the BRAF mutation. Multivariate analyses were performed to investigate (1) the association between clinical-pathologic prognostic factors and the BRAF mutation found in fine-needle aspirates, based on both its presence and corresponding Ct values, and (2) the association between prognostic factors and suspicious TIRADS US features.BRAF-positive patients had a higher proportion of multiple tumors (P = 0.017). The number of suspicious US features classified by the TIRADS was an independent factor for predicting lateral lymph node metastasis, both in all 258 patients (odds ratio [OR] = 1.902, P = 0.005) and in 214 BRAF-positive patients (OR = 1.686, P = 0.037). The BRAF mutation status or BRAFCt values were not associated with any of the clinical-pathologic prognostic factors.In conclusion, a higher number of suspicious US features classified by the TIRADS, but not the BRAF mutation, are associated with lateral lymph node metastasis in patients with PTC, and can aid in the preoperative identification of patients at increased risk of lateral lymph node metastasis.

Wei S, LiVolsi VA, Montone KT, et al.
Detection of Molecular Alterations in Medullary Thyroid Carcinoma Using Next-Generation Sequencing: an Institutional Experience.
Endocr Pathol. 2016; 27(4):359-362 [PubMed] Related Publications
Medullary thyroid carcinoma (MTC) harbors rearranged during transfection (RET) gene and rarely RAS gene mutations. The knowledge of the type of gene mutation in MTC is important to determine the treatment of the patients and the management of their family members. Targeted next-generation sequencing with a panel of 47 genes was performed in a total of 12 cases of sporadic (9/12) and hereditary MTC (3/12). Two of three hereditary MTCs had RET/C634R mutation, while the other one harbored two RET mutations (L790F and S649L). All the sporadic MTC had RET/M918T mutation except one case with HRAS mutation. Next-generation sequencing (NGS) can provide comprehensive analysis of molecular alterations in MTC in a routine clinical setting, which facilitate the management of the patient and the family members.

Xu B, Ghossein R
Genomic Landscape of poorly Differentiated and Anaplastic Thyroid Carcinoma.
Endocr Pathol. 2016; 27(3):205-12 [PubMed] Related Publications
Poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are aggressive thyroid tumors associated with a high mortality rate of 38-57 % and almost 100 % respectively. Several recent studies utilizing next generation sequencing techniques have shed lights on the molecular pathogenesis of these tumors, providing evidence to support a stepwise tumoral progression from well-differentiated to poorly differentiated, and finally to anaplastic thyroid carcinomas. While BRAF (V600E) and RAS mutations remain the main drivers in aggressive thyroid carcinoma, PDTC and ATC gains additional mutations, e.g., TERT promoter mutation, TP53 mutation, as well as frequent alterations in PIK3CA-PTEN-AKT-mTOR pathway, SWI-SNF complex, histomethyltransferases, and mismatch repair genes. RAS-mutated PDTCs are commonly associated with a histologic phenotype defined by Turin proposal, high frequency of distant metastasis, high thyroid differentiation score, and a RAS-like gene expression profile, whereas BRAF-mutated PDTCs are usually defined solely by the Memorial Sloan Kettering Cancer Center (MSKCC) criteria with a propensity for nodal metastasis and are less differentiated with a BRAF-like expression signature. Such demarcation is largely lost in ATC which is characterized by genomic complexity, heavy mutation burden, and profound undifferentiation. Additionally, several molecular events, e.g., EIF1AX mutation, mutation burden, and chromosome 1q gain in PDTCs, as well as EIF1AX mutation, chromosome 13q loss, and 20q gains in ATCs, may serve as adverse prognostic markers predicting poor clinical outcome.

