Thyroid Cancer


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

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Tag cloud generated 08 August, 2015 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (155)

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'.

RET 10q11.2 PTC, MTC1, HSCR1, MEN2A, MEN2B, RET51, CDHF12, CDHR16, RET-ELE1 Fusion
-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
BRAF 7q34 NS7, BRAF1, RAFB1, B-RAF1 -BRAF and Thyroid Cancer
SLC5A5 19p13.11 NIS, TDH1 -SLC5A5 and Thyroid Cancer
CCDC6 10q21 H4, PTC, TPC, TST1, D10S170 Fusion
-RET-PTC1 Rearangements in Papillary Thyroid Cancer
-CCDC6 and Thyroid Cancer
NCOA4 10q11.2 RFG, ELE1, PTC3, ARA70 Fusion
-RET-PTC3 (RET-ELE1) Rearangements in Papillary Thyroid Cancer
NRAS 1p13.2 NS6, CMNS, NCMS, ALPS4, N-ras, NRAS1 -NRAS and Thyroid Cancer
PTEN 10q23.3 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN and Thyroid Cancer
CTNNB1 3p21 CTNNB, MRD19, armadillo -CTNNB1 and Thyroid Cancer
NODAL 10q22.1 HTX5 -NODAL and Thyroid Cancer
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
PAX8 2q13 Translocation
-PAX8-PPARG fusion in Folicular Thyroid Cancer
PPARG 3p25 GLM1, CIMT1, NR1C3, PPARG1, PPARG2, PPARgamma Translocation
-PAX8-PPARG fusion in Folicular Thyroid Cancer
HRAS 11p15.5 CTLO, HAMSV, HRAS1, RASH1, p21ras, C-H-RAS, H-RASIDX, C-BAS/HAS, C-HA-RAS1 -HRAS and Thyroid Cancer
APC 5q21-q22 GS, DP2, DP3, BTPS2, DP2.5, PPP1R46 -APC and Thyroid Cancer (FAP Associated)
MEN1 11q13 MEAI, SCG2 -MEN1 and Thyroid Cancer
KIT 4q12 PBT, SCFR, C-Kit, CD117 -KIT and Thyroid Cancer
TPO 2p25 MSA, TPX, TDH2A -TPO and Thyroid Cancer
NTRK1 1q21-q22 MTC, TRK, TRK1, TRKA, Trk-A, p140-TrkA Fusion
-RET-NTRK1 Rearangements in Papillary Thyroid Cancer
CDKN1B 12p13.1-p12 KIP1, MEN4, CDKN4, MEN1B, P27KIP1 -CDKN1B and Thyroid Cancer
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
BIRC5 17q25 API4, EPR-1 -BIRC5 and Thyroid Cancer
TIMP1 Xp11.3-p11.23 EPA, EPO, HCI, CLGI, TIMP -TIMP1 and Thyroid Cancer
GSTM1 1p13.3 MU, H-B, GST1, GTH4, GTM1, MU-1, GSTM1-1, GSTM1a-1a, GSTM1b-1b -GSTM1 and Thyroid Cancer
GSTT1 22q11.23 -GSTT1 and Thyroid Cancer
SLC2A1 1p34.2 PED, DYT9, GLUT, DYT17, DYT18, EIG12, GLUT1, HTLVR, GLUT-1, GLUT1DS -GLUT1 expression in Thyroid Cancers
MAPK1 22q11.21 ERK, p38, p40, p41, ERK2, ERT1, ERK-2, MAPK2, PRKM1, PRKM2, P42MAPK, p41mapk, p42-MAPK -MAPK1 and Thyroid Cancer
GSTP1 11q13 PI, DFN7, GST3, GSTP, FAEES3, HEL-S-22 -GSTP1 and Thyroid Cancer
RAP1A 1p13.3 RAP1, C21KG, G-22K, KREV1, KREV-1, SMGP21 -Thyroid Cancer and RAP1A
NOTCH1 9q34.3 hN1, AOS5, TAN1, AOVD1 -NOTCH1 and Thyroid Cancer
TERC 3q26 TR, hTR, TRC3, DKCA1, PFBMFT2, SCARNA19 -TERC and Thyroid Cancer
AKT2 19q13.1-q13.2 PKBB, PRKBB, HIHGHH, PKBBETA, RAC-BETA -AKT2 and Thyroid Cancer
TTF1 9q34.13 TTF-1, TTF-I -TTF1 and Thyroid Cancer
HMGA1 6p21 HMG-R, HMGIY, HMGA1A -HMGA1 and Thyroid Cancer
TGFBR2 3p22 AAT3, FAA3, LDS2, MFS2, RIIC, LDS1B, LDS2B, TAAD2, TGFR-2, TGFbeta-RII -TGFBR2 and Thyroid Cancer
PRKAR1A 17q24.2 CAR, CNC, CNC1, PKR1, TSE1, ADOHR, PPNAD1, PRKAR1, ACRDYS1 -PRKAR1A and Thyroid Cancer
THRB 3p24.2 GRTH, PRTH, THR1, ERBA2, NR1A2, THRB1, THRB2, C-ERBA-2, C-ERBA-BETA -THRB and Thyroid Cancer
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
ATM 11q22-q23 AT1, ATA, ATC, ATD, ATE, ATDC, TEL1, TELO1 -ATM and Thyroid Cancer
CITED1 Xq13.1 MSG1 -CITED1 and Thyroid Cancer
AKAP9 7q21-q22 LQT11, PRKA9, AKAP-9, CG-NAP, YOTIAO, AKAP350, AKAP450, PPP1R45, HYPERION, MU-RMS-40.16A -AKAP9 and Thyroid Cancer
GNAS 20q13.3 AHO, GSA, GSP, POH, GPSA, NESP, GNAS1, PHP1A, PHP1B, PHP1C, C20orf45 -GNAS and Thyroid Cancer
TERT 5p15.33 TP2, TRT, CMM9, EST2, TCS1, hTRT, DKCA2, DKCB4, hEST2, PFBMFT1 Prognostic
-TERT Promoter Mutations in Thyroid Cancer
CHEK2 22q12.1 CDS1, CHK2, LFS2, RAD53, hCds1, HuCds1, PP1425 -CHEK2 and Thyroid Cancer
TPR 1q25 -TPR and Thyroid Cancer
IGF1R 15q26.3 IGFR, CD221, IGFIR, JTK13 -IGF1R and Thyroid Cancer
TRIM27 6p22 RFP, RNF76 -TRIM27 and Thyroid Cancer
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2, RHEPDGFRA -PDGFRA and Thyroid Cancer
GFRA1 10q26.11 GDNFR, RET1L, RETL1, TRNR1, GDNFRA, GFR-ALPHA-1 -GFRA1 and Thyroid Cancer
ITGB1 10p11.2 CD29, FNRB, MDF2, VLAB, GPIIA, MSK12, VLA-BETA -ITGB1 (CD29) and Thyroid Cancer
MTHFR 1p36.3 -MTHFR and Thyroid Cancer
NAT2 8p22 AAC2, PNAT, NAT-2 -NAT2 and Thyroid Cancer
SLC5A8 12q23.1 AIT, SMCT, SMCT1 -SLC5A8 and Thyroid Cancer
HIF1A 14q23.2 HIF1, MOP1, PASD8, HIF-1A, bHLHe78, HIF-1alpha, HIF1-ALPHA -HIF1A and Thyroid Cancer
PTPRH 19q13.4 SAP1, R-PTP-H -PTPRH and Thyroid Cancer
TFG 3q12.2 TF6, HMSNP, SPG57, TRKT3 -TFG and Thyroid Cancer
PRKCA 17q22-q23.2 AAG6, PKCA, PRKACA, PKC-alpha -PRKCA and Thyroid Cancer
IGF1 12q23.2 IGFI, IGF-I, IGF1A -IGF1 Expression in Thyroid Cancer
CDK6 7q21-q22 MCPH12, PLSTIRE -CDK6 and Thyroid Cancer
PTPRJ 11p11.2 DEP1, SCC1, CD148, HPTPeta, R-PTP-ETA -PTPRJ and Thyroid Cancer
PTPRQ 12q21.2 DFNB84, DFNB84A, PTPGMC1, R-PTP-Q -PTPRQ and Thyroid Cancer
CAV1 7q31.1 CGL3, PPH3, BSCL3, LCCNS, VIP21, MSTP085 -CAV1 and Thyroid Cancer
PTPRC 1q31-q32 LCA, LY5, B220, CD45, L-CA, T200, CD45R, GP180 -PTPRC and Thyroid Cancer
MT1G 16q13 MT1, MT1K -MT1G and Thyroid Cancer
CALCA 11p15.2 CT, KC, CGRP, CALC1, CGRP1, CGRP-I -CALCA and Thyroid Cancer
RBP3 10q11.2 IRBP, RBPI, RP66, D10S64, D10S65, D10S66 -RBP3 and Thyroid Cancer
DUSP6 12q22-q23 HH19, MKP3, PYST1 -DUSP6 and Thyroid Cancer
PIGS 17p13.2 -PIGS and Thyroid Cancer
PITX2 4q25 RS, RGS, ARP1, Brx1, IDG2, IGDS, IHG2, PTX2, RIEG, IGDS2, IRID2, Otlx2, RIEG1 -PITX2 and Thyroid Cancer