Aherne ST, Smyth P, Freeley M, et al.
Altered expression of mir-222 and mir-25 influences diverse gene expression changes in transformed normal and anaplastic thyroid cells, and impacts on MEK and TRAIL protein expression.
Int J Mol Med. 2016; 38(2):433-45 [PubMed] Article available free on PMC after 01/03/2018 Related Publications
Thyroid cancer is the most common endocrine malignancy and accounts for the majority of endocrine cancer-related deaths each year. Our group and others have previously demonstrated dysfunctional microRNA (miRNA or miR) expression in the context of thyroid cancer. The objective of the present study was to investigate the impact of synthetic manipulation of expression of miR-25 and miR-222 in benign and malignant thyroid cells. miR-25 and miR-222 expression was upregulated in 8505C (an anaplastic thyroid cell line) and Nthy-ori (a SV40-immortalised thyroid cell line) cells, respectively. A transcriptomics-based approach was utilised to identify targets of the two miRNAs and real-time PCR and western blotting were used to validate a subset of the targets. Almost 100 mRNAs of diverse functions were found to be either directly or indirectly targeted by both miR-222 and miR-25 [fold change ≥2, false discovery rate (FDR) ≤0.05]. Gene ontology analysis showed the miR-25 gene target list to be significantly enriched for genes involved in cell adhesion. Fluidigm real-time PCR technologies were used to validate the downregulation of 23 and 22 genes in response to miR-25 and miR-222 overexpression, respectively. The reduction of the expression of two miR-25 protein targets, TNF-related apoptosis‑inducing ligand (TRAIL) and mitogen-activated protein kinase kinase 4 (MEK4), was also validated. Manipulating the expression of both miR-222 and miR-25 influenced diverse gene expression changes in thyroid cells. Increased expression of miR-25 reduced MEK4 and TRAIL protein expression, and cell adhesion and apoptosis are important aspects of miR-25 functioning in thyroid cells.

Kheiroddin P, Rasihashemi SZ, Estiar MA, et al.
RET Gene Analysis in Patients with Medullary Thyroid Carcinoma.
Clin Lab. 2016; 62(5):871-6 [PubMed] Related Publications
BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor from the para follicular C cells of the thyroid gland. It occurs either sporadically or as part of an inherited syndrome. It is caused by an autosomal dominant mutation in the RET (Rearranged during Transfection) proto-oncogene.
METHODS: The studied population consisted of 47 patients diagnosed with MTC in a specific population of northwest Iran along with their three children. Blood samples were collected from all subjects, genomic DNA was extracted and RET exons 10, 11, 13, 14, 15, and 16 were analyzed using PCR and direct sequencing.
RESULTS: 32 missense mutations were identified in exons 10 (6.25%) and 11 (84.4%). Moreover, two novel mutations in codon 595 in exon 10 (E595D and E595A) and a new mutation in codon 689 exon 11 (S689T) were detected, and a new nucleotide change was found in exon 11 (T675T). Four different polymorphisms were also identified in exons 11, 13, 14, and 15. Based on our data, the frequency profile of RET mutations in the Azari population of Iran with MTC is 61.7%. The most frequent mutation in our population was C364G, whereas in most populations it is C634R.
CONCLUSIONS: These results underline the importance of the genetic background of family members of any patient with MTC.

Chaudhary S, Hou Y, Shen R, et al.
Impact of the Afirma Gene Expression Classifier Result on the Surgical Management of Thyroid Nodules with Category III/IV Cytology and Its Correlation with Surgical Outcome.
Acta Cytol. 2016; 60(3):205-10 [PubMed] Related Publications
OBJECTIVE: The Afirma gene expression classifier (GEC) is a molecular test to further classify indeterminate fine-needle aspiration (FNA) as benign or suspicious for malignancy.
STUDY DESIGN: A total of 158 FNAs with Bethesda category III/IV cytology were sent for an Afirma GEC test. We correlated the Afirma GEC results with surgical outcome and also compared the data after Afirma's implementation with the data before.
RESULTS: Among the 158 FNAs, the Afirma result was benign in 63 (40%), suspicious in 85 (54%) and unsatisfactory in 10 (6%). In total, 73 (86%) suspicious Afirma cases had surgery and 28 (38%) showed carcinoma. In contrast, only 8 (13%) benign Afirma cases had surgery and all of them were benign. The sensitivity, specificity, negative predictive value and positive predictive value (PPV) of Afirma were 100, 15, 100 and 38%, respectively. The PPV was 20% in cases with follicular lesion of undetermined significance, but was 50% in cases suspicious for follicular neoplasm (SFN). The surgical excisional rate was significantly decreased in SFN cases after the Afirma test.
CONCLUSIONS: The Afirma GEC is useful for further risk stratifying SFN cases.