CD82 11p11.2 R2, 4F9, C33, IA4, ST6, GR15, KAI1, SAR2, TSPAN27 -CD82 and Thyroid Cancer
AXL 19q13.1 ARK, UFO, JTK11, Tyro7 -AXL Expression in Thyroid Cancer
ARAF Xp11.4-p11.2 PKS2, A-RAF, ARAF1, RAFA1 -ARAF and Thyroid Cancer
HHEX 10q23.33 HEX, PRH, HMPH, PRHX, HOX11L-PEN -HHEX and Thyroid Cancer
ZNF331 19q13.42 RITA, ZNF361, ZNF463 -ZNF331 and Thyroid Cancer
PDK1 2q31.1 -PDK1 and Thyroid Cancer
SSTR5 16p13.3 SS-5-R -SSTR5 and Thyroid Cancer
GPC3 Xq26.1 SGB, DGSX, MXR7, SDYS, SGBS, OCI-5, SGBS1, GTR2-2 -GPC3 and Thyroid Cancer
MAP2K1 15q22.1-q22.33 CFC3, MEK1, MKK1, MAPKK1, PRKMK1 -MAP2K1 and Thyroid Cancer
AURKB 17p13.1 AIK2, AIM1, ARK2, AurB, IPL1, STK5, AIM-1, STK12, PPP1R48, aurkb-sv1, aurkb-sv2 -AURKB and Thyroid Cancer
BAG3 10q25.2-q26.2 BIS, MFM6, BAG-3, CAIR-1 -BAG3 and Thyroid Cancer
FAS 10q24.1 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Thyroid Cancer
BUB1 2q14 BUB1A, BUB1L, hBUB1 -BUB1 and Thyroid Cancer
CCK 3p22.1 -CCK and Thyroid Cancer
HLA-G 6p21.3 MHC-G -HLA-G and Thyroid Cancer
SLC34A2 4p15.2 NPTIIb, NAPI-3B, NAPI-IIb -SLC34A2 and Thyroid Cancer
DAPK1 9q21.33 DAPK -DAPK1 and Thyroid Cancer
SERPINA1 14q32.1 PI, A1A, AAT, PI1, A1AT, PRO2275, alpha1AT -SERPINA1 and Thyroid Cancer
IKBKB 8p11.2 IKK2, IKKB, IMD15, NFKBIKB, IKK-beta -IKBKB and Thyroid Cancer
PTTG1 5q35.1 EAP1, PTTG, HPTTG, TUTR1 -PTTG1 and Thyroid Cancer
CASP7 10q25 MCH3, CMH-1, LICE2, CASP-7, ICE-LAP3 -CASP7 and Thyroid Cancer
CD63 12q12-q13 MLA1, ME491, LAMP-3, OMA81H, TSPAN30 -CD63 and Thyroid Cancer
HIPK2 7q34 PRO0593 -HIPK2 and Thyroid Cancer
POT1 7q31.33 CMM10, HPOT1 -POT1 and Thyroid Cancer
SPRY2 13q31.1 hSPRY2 -SPRY2 and Thyroid Cancer
LIMK1 7q11.23 LIMK, LIMK-1 -LIMK1 and Thyroid Cancer
APEX1 14q11.2 APE, APX, APE1, APEN, APEX, HAP1, REF1 -APEX1 and Thyroid Cancer
FGF7 15q21.2 KGF, HBGF-7 -FGF7 and Thyroid Cancer
CDKN1C 11p15.5 BWS, WBS, p57, BWCR, KIP2, p57Kip2 -CDKN1C and Thyroid Cancer
OLAH 10p13 SAST, AURA1, THEDC1 -OLAH and Thyroid Cancer
PMS2 7p22.2 PMSL2, HNPCC4, PMS2CL -PMS2 and Thyroid Cancer
DAPK2 15q22.31 DRP1, DRP-1 -DAPK2 and Thyroid Cancer
EPHB4 7q22 HTK, MYK1, TYRO11 -EPHB4 and Thyroid Cancer
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Thyroid Cancer
NOTCH4 6p21.3 INT3 -NOTCH4 and Thyroid Cancer
CA12 15q22 CAXII, HsT18816 -CA12 and Thyroid Cancer
IGFBP5 2q35 IBP5 -IGFBP5 and Thyroid Cancer
PTMS 12p13 ParaT -PTMS and Thyroid Cancer
FTCDNL1 2q33.1 FONG -FONG and Thyroid Cancer
MAP3K8 10p11.23 COT, EST, ESTF, TPL2, AURA2, MEKK8, Tpl-2, c-COT -MAP3K8 and Thyroid Cancer
CCKBR 11p15.4 GASR, CCK-B, CCK2R -CCKBR and Thyroid Cancer
HOOK3 8p11.21 HK3 Translocation
-t(8,10) RET-HOOK Reaarangements in Papillary Thyroid Cancer
PCM1 8p22-p21.3 PTC4 -PCM1 and Thyroid Cancer
RAD52 12p13-p12.2 -RAD52 and Thyroid Cancer
CTSL 9q21.33 MEP, CATL, CTSL1 -CTSL1 and Thyroid Cancer
HDAC4 2q37.3 HD4, AHO3, BDMR, HDACA, HA6116, HDAC-4, HDAC-A -HDAC4 and Thyroid Cancer
RXRB 6p21.3 NR2B2, DAUDI6, RCoR-1, H-2RIIBP -RXRB and Thyroid Cancer
SSTR3 22q13.1 SS3R, SS3-R, SS-3-R, SSR-28 -SSTR3 and Thyroid Cancer
GOLGA5 14q32.12 RFG5, GOLIM5, ret-II -GOLGA5 and Thyroid Cancer
PIK3CB 3q22.3 PI3K, PIK3C1, P110BETA, PI3KBETA -PIK3CB and Thyroid Cancer
SSTR1 14q13 SS1R, SS1-R, SRIF-2, SS-1-R -SSTR1 and Thyroid Cancer
MSH3 5q14.1 DUP, MRP1 -MSH3 and Thyroid Cancer
CTSB 8p22 APPS, CPSB -CTSB and Thyroid Cancer
RASAL1 12q23-q24 RASAL -RASAL1 and Thyroid Cancer
KAT5 11q13 TIP, ESA1, PLIP, TIP60, cPLA2, HTATIP, ZC2HC5, HTATIP1 -KAT5 and Thyroid Cancer
CASP9 1p36.21 MCH6, APAF3, APAF-3, PPP1R56, ICE-LAP6 -CASP9 and Thyroid Cancer
HDAC6 Xp11.23 HD6, JM21, CPBHM, PPP1R90 -HDAC6 and Thyroid Cancer
RXRG 1q22-q23 RXRC, NR2B3 -RXRG and Thyroid Cancer
KTN1 14q22.1 CG1, KNT, MU-RMS-40.19 -KTN1 and Thyroid Cancer
TSPO 22q13.31 DBI, IBP, MBR, PBR, PBS, BPBS, BZRP, PKBS, PTBR, mDRC, pk18 -TSPO and Thyroid Cancer
CASR 3q13 CAR, FHH, FIH, HHC, EIG8, HHC1, NSHPT, PCAR1, GPRC2A, HYPOC1 -CASR and Thyroid Cancer
IL1A 2q14 IL1, IL-1A, IL1F1, IL1-ALPHA -IL1A and Thyroid Cancer
CD24 6q21 CD24A -CD24 and Thyroid Cancer
KLLN 10q23 CWS4, KILLIN -KLLN and Thyroid Cancer
IDO1 8p12-p11 IDO, INDO, IDO-1 -IDO1 and Thyroid Cancer
SPARC 5q31.3-q32 ON -SPARC and Thyroid Cancer
ASAH1 8p22 AC, PHP, ASAH, PHP32, ACDase, SMAPME -ASAH1 and Thyroid Cancer
IL11 19q13.3-q13.4 AGIF, IL-11 -IL11 and Thyroid Cancer
ERC1 12p13.3 ELKS, Cast2, ERC-1, RAB6IP2 -ERC1 and Thyroid Cancer
MMP13 11q22.3 CLG3, MANDP1, MMP-13 -MMP13 and Thyroid Cancer
MYCL 1p34.2 LMYC, L-Myc, MYCL1, bHLHe38 -MYCL and Thyroid Cancer
ST5 11p15 HTS1, p126, DENND2B -ST5 and Thyroid Cancer
DLL4 15q14 hdelta2 -DLL4 and Thyroid Cancer
RASSF2 20p13 CENP-34, RASFADIN Methylation
-Inactivation of RASSF2 in thyroid cancer
C2orf40 2q12.2 ECRG4 -C2orf40 and Thyroid Cancer
GPX3 5q33.1 GPx-P, GSHPx-3, GSHPx-P -GPX3 and Thyroid Cancer
CBX7 22q13.1 -CBX7 and Thyroid Cancer
GAGE1 Xp11.23 CT4.1, GAGE-1 -GAGE1 and Thyroid Cancer
FOXP1 3p14.1 MFH, QRF1, 12CC4, hFKH1B, HSPC215 -FOXP1 and Thyroid Cancer
G6PD Xq28 G6PD1 -G6PD and Thyroid Cancer
PTHLH 12p12.1-p11.2 HHM, PLP, BDE2, PTHR, PTHRP -PTHLH and Thyroid Cancer
PYGM 11q12-q13.2 -PYGM and Thyroid Cancer
GRASP 12q13.13 TAMALIN -GRASP and Thyroid Cancer
CA9 9p13.3 MN, CAIX -CA9 and Thyroid Cancer
CYP2D6 22q13.1 CPD6, CYP2D, CYP2DL1, CYPIID6, P450C2D, P450DB1, CYP2D7AP, CYP2D7BP, CYP2D7P2, CYP2D8P2, P450-DB1 -CYP2D6 and Thyroid Cancer
MAD2L1 4q27 MAD2, HSMAD2 -MAD2L1 and Thyroid Cancer
POLI 18q21.1 RAD30B, RAD3OB -POLI 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

Chernock RD, Hagemann IS
Molecular pathology of hereditary and sporadic medullary thyroid carcinomas.
Am J Clin Pathol. 2015; 143(6):768-77 [PubMed] Related Publications
OBJECTIVES: Medullary thyroid carcinoma (MTC) is a relatively uncommon type of thyroid malignancy, with unique histologic features and molecular pathology. It is important to recognize, because its management, which is in part driven by the genetic basis of this disease, is different from follicular-derived thyroid tumors. The aim of this article is to briefly review the histopathologic features of MTC and then explore its molecular pathology, including the role of molecular diagnostic testing and the use of targeted therapy for advanced disease.
METHODS: A review of published literature was performed.
RESULTS: A subset of MTC cases is hereditary and due to germline mutations in the RET tyrosine kinase receptor gene. Somatic mutations in either RET or RAS are also present in most sporadic tumors.
CONCLUSIONS: Molecular genetic testing is routinely performed to identify hereditary cases. In addition, understanding the molecular basis of both hereditary and sporadic MTC has led to the development of targeted therapy with tyrosine kinase inhibitors. Although additional data are needed, tumor mutation status may affect response to targeted therapy. Therefore, it is possible that genetic testing of tumor tissue to predict treatment response, as is currently done for other cancer types, may come into practice in the future.

Nagarajah J, Ho AL, Tuttle RM, et al.
Correlation of BRAFV600E Mutation and Glucose Metabolism in Thyroid Cancer Patients: An ¹⁸F-FDG PET Study.
J Nucl Med. 2015; 56(5):662-7 [PubMed] Related Publications
UNLABELLED: There is significant interest in a better understanding of the genetic underpinnings of the increased glucose metabolic rates of cancer cells. Thyroid cancer demonstrates a broad variability of (18)F-FDG uptake as well as several well-characterized oncogenic mutations. In this study, we evaluated the differences in glucose metabolism of the BRAF(V600E) mutation versus BRAF wild-type (BRAF-WT) in patients with metastatic differentiated thyroid cancer (DTC) and poorly differentiated thyroid cancer (PDTC).
METHODS: Forty-eight DTC and 34 PDTC patients who underwent (18)F-FDG PET/CT for tumor staging were identified from a database search. All patients were tested for the BRAF(V600E) mutation and assigned to 1 of 2 groups: BRAF(V600E) mutated and BRAF-WT. (18)F-FDG uptake of tumor tissue was quantified by maximum standardized uptake value (SUVmax) of the hottest malignant lesion in 6 prespecified body regions (thyroid bed, lymph nodes, lung, bone, soft tissue, and other). When there were multiple lesions in 1 of the prespecified body regions, only the 1 with the highest (18)F-FDG uptake was analyzed.
RESULTS: In the DTC cohort, 24 tumors harbored a BRAF(V600E) mutation, whereas 24 tumors were BRAF-WT. (18)F-FDG uptake of BRAF(V600E)-positive lesions (median SUVmax, 6.3; n = 53) was significantly higher than that of BRAF-WT lesions (n = 39; median SUVmax, 4.7; P = 0.019). In the PDTC group, only 5 tumors were BRAF(V600E)-positive, and their (18)F-FDG uptake was not significantly different from the BRAF-WT tumors. There was also no significant difference between the SUVmax of all DTCs and PDTCs, regardless of BRAF mutational status (P = 0.90).
CONCLUSION: These data suggest that BRAF(V600E)-mutated DTCs are significantly more (18)F-FDG-avid than BRAF-WT tumors. The effect of BRAF(V600E) on tumor glucose metabolism in PDTC needs further study in larger groups of patients.

Shi Q, Ibrahim A, Herbert K, et al.
Detection of BRAF mutations on direct smears of thyroid fine-needle aspirates through cell transfer technique.
Am J Clin Pathol. 2015; 143(4):500-4 [PubMed] Related Publications
OBJECTIVES: To determine the utility of the cell transfer technique (CTT) for BRAF molecular testing on thyroid fine-needle aspiration (FNA) specimens.
METHODS: Polymerase chain reaction (PCR)-based BRAF molecular testing was performed on tissues obtained through CTT from both air-dried and ethanol-fixed direct smears of thyroid FNA specimens and then compared with the corresponding thyroidectomy formalin-fixed, paraffin-embedded (FFPE) tissues on 30 cases.
RESULTS: BRAF testing was successfully performed on 29 of 30 air-dried CTT, 27 of 30 ethanol-fixed CTT, and 27 of 30 FFPE tissues. The results exhibited 11, 13, and 13 BRAF mutations and 18, 14, and 14 wild types for the air-dried CTT, the ethanol-fixed CTT, and the FFPE tissues, respectively. The concordance rate was 96% between air-dried and ethanol-fixed CTT tissues, 88% between air-dried CTT and FFPE tissues, and 92% between ethanol-fixed CTT and FFPE tissues.
CONCLUSIONS: PCR-based BRAF mutational testing can be reliably performed on the direct smears of the thyroid FNA specimens through the application of CTT.

Wei WJ, Lu ZW, Wang Y, et al.
Clinical significance of papillary thyroid cancer risk loci identified by genome-wide association studies.
Cancer Genet. 2015; 208(3):68-75 [PubMed] Related Publications
Four single nucleotide polymorphisms (SNPs) have been reported to be associated with thyroid cancer risk in two genome-wide association studies (GWASs) and were validated in a Chinese population. Because of a lack of further clinical and functional evidence, the clinical significances of these SNPs remain unknown. Four GWAS-identified SNPs of papillary thyroid cancer (PTC), rs965513, rs944289, rs966423 and rs2439302, were genotyped in a case-control study of 838 patients with PTC and 501 patients with benign thyroid tumor (BTT) from the Chinese Han population. The associations between these SNPs, clinicopathologic features, and the outcome of the PTC patients were examined. The CT and CT + TT genotypes of rs966423 were more common in PTC patients with extrathyroidal extension and more advanced T stage. The TC and TC + CC genotypes and the C allele of rs944289 were significantly less frequent in patients with multifocal disease. No correlation was observed between GWAS-identified SNPs and disease persistence of PTC after a short-term follow-up. Significantly different allele distributions between the PTC and BTT groups were observed for all four selected SNPs. Individuals with more than five risk alleles were 8.84-fold (95% CI 3.23-24.17) more likely to suffer from PTC compared with those with zero or 1 risk allele. GWAS-identified SNPs affect the individual predisposition to PTC without interacting with existing Hashimoto thyroiditis and BTT lesions. GWAS-identified SNPs were associated with certain clinicopathologic features of PTC, and may contribute to identifying PTC patients with different clinical patterns. Large prospective studies are required to further evaluate the diagnostic and prognostic power of these genetic markers.

Heineman TE, Joshi R, Cohen MA, et al.
In silico analysis of RET variants in medullary thyroid cancer: from the computer to the bedside.
Otolaryngol Head Neck Surg. 2015; 152(4):650-4 [PubMed] Related Publications
OBJECTIVE: The American Thyroid Association (ATA) medullary thyroid cancer (MTC) guidelines group RET variants, in the setting of familial medullary thyroid cancer and multiple endocrine neoplasia type 2, into 4 classes of severity based on epidemiological data. The aim of this study was to determine if genotype correlates with phenotype in RET missense mutations.
STUDY DESIGN: In silico mutational tolerance prediction.
SETTING: Academic research hospital.
SUBJECTS AND METHODS: We analyzed all RET variants currently listed in the ATA guidelines for the management of MTC using 2 computer-based (in silico) mutation tolerance prediction approaches: PolyPhen-2 HumVar and PolyPhen-2 HumDiv. Our analysis also included 27 different RET single-nucleotide polymorphisms resulting in missense variants.
RESULTS: There was a statistically significant difference in the overall HumDiv score between ATA groups A and B (P = .025) and a statistically significant different HumVar score between benign polymorphisms and ATA group A (P = .023). Overall, RET variants associated with a less aggressive clinical phenotype generally had a lower Hum Div/Var score.
CONCLUSIONS: Polyphen-2 Hum Div/Var may provide additional clinical data to help distinguish benign from MEN2/familial medullary thyroid carcinoma-causing RET variants as well as less aggressive phenotypes (ATA A) from more aggressive ones (ATA B-C). In silico genetic analyses, with proper validation, may predict the phenotypic severity of RET variants, providing clinicians with a tool to aid clinical decision making in cases in which the RET variant is currently unknown or little epidemiological data are available.

Colato C, Vicentini C, Cantara S, et al.
Break-apart interphase fluorescence in situ hybridization assay in papillary thyroid carcinoma: on the road to optimizing the cut-off level for RET/PTC rearrangements.
Eur J Endocrinol. 2015; 172(5):571-82 [PubMed] Related Publications
OBJECTIVE: Chromosomal rearrangements of the RET proto-oncogene is one of the most common molecular events in papillary thyroid carcinoma (PTC). However, their pathogenic role and clinical significance are still debated. This study aimed to investigate the prevalence of RET/PTC rearrangement in a cohort of BRAF WT PTCs by fluorescence in situ hybridization (FISH) and to search a reliable cut-off level in order to distinguish clonal or non-clonal RET changes.
DESIGN: Forty BRAF WT PTCs were analyzed by FISH for RET rearrangements. As controls, six BRAFV600E mutated PTCs, 13 follicular adenomas (FA), and ten normal thyroid parenchyma were also analyzed.
METHODS: We performed FISH analysis on formalin-fixed, paraffin-embedded tissue using a commercially available RET break-apart probe. A cut-off level equivalent to 10.2% of aberrant cells was accepted as significant. To validate FISH results, we analyzed the study cohort by qRT-PCR.
RESULTS: Split RET signals above the cut-off level were observed in 25% (10/40) of PTCs, harboring a percentage of positive cells ranging from 12 to 50%, and in one spontaneous FA (1/13, 7.7%). Overall, the data obtained by FISH matched well with qRT-PCR results. Challenging findings were observed in five cases showing a frequency of rearrangement very close to the cut-off.
CONCLUSIONS: FISH approach represents a powerful tool to estimate the ratio between broken and non-broken RET tumor cells. Establishing a precise FISH cut-off may be useful in the interpretation of the presence of RET rearrangement, primarily when this strategy is used for cytological evaluation or for targeted therapy.

Lee J, Jeong S, Park JH, et al.
Aberrant expression of COT is related to recurrence of papillary thyroid cancer.
Medicine (Baltimore). 2015; 94(6):e548 [PubMed] Related Publications
Aberrant expression of Cancer Osaka Thyroid Oncogene mitogen-activated protein kinase kinase kinase 8 (COT) (MAP3K8) is a driver of resistance to B-RAF inhibition. However, the de novo expression and clinical implications of COT in papillary thyroid cancer (PTC) have not been investigated.The aim of this study is to investigate the expression of A-, B-, C-RAF, and COT in PTC (n = 167) and analyze the clinical implications of aberrant expression of these genes.Quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC) were performed on primary thyroid cancers. Expression of COT was compared with clinicopathological characteristics including recurrence-free survival. Datasets from public repository (NCBI) were subjected to Gene Set Enrichment Analysis (GSEA).qPCR data showed that the relative mRNA expression of A-, B-, C-RAF and COT of PTC were higher than normal tissues (all P < 0.01). In addition, the expression of COT mRNA in PTC showed positive correlation with A- (r = 0.4083, P < 0.001), B- (r = 0.2773, P = 0.0003), and C-RAF (r = 0.5954, P < 0.001). The mRNA expressions of A-, B,- and C-RAF were also correlated with each other (all P < 0.001). In IHC, the staining intensities of B-RAF and COT were higher in PTC than in normal tissue (P < 0.001). Interestingly, moderate-to-strong staining intensities of B-RAF and COT were more frequent in B-RAF-positive PTC (P < 0.001, P = 0.013, respectively). In addition, aberrant expression of COT was related to old age at initial diagnosis (P = 0.045) and higher recurrence rate (P = 0.025). In multivariate analysis, tumor recurrence was persistently associated with moderate-to-strong staining of COT after adjusting for age, sex, extrathyroidal extension, multifocality, T-stage, N-stage, TNM stage, and B-RAF mutation (odds ratio, 4.662; 95% confidence interval 1.066 - 21.609; P = 0.045). Moreover, moderate-to-strong COT expression in PTC was associated with shorter recurrence-free survival (mean follow-up duration, 14.2 ± 4.1 years; P = 0.0403). GSEA indicated that gene sets related to B-RAF-RAS (P < 0.0001, false discovery rate [FDR] q-value = 0.000) and thyroid differentiation (P = 0.048, FDR q-value = 0.05) scores were enriched in lower COT expression group and gene sets such as T-cell receptor signaling pathway and Toll-like receptor signaling pathway are coordinately upregulated in higher COT expression group (both, P < 0.0001, FDR q-value = 0.000).Aberrant expression of A-, B-, and C-RAF, and COT is frequent in PTC; increased expression of COT is correlated with recurrence of PTC.

Schechter RB, Nagilla M, Joseph L, et al.
Genetic profiling of advanced radioactive iodine-resistant differentiated thyroid cancer and correlation with axitinib efficacy.
Cancer Lett. 2015; 359(2):269-74 [PubMed] Related Publications
Biomarkers predicting which patients with advanced radioiodine-resistant differentiated thyroid cancer (DTC) may benefit from multi-kinase inhibitors are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Pretreatment thyroid cancer blocks from 18 patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta™ Mutation Panel was used to test for 238 oncogenic mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR on enriched tumor samples. Genomic DNA was analyzed for all coding regions of VEGFR1-3 with custom primers. Protein expressions of VEGFR1-3, c-Met, and PIK3CA were evaluated with immunohistochemistry. Clinical response to axitinib, including best response (BR) and progression free survival (PFS), was ascertained from corresponding patients. Fisher's exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. A total of 22 pathology samples (10 primary, 12 metastatic) were identified. In patients with 2 samples (n = 4), genetic results were concordant and only included once for analysis. Tumors from 4 patients (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One metastatic sample with mutated KRAS also harbored a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing was significant for a possibly damaging non-synonymous SNP in VEGFR2 (G539R) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350V) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439I) in 2 samples (11%). Immunohistochemistry (VEGFR1, -2, -3; c-MET; PIK3CA) revealed positive staining in the majority of samples. No significant relationship was seen between BR or PFS and the presence of molecular alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but our data were limited by sample size. We did identify molecular changes in VEGFR that should be further explored. While DTC is genetically heterogeneous, primary and metastatic lesions showed identical oncogenic alterations in four cases.

Sarika HL, Papathoma A, Garofalaki M, et al.
Genetic screening of patients with medullary thyroid cancer in a referral center in Greece during the past two decades.
Eur J Endocrinol. 2015; 172(4):501-9 [PubMed] Related Publications
OBJECTIVE: Mutations in the RET gene are responsible for hereditary medullary thyroid cancer (MTC) and may vary between ethnic groups. We report the spectrum of mutations detected in patients with MTC in a referral center in Greece.
PATIENTS AND METHODS: Screening for RET mutations was performed in 313 subjects from 188 unrelated families: 51 patients had clinical suspicion for familial disease, 133 were apparently sporadic, four patients had only C cell hyperplasia, and 125 were family members. Exons 8, 10, 11, and 13-16 were screened.
RESULTS: A total of 58 individuals (30.85%) were RET mutations carriers, 120 (63.8%) were finally classified as sporadic, 13 apparently sporadic cases (9.8%) were identified with RET mutation: ten carried the exon 8 at codon 533 mutation (previously reported), two the exon 14 at codon 804 mutation, and one the exon 13 at codon 768 mutation. Six patients (3.19%) with clinical features of multiple endocrine neoplasia type 2A and negative for RET mutations were classified as 'unknown cause'. The mutations of hereditary cases were as follows: 21 cases (36.2%) in exon 8 codon 533, 19 (32.8%) in exon 11 codon 634, nine (15.5%) in exon 10, five (8.6%) in exon 16, three (5.2%) in exon 14 codon 804, and one in exon 13 codon 768 (1.7%).
CONCLUSION: The spectrum of RET mutations in Greece differs from that in other populations and the prevalence of familial cases is higher. The exon 8 (Gly533Cys) mutation was the most prevalent in familial cases unlike other series, followed by exon 11 (codon 634) mutations which are the most frequent elsewhere. The wide application of genetic screening in MTC reveals new molecular defects and helps to characterize the spectrum of mutations in each ethnic group.

Kim SY, Kim EK, Kwak JY, et al.
What to do with thyroid nodules showing benign cytology and BRAF(V600E) mutation? A study based on clinical and radiologic features using a highly sensitive analytic method.
Surgery. 2015; 157(2):354-61 [PubMed] Related Publications
BACKGROUND: BRAF(V600E) mutation analysis has been used as a complementary diagnostic tool to ultrasonography-guided, fine-needle aspiration (US-FNA) in the diagnosis of thyroid nodule with high specificity reported up to 100%. When highly sensitive analytic methods are used, however, false-positive results of BRAF(V600E) mutation analysis have been reported. In this study, we investigated the clinical, US features, and outcome of patients with thyroid nodules with benign cytology but positive BRAF(V600E) mutation using highly sensitive analytic methods from US-FNA.
METHODS: This study included 22 nodules in 22 patients (3 men, 19 women; mean age, 53 years) with benign cytology but positive BRAF(V600E) mutation from US-FNA. US features were categorized according to the internal components, echogenicity, margin, calcifications, and shape. Suspicious US features included markedly hypoechogenicity, noncircumscribed margins, micro or mixed calcifications, and nonparallel shape. Nodules were considered to have either concordant or discordant US features to benign cytology. Medical records and imaging studies were reviewed for final cytopathology results and outcomes during follow-up.
RESULTS: Among the 22 nodules, 17 nodules were reviewed. Fifteen of 17 nodules were malignant, and 2 were benign. The benign nodules were confirmed as adenomatous hyperplasia with underlying lymphocytic thyroiditis and a fibrotic nodule with dense calcification. Thirteen of the 15 malignant nodules had 2 or more suspicious US features, and all 15 nodules were considered to have discordant cytology considering suspicious US features. Five nodules had been followed with US or US-FNA without resection, and did not show change in size or US features on follow-up US examinations.
CONCLUSION: BRAF(V600E) mutation analysis is a highly sensitive diagnostic tool in the diagnosis of papillary thyroid carcinomas. In the management of thyroid nodules with benign cytology but positive BRAF(V600E) mutation, thyroidectomy should be considered in nodules which have 2 or more suspicious US features and are considered discordant on image-cytology correlation.

Liu L, Wang J, Li X, et al.
MiR-204-5p suppresses cell proliferation by inhibiting IGFBP5 in papillary thyroid carcinoma.
Biochem Biophys Res Commun. 2015; 457(4):621-6 [PubMed] Related Publications
microRNAs (miRNAs) are frequently dysregulated in human malignancies. It was recently shown that miR-204-5p is downregulated in papillary thyroid carcinoma (PTC); however, the functional significance of this observation is not known. This study investigated the role of miR-204-5p in PTC. Overexpressing miR-204-5p suppressed PTC cell proliferation and induced cell cycle arrest and apoptosis. The results of a luciferase reporter assay showed that miR-204-5p can directly bind to the 3' untranslated region (UTR) of insulin-like growth factor-binding protein 5 (IGFBP5) mRNA, and IGFBP5 overexpression partially reversed the growth-inhibitory effects of miR-204-5p. These results indicate that miR-204-5p acts as a tumor suppressor in PTC by regulating IGFBP5 expression and that miR-204-5p can potentially serve as an antitumorigenic agent in the treatment of PTC.

Lee J, Seol MY, Jeong S, et al.
A metabolic phenotype based on mitochondrial ribosomal protein expression as a predictor of lymph node metastasis in papillary thyroid carcinoma.
Medicine (Baltimore). 2015; 94(2):e380 [PubMed] Related Publications
Metabolic reprogramming has been regarded as an essential component of malignant transformation. However, the clinical significance of metabolic heterogeneity remains poorly characterized. The aim of this study was to characterize metabolic heterogeneity in thyroid cancers via the analysis of the expression of mitochondrial ribosomal proteins (MRPs) and genes involved in oxidative phosphorylation (OxPhos), and investigate potential prognostic correlations. Gene set enrichment analysis (GSEA) verified by reverse transcription polymerase chain reaction and gene network analysis was performed using public repository data. Cross-sectional observational study was conducted to classify papillary thyroid cancer (PTC) by the expression of MRP L44 (MRPL44) messenger RNA (mRNA), and to investigate the clinicopathological features. GSEA clearly showed that the expression of OxPhos and MRP gene sets was significantly lower in primary thyroid cancer than in matched normal thyroid tissue. However, 8 of 49 primary thyroid tumors (16.3%) in the public repository did not show a reduction in OxPhos mRNA expression. Remarkably, strong positive correlations between MRPL44 expression and those of OxPhos and MRPs such as reduced nicotinamide adenine dinucleotide dehydrogenase (ubiquinone) 1 α subcomplex, 5; succinate dehydrogenase complex, subunit D; cytochrome c, somatic; adenosine triphosphate synthase, H+ transporting, mitochondrial Fo complex, subunit C1 (subunit 9); and MRP S5 (MRPS5) (P < 0.0001) were clearly denoted, suggesting that MRPL44 is a representative marker of OxPhos and MRP expressions. In laboratory experiments, metabolic heterogeneity in oxygen consumption, extracellular acidification rates (ECARs), and amounts of OxPhos complexes were consistently observed in BCPAP, TPC1, HTH-7, and XTC.UC1 cell lines. In PTCs, metabolic phenotype according to OxPhos amount defined by expression of MRPL44 mRNA was significantly related to lymph node metastasis (LNM) (P < 0.001). Furthermore, multivariate analysis clearly indicated that expression of MRPL44 is associated with an increased risk of lateral neck LNM (odds ratio 9.267, 95% confidence interval 1.852-46.371, P = 0.007). MRPL44 expression may be a representative marker of metabolic phenotype according to OxPhos amount and a useful predictor of LNM.

Gandolfi G, Ragazzi M, Frasoldati A, et al.
TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma.
Eur J Endocrinol. 2015; 172(4):403-13 [PubMed] Related Publications
OBJECTIVE: Transcriptional activating mutations in the promoter of the telomerase reverse transcriptase (TERT) gene were reported at high frequency in aggressive poorly differentiated and anaplastic thyroid cancers. By contrast, the relevance of these mutations in the metastatic behavior of well-differentiated thyroid cancer is still to be defined. The aim of this work was to investigate the frequency of TERT promoter mutations in a remarkable cohort of well-differentiated papillary thyroid carcinoma that developed distant metastases (DM-PTCs) and to establish whether these mutations may be predictive of metastatic behavior.
DESIGN: We analyzed the frequency of TERT promoter mutations in a group of 43 highly aggressive DM-PTCs. As controls, we analyzed these mutations in a group of 78 PTCs without distant metastases (control-PTCs). The possible correlation between TERT promoter mutations and BRAF V600E mutation was also investigated.
METHODS: TERT promoter mutational status was evaluated by direct sequencing of the hotspot harboring the C228T and the C250T mutations.
RESULTS: In the overall cohort of 121 PTCs analyzed, 17% of cases (21/121) carried a mutation in the TERT promoter. Noticeably, 33% of DM-PTCs were mutated in the TERT promoter while only 9% of the control-PTCs showed a mutation in this locus. We also observed a positive association between BRAF V600E and TERT C228T mutations in the cohort of DM-PTCs.
CONCLUSIONS: These results indicate that TERT promoter mutations are associated with the development of distant metastases in PTCs and may help in predicting aggressive behavior in this type of tumor.

Siołek M, Cybulski C, Gąsior-Perczak D, et al.
CHEK2 mutations and the risk of papillary thyroid cancer.
Int J Cancer. 2015; 137(3):548-52 [PubMed] Related Publications
Mutations in the cell cycle checkpoint kinase 2 (CHEK2) tumor suppressor gene are associated with multi-organ cancer susceptibility including cancers of the breast and prostate. A genetic association between thyroid and breast cancer has been suggested, however little is known about the determinants of this association. To characterize the association of CHEK2 mutations with thyroid cancer, we genotyped 468 unselected patients with papillary thyroid cancer and 468 (matched) cancer-free controls for four founder mutations of CHEK2 (1100delC, IVS2 + 1G>A, del5395 and I157T). We compared the family histories reported by patients with a CHEK2 mutation to those of non-carriers. A CHEK2 mutation was seen in 73 of 468 (15.6%) unselected patients with papillary thyroid cancer, compared to 28 of 460 (6.0%) age- and sex-matched controls (OR 3.3; p < 0.0001). A truncating mutation (IVS2 + 1G>A, 1100delC or del5395) was associated with a higher risk of thyroid cancer (OR = 5.7; p = 0.006), than was the missense mutation I157T (OR = 2.8; p = 0.0001). CHEK2 mutation carriers reported a family history of breast cancer 2.2 times more commonly than non-carriers (16.4% vs.8.1%; p = 0.05). A CHEK2 mutation was found in seven of 11 women (63%) with multiple primary cancers of the breast and thyroid (OR = 10; p = 0.0004). These results suggest that CHEK2 mutations predispose to thyroid cancer, familial aggregations of breast and thyroid cancer and to double primary cancers of the breast and thyroid.

Barbieri RB, Bufalo NE, Secolin R, et al.
Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma.
Eur J Endocrinol. 2014; 171(6):761-7 [PubMed] Related Publications
BACKGROUND: The role of key cell cycle regulation genes such as, CDKN1B, CDKN2A, CDKN2B, and CDKN2C in sporadic medullary thyroid carcinoma (s-MTC) is still largely unknown.
METHODS: In order to evaluate the influence of inherited polymorphisms of these genes on the pathogenesis of s-MTC, we used TaqMan SNP genotyping to examine 45 s-MTC patients carefully matched with 98 controls.
RESULTS: A multivariate logistic regression analysis demonstrated that CDKN1B and CDKN2A genes were related to s-MTC susceptibility. The rs2066827*GT+GG CDKN1B genotype was more frequent in s-MTC patients (62.22%) than in controls (40.21%), increasing the susceptibility to s-MTC (OR=2.47; 95% CI=1.048-5.833; P=0.038). By contrast, the rs11515*CG+GG of CDKN2A gene was more frequent in the controls (32.65%) than in patients (15.56%), reducing the risk for s-MTC (OR=0.174; 95% CI=0.048-0.627; P=0.0075). A stepwise regression analysis indicated that two genotypes together could explain 11% of the total s-MTC risk. In addition, a relationship was found between disease progression and the presence of alterations in the CDKN1A (rs1801270), CDKN2C (rs12885), and CDKN2B (rs1063192) genes. WT rs1801270 CDKN1A patients presented extrathyroidal tumor extension more frequently (92%) than polymorphic CDKN1A rs1801270 patients (50%; P=0.0376). Patients with the WT CDKN2C gene (rs12885) presented larger tumors (2.9±1.8 cm) than polymorphic patients (1.5±0.7 cm; P=0.0324). On the other hand, patients with the polymorphic CDKN2B gene (rs1063192) presented distant metastases (36.3%; P=0.0261).
CONCLUSION: In summary, we demonstrated that CDKN1B and CDKN2A genes are associated with susceptibility, whereas the inherited genetic profile of CDKN1A, CDKN2B, and CDKN2C is associated with aggressive features of tumors. This study suggests that profiling cell cycle genes may help define the risk and characterize s-MTC aggressiveness.

Grubbs EG, Ng PK, Bui J, et al.
RET fusion as a novel driver of medullary thyroid carcinoma.
J Clin Endocrinol Metab. 2015; 100(3):788-93 [PubMed] Article available free on PMC after 01/03/2016 Related Publications
INTRODUCTION: Oncogenic RET tyrosine kinase gene fusions and activating mutations have recently been identified in lung cancers, prompting initiation of targeted therapy trials in this disease. Although RET point mutation has been identified as a driver of tumorigenesis in medullary thyroid carcinoma (MTC), no fusions have been described to date.
OBJECTIVE: We evaluated the role of RET fusion as an oncogenic driver in MTC.
METHODS: We describe a patient who died from aggressive sporadic MTC < 10 months after diagnosis. Her tumor was evaluated by means of next-generation sequencing, including an intronic capture strategy.
RESULTS: A reciprocal translocation involving RET intron 12 was identified. The fusion was validated using a targeted break apart fluorescence in situ hybridization probe, and RNA sequencing confirmed the existence of an in-frame fusion transcript joining MYH13 exon 35 with RET exon 12. Ectopic expression of fusion product in a murine Ba/F3 cell reporter model established strong oncogenicity. Three tyrosine kinase inhibitors currently used to treat MTC in clinical practice blocked tumorigenic cell growth.
CONCLUSION: This finding represents the report of a novel RET fusion, the first of its kind described in MTC. The finding of this potential novel oncogenic mechanism has clear implications for sporadic MTC, which in the majority of cases has no driver mutation identified. The presence of a RET fusion also provides a plausible target for RET tyrosine kinase inhibitor therapies.

Leone V, Ferraro A, Schepis F, et al.
The cl2/dro1/ccdc80 null mice develop thyroid and ovarian neoplasias.
Cancer Lett. 2015; 357(2):535-41 [PubMed] Related Publications
We have previously reported that the expression of the CL2/CCDC80 gene is downregulated in human papillary thyroid carcinomas, particularly in follicular variants. We have also reported that the restoration of CL2/CCDC80 expression reverted the malignant phenotype of thyroid carcinoma cell lines and that CL2/CCDC80 positively regulated E-cadherin expression, an ability that likely accounts for the role of the CL2/CCDC80 gene in thyroid cancer progression. In order to validate the tumour suppressor role of the CL2/CCDC80 gene in thyroid carcinogenesis we generated cl2/ccdc80 knock-out mice. We found that embryonic fibroblasts from cl2/ccdc80(-/-) mice showed higher proliferation rate and lower susceptibility to apoptosis. Furthermore, cl2/ccdc80(-/-) mice developed thyroid adenomas and ovarian carcinomas. Finally, ret/PTC1 transgenic mice crossed with the cl2/ccdc80 knock-out mice developed more aggressive thyroid carcinomas compared with those observed in the single ret/PTC1 transgenic mice. Together, these results indicate CL2/CCDC80 as a putative tumour suppressor gene in human thyroid carcinogenesis.

Boufraqech M, Nilubol N, Zhang L, et al.
miR30a inhibits LOX expression and anaplastic thyroid cancer progression.
Cancer Res. 2015; 75(2):367-77 [PubMed] Related Publications
Anaplastic thyroid cancer (ATC) is one of the most lethal human malignancies, but its genetic drivers remain little understood. In this study, we report losses in expression of the miRNA miR30a, which is downregulated in ATC compared with differentiated thyroid cancer and normal tissue. miR30a downregulation was associated with advanced differentiated thyroid cancer and higher mortality. Mechanistically, we found miR30a decreased cellular invasion and migration, epithelial-mesenchymal transition marker levels, lysyl oxidase (LOX) expression, and metastatic capacity. LOX was identified as a direct target of miR30a that was overexpressed in ATC and associated with advanced differentiated thyroid cancer and higher mortality rate. Consistent with its role in other cancers, we found that LOX inhibited cell proliferation, cellular invasion, and migration and metastasis in vitro and in vivo. Together, our findings establish a critical functional role for miR30a downregulation in mediating LOX upregulation and thyroid cancer progression, with implications for LOX targeting as a rational therapeutic strategy in ATC.

Niederer-Wüst SM, Jochum W, Förbs D, et al.
Impact of clinical risk scores and BRAF V600E mutation status on outcome in papillary thyroid cancer.
Surgery. 2015; 157(1):119-25 [PubMed] Related Publications
BACKGROUND: To evaluate the relationship between the BRAF V600E mutation and clinicopathologic parameters and to assess the impact of the BRAF V600E mutation and established risk scores on survival in patients with papillary thyroid carcinoma (PTC).
METHODS: Retrospective analysis of a consecutive, single-institutional cohort of patients with PTC larger than 1 cm. Clinical risk scores according to the Metastases, Age, Completeness of Resection, Invasion, Size (MACIS), European Organisation for Research and Treatment of Cancer (EORTC), and tumor, node, metastases (TNM) scoring systems were determined. BRAF exon 15 mutation analysis was performed by polymerase chain reaction and Sanger sequencing.
RESULTS: BRAF V600E mutations were found in 75/116 (65%) PTC. The rates for 5- and 10-year overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were 92% and 87%, 98% and 96%, and 96% and 94%, respectively. Low MACIS scores were associated with longer OS (10 y 95% vs 75%, P = .008), DSS (10 y 100% vs 89%, P = .02) and RFS (100% vs 85%, P = .006). Comparable survival advantages were observed for patients with early EORTC scores and low TNM stage. BRAF V600E mutation status was not associated with clinicopathologic characteristics of aggressive behavior such as extrathyroidal extension, lymph node metastases, higher T-categories, male sex, and greater age. Furthermore, BRAF V600E mutation status was not correlated with clinical risk scores and decreased survival.
CONCLUSION: In concordance with other studies, we did not find a negative prognostic impact of a positive BRAF V600E mutation status on survival. In contrast, the risk algorithms MACIS, EORTC score, and TNM stage were associated with impaired prognosis. Therefore, clinical staging systems represent better tools for risk stratification than BRAF V600E mutation status.

Chai YJ, Kim YA, Jee HG, et al.
Expression of the embryonic morphogen Nodal in differentiated thyroid carcinomas: Immunohistochemistry assay in tissue microarray and The Cancer Genome Atlas data analysis.
Surgery. 2014; 156(6):1559-67; discussion 1567-8 [PubMed] Related Publications
BACKGROUND: Nodal, an embryonic morphogen, plays a role in tumorigenesis of melanoma, breast, and prostate cancer; however, its role in thyroid carcinoma is unknown. We examined Nodal expression in thyroid tumors by immunohistochemistry assay and The Cancer Genome Atlas (TCGA) analysis.
METHODS: An immunohistochemistry assay was performed in a tissue microarray comprising 128 classic papillary thyroid carcinomas (PTC), 58 follicular thyroid carcinomas (FTC), 19 follicular variants of PTC (FVPTC), 57 follicular adenomas (FA), 54 adenomatous goiters (AG), and 5 normal thyroid tissues. The TCGA database was examined to evaluate the expression of Nodal mRNA in normal thyroid and PTC.
RESULTS: The proportion of tumors showing negative Nodal expression in PTC, FTC, FVPTC, FA, and AG was 0%, 1.7%, 0%, 14%, and 41%, respectively. For the diagnosis of malignant tumors, the sensitivity, specificity, positive predictive value, and negative predictive value of positive Nodal staining was 99%, 27%, 72%, and 97%, respectively. High Nodal expression was associated with older age and BRAF mutation in PTC. TCGA analysis revealed PTC had greater Nodal mRNA expression than normal thyroid (P = .012).
CONCLUSION: Nodal staining might be useful "rule-out test" for the diagnosis of malignant thyroid tumor. Nodal may be associated with the tumorigenesis of thyroid malignancy.

Miccoli P, Torregrossa L, Borrelli N, et al.
E-selectin expression and BRAF status in papillary thyroid carcinomas: Correlation with clinicopathologic features.
Surgery. 2014; 156(6):1550-7; discussion 1557-8 [PubMed] Related Publications
BACKGROUND: Cell adhesion molecules, represented by the immunoglobulin family and selectins, play an important role in the progression of cancer. A correlation between selectins and tumor aggressiveness has been demonstrated in several reports.
METHODS: Eighty-eight patients (mean age, 41.0 ± 14 years) with papillary thyroid carcinoma (conventional variant and sized approximately 20 mm) were divided in 2 groups: 41 with encapsulated tumors and 47 with tumors with extrathyroidal extension. E-selectin expression was evaluated by immunohistochemical staining and semiquantitative real-time reverse-transcription polymerase chain reaction and normalized by calculating the z-score (positive: value above the population mean; negative: below the mean).
RESULTS: Lymph node metastasis (LNM) was found in 2 of 41 encapsulated tumors (4.8%) and in 19 of 47 tumors (40.4%) with extrathyroidal extension. BRAF mutation was present in 21 encapsulated tumors (51.2%) and in 31 tumors with extrathyroidal extension (65.9%). The mean E-selectin z-score was -0.32 for encapsulated tumors and 0.28 for tumors with extrathyroidal extension. E-selectin expression correlates with neoplastic infiltration (P = .04), the American Joint Commission on Cancer stage (P = .02), and BRAF mutation (P = .03).
CONCLUSION: E-selectin overexpression in association with BRAF mutation status could promote a more aggressive phenotype in papillary thyroid carcinoma.

Moraitis D, Karanikou M, Liakou C, et al.
SIN1, a critical component of the mTOR-Rictor complex, is overexpressed and associated with AKT activation in medullary and aggressive papillary thyroid carcinomas.
Surgery. 2014; 156(6):1542-8; discussion 1548-9 [PubMed] Related Publications
BACKGROUND: Mammalian target of rapamycin (mTOR) forms 2 active complexes in the cell: the rapamycin-sensitive mTOR-Raptor (mTORC1) and the rapamycin-insensitive mTOR-Rictor (mTORC2). The latter activates AKT kinase, which promotes tumor cell survival and proliferation by multiple downstream targets. Mammalian stress-activated protein kinase interacting protein 1 (SIN1), an essential subunit of the mTORC2 complex, maintains the integrity of the complex and substrate specificity and regulates Akt activation. The role of mTOR-Rictor complex activation in thyroid carcinogenesis remains unknown. Therefore, we investigated expression patterns of Sin1 in the cells lines of thyroid carcinoma and tumors and their association with AKT activation, histologic type, and tumor aggressiveness.
METHODS: Tissue specimens from 42 patients with thyroid cancer, including follicular (5), papillary (18), medullary (16), and poorly differentiated (3) carcinomas were analyzed via immunohistochemistry for SIN1 expression and AKT phosphorylation at Ser473 residue (Ser473-p-AKT). Eight of 18 papillary carcinomas were aggressive histologic variants. In addition, expression of Sin1 and activation of AKT kinase were analyzed in fresh-frozen tissue samples (normal/tumor), primary cell cultures (papillary thyroid carcinoma [PTC]), and an established thyroid cancer cell line (medullary thyroid carcinoma) by Western blotting.
RESULTS: With immunohistochemistry, we found that Sin1 was overexpressed in medullary thyroid carcinomas and aggressive variants of papillary thyroid carcinoma compared with conventional papillary and follicular carcinomas (P < .001). Sin1 expression correlated with AKT activation in the entire study group (P = .002). Using Western blot analysis, we found that Sin1 and p-AKT were detected at a greater level in cultured primary cells from aggressive PTC compared with conventional PTC as well as in cell lines of medullary and anaplastic thyroid carcinoma. High expression levels of SIN1 were detected in papillary thyroid carcinomas compared with benign nodules in immunoblots in which we used fresh-frozen patient samples. Two of the Sin1 protein isoforms, p76 and p55, were detected predominantly in PTC samples.
CONCLUSION: Sin1, a critical factor of the mTORC2 complex is overexpressed in clinically aggressive thyroid cancer types and is associated strongly with activation of AKT kinase. Sin1-dependent AKT activation might represent a target for experimental therapy.

Erler P, Keutgen XM, Crowley MJ, et al.
Dicer expression and microRNA dysregulation associate with aggressive features in thyroid cancer.
Surgery. 2014; 156(6):1342-50; discussion 1350 [PubMed] Related Publications
BACKGROUND: Altered miRNA expression and down-regulation of Dicer has been shown in various cancers. We investigated Dicer expression and global miRNA environment in correlation with malignant features of thyroid tumors.
METHODS: Dicer gene expression was assessed for 22 normal thyroids, 16 follicular adenomas, 28 papillary thyroid cancers (PTCs), 10 tall-cell variants of PTC, 11 follicular variants of PTC, as well as the four thyroid cell lines BCPAP, TPC1, KTC1, and TAD2 via quantitative polymerase chain reaction. BRAF((V600E)) mutation screening was completed for 31 neoplasms. Next-generation sequencing was performed on a subset of PTC and normal thyroid. Protein levels were assessed via Western blotting and immunohistochemistry.
RESULTS: Dicer mRNA was down-regulated in malignant thyroid samples and cell lines compared with normal tissues, benign neoplasms, and the fetal cell line TAD2. Decreased Dicer gene expression in malignant tissues was correlated greatly with aggressive features: extrathyroidal extension, angiolymphatic invasion, multifocality, lymph node and distant metastasis, recurrence, and BRAF((V600E)) mutation. Conversely, increased levels of Dicer protein were observed in malignant tissues and cell lines. Sequencing yielded 19 differentially expressed miRNAs. Eight samples had a nonsignificant a global down-regulation in malignant tissues.
CONCLUSION: Dysregulation of Dicer and possibly altered expression of miRNAs are associated with aggressive features in thyroid cancers. These findings suggest that disruption in normal miRNA processing involving Dicer may play a role in thyroid cancer progression.

Muzza M, Colombo C, Rossi S, et al.
Telomerase in differentiated thyroid cancer: promoter mutations, expression and localization.
Mol Cell Endocrinol. 2015; 399:288-95 [PubMed] Related Publications
Telomerase-reverse-transcriptase (TERT) promoter mutations have been recently described in tumors. In the present large series, TERT mutations were found in 12% of papillary thyroid cancers (PTCs) and in 14% of follicular thyroid cancers (FTCs), and were found to significantly correlate with older age at diagnosis and poorer outcome. Interestingly, the prognostic value of TERT mutations resulted to be significantly stronger than that of BRAF(V600E). Moreover, the outcome was not different among tumors with isolated TERT mutation and those with coexistent mutations (TERT/BRAF in PTCs or TERT/RAS in FTCs). TERT rs2853669 polymorphism was found in 44.4% of tumors. At WB, TERT was significantly more expressed in tumors than in normal samples, being the highest levels of expression recorded in TERT mutated cases. At IHC, in tumors and in metastatic lymph-nodes TERT staining was significantly higher in the cytoplasm than in the nucleus, whereas in normal tissue the degree of staining did not differ in the two cellular compartments. In conclusion, TERT mutations were shown to strongly correlate with a poorer outcome in differentiated thyroid tumors, and neither BRAF nor RAS mutation were found to confer an additional effect in the disease persistence. TERT protein was found to be more expressed in neoplastic than in normal tissues, and to display a different cellular localization, suggesting that it could contribute to thyroid cancer progression by mechanisms taking place in the cytoplasm.

Lee WS, Palmer BJ, Garcia A, et al.
BRAF mutation in papillary thyroid cancer: A cost-utility analysis of preoperative testing.
Surgery. 2014; 156(6):1569-77; discussion 1577-8 [PubMed] Related Publications
BACKGROUND: Papillary thyroid carcinoma (PTC) with BRAF mutation carries a poorer prognosis. Prophylactic central neck dissection (CND) reduces locoregional recurrences, and we hypothesize that initial total thyroidectomy (TT) with CND in patients with BRAF-mutated PTC is cost effective.
METHODS: This cost-utility analysis is based on a hypothetical cohort of 40-year-old women with small PTC [2 cm, confined to the thyroid, node(-)]. We compared preoperative BRAF testing and TT+CND if BRAF-mutated or TT alone if BRAF-wild type, versus no testing with TT. This analysis took into account treatment costs and opportunity losses. Key variables were subjected to sensitivity analysis.
RESULTS: Both approaches produced comparable outcomes, with costs of not testing being lower (-$801.51/patient). Preoperative BRAF testing carried an excess expense of $33.96 per quality-adjusted life-year per patient. Sensitivity analyses revealed that when BRAF positivity in the testing population decreases to 30%, or if the overall noncervical recurrence in the population increases above 11.9%, preoperative BRAF testing becomes the more cost-effective strategy.
CONCLUSION: Outcomes with or without preoperative BRAF testing are comparable, with no testing being the slightly more cost-effective strategy. Although preoperative BRAF testing helps to identify patients with higher recurrence rates, implementing a more aggressive initial operation does not seem to offer a cost advantage.

Tabur S, Aksoy ŞN, Korkmaz H, et al.
Investigation of the role of 8-OHdG and oxidative stress in papillary thyroid carcinoma.
Tumour Biol. 2015; 36(4):2667-74 [PubMed] Related Publications
The aim of this study was to determine levels of serum 8-hydroxy-2'-deoxyguanosine (8-OHdG) as an indicator of oxidant-induced DNA damage and oxidant status in patients with papillary thyroid carcinoma before and after surgery. This study included 25 patients with papillary thyroid carcinoma and age-matched 27 healthy controls. Total antioxidant status (TAS), total oxidant status (TOS), lipid hydroperoxide (LOOH), and 8-OHdG levels were measured. 8-OHdG levels were significantly higher in the preoperative papillary thyroid carcinoma (PTC) group compared with the healthy control group (p < 0.001) and were significantly lower after operation in patients with papillary thyroid carcinoma (p = 0.004). Oxidative stress index (OSI) levels were significantly higher in both preoperative and postoperative PTC patients compared with the healthy control group (p < 0.001 and p < 0.001, respectively). TOS levels were higher in the preoperative and postoperative PTC groups compared to the healthy control group (p < 0.001 and p < 0.001, respectively). TAS levels was lower in the preoperative PTC groups compared to the healthy control group (p = 0.011). Serum LOOH levels were higher in both preoperative and postoperative PTC groups compared to the healthy control group (p < 0.001 and p < 0.001, respectively). Correlation analysis yielded that serum 8-OHdG levels were positively correlated with OSİ and LOOH levels in patients with PTC before surgery (r = 0.668, p < 0.001; r = 0.446, p = 0.025, respectively) and had a negative correlation with TAS levels (r = -0.616, p = 0.001). We have shown severe oxidative DNA damage and impaired antioxidant status in papillary thyroid carcinoma.

Knief J, Gebauer N, Bernard V, et al.
Oncogenic mutations and chromosomal aberrations in primary extranodal diffuse large B-cell lymphomas of the thyroid--a study of 21 cases.
J Clin Endocrinol Metab. 2015; 100(2):754-62 [PubMed] Related Publications
CONTEXT: Primary extranodal diffuse large B-cell lymphomas of the thyroid (ptDLBCL) constitute a rare entity, which until now was not fully explored.
OBJECTIVE: Due to recently published data genetically linking ptDLBCL to a subset of thyroid carcinoma, we assessed the occurrence of oncogenic mutations and copy number alterations.
DESIGN: A high-resolution array-based comparative genomic hybridization approach was applied to quantify genomic aberrations in a study population of 21 ptDLBCL patients. In addition, we investigated the frequency of mutations involving the BRAF, NRAS, and MYD88 genes in correlation with immunohistochemical data.
RESULTS: Chromosomal gains were recurrently detected at 6p21.33-p21.31, 6p22.2, 12p13.31, 14q31.1, 14q32.33, 19p13.3, and 22q11.22; numeric losses were most frequently observed at 6p21.3-p21.31, 10q26.3, 19p13.3, 20q13.33, and 21q11.2. Aberrations affecting 6p22.2 and 14q32.33 as well as 22q11.22 differed slightly between germinal center B-cell (GCB) and non-GCB groups. Statistically significant deviations were detected at 20q13.33 and 21q11.2. These specific alterations do not seem to occur in thyroid carcinomas or other DLBCL, according to previously published literature. Analysis of BRAF and NRAS showed mutation frequencies of 4.8 and 9.5%, respectively. No MYD88 mutations could be detected in any of the analyzed cases. Fluorescence in situ hybridization demonstrated breakage events involving the BCL2, BCL6, and cMYC locus in 14.3, 9.5, and 9.5%, respectively.
CONCLUSIONS: Our study revealed ptDLBCL to be predominantly composed of the GCB type, harboring no MYD88 mutations and showing infrequent mutations in the BRAF and NRAS genes. Additionally, array comparative genomic hybridization showed no overlapping alterations between ptDLBCL and thyroid carcinomas or other nodal or extranodal DLBCL.

Integrated genomic characterization of papillary thyroid carcinoma.
Cell. 2014; 159(3):676-90 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Here, we describe the genomic landscape of 496 PTCs. We observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AX, PPM1D, and CHEK2 and diverse gene fusions. These discoveries reduced the fraction of PTC cases with unknown oncogenic driver from 25% to 3.5%. Combined analyses of genomic variants, gene expression, and methylation demonstrated that different driver groups lead to different pathologies with distinct signaling and differentiation characteristics. Similarly, we identified distinct molecular subgroups of BRAF-mutant tumors, and multidimensional analyses highlighted a potential involvement of oncomiRs in less-differentiated subgroups. Our results propose a reclassification of thyroid cancers into molecular subtypes that better reflect their underlying signaling and differentiation properties, which has the potential to improve their pathological classification and better inform the management of the disease.

Wei WJ, Lu ZW, Li DS, et al.
Association of the miR-149 Rs2292832 polymorphism with papillary thyroid cancer risk and clinicopathologic characteristics in a Chinese population.
Int J Mol Sci. 2014; 15(11):20968-81 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
(1) BACKGROUND: The genetic predisposition to papillary thyroid cancer (PTC) is far from clearly elucidated. Rs2292832 is a genetic polymorphism that located in the precursor of mir-149 and has been studied in diverse cancers. Thus far, the role of rs2292832 in PTC tumorigenesis and progression was unclear; (2) METHOD: Rs2292832 was genotyped