Halkova T, Dvorakova S, Sykorova V, et al.
Polymorphisms in selected DNA repair genes and cell cycle regulating genes involved in the risk of papillary thyroid carcinoma.
Cancer Biomark. 2016; 17(1):97-106 [PubMed] Related Publications
BACKGROUND: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. In addition to causal somatic mutations in the BRAF gene and RET/PTC rearrangements, the contribution of single nucleotide polymorphisms (SNPs) in low-penetrance genes in the development of PTC has been proposed.
METHODS: Four SNPs in the XRCC1 (Arg399Gln, Arg280His, Arg194Trp and T-77C) and one SNP from each of three other genes participating in DNA repair pathways and/or cell cycle regulation (ATM Asp1853Asn, TP53 Arg72Pro, CDKN1B Val109Gly) were selected. The allelic and genotypic distributions of these variants as well as haplotypes of the XRCC1 were examined in 583 individuals comprising well-characterized cohorts of 209 PTC patients and 374 healthy volunteers. Correlations of polymorphism with clinical-pathological data and mutation status were performed.
RESULTS: XRCC1 T-77C polymorphism affects the genetic susceptibility for PTC development in men, the specific combination of XRCC1 haplotypes correlates with RET/PTC incidence, CDKN1B Val109Gly significantly influences the risk of developing PTC regardless of gender and in PTC cases, selected genotypes of TP53 Arg72Pro and ATM Asp1853Asn were significantly associated with monitored tumour characteristics.
CONCLUSION: It seems that SNPs in studied regulating genes contribute to the development of PTC and modify the tumour behaviour or characteristics.

Tiedje V, Ting S, Walter RF, et al.
Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients.
Eur J Endocrinol. 2016; 175(3):173-80 [PubMed] Related Publications
OBJECTIVE: Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.
DESIGN AND METHODS: Clinical courses of 32 patients with sporadic MTC (n=10 pN0cM0, n=8 pN1cM0, n=14 pN1cM1) were compared with genetic profiles of the patients' primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis.
RESULTS: Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P=0.019), FGFR2 (P=0.007), FGFR3 (P=0.044) and VEGFC (P=0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P=0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P=0.039), FLT4 (P=0.025) and VEGFB (P=0.042) was significantly higher in therapy responders.
CONCLUSIONS: In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.

Xu J, Li Z, Su Q, et al.
Embryonic develop-associated gene 1 is overexpressed and acts as a tumor promoter in thyroid carcinoma.
Biomed Pharmacother. 2016; 81:86-92 [PubMed] Related Publications
Embryonic develop-associated gene 1 (EDAG-1), a hematopoietic tissue-specific protein, is usually highly expressed in the placenta, fetal liver, bone marrow and leukemia cells, but the expression status in normal or solid tumor tissues is rarely reported. In this study, we found that EDAG-1 was up-regulated in thyroid carcinoma tissues and cells. Knockdown of EDAG-1 suppressed proliferation and enhanced cisplatin-induced apoptosis of thyroid carcinoma cells. We also demonstrated that knockdown of EDAG-1 inactivated the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway in vitro and in vivo. Moreover, knockdown of EDAG-1 suppressed tumorigenesis of thyroid carcinoma in vivo. Taken together, these results suggest that EDAG-1 regulates the proliferation and apoptosis of thyroid carcinoma via the PI3K/Akt signaling pathway.

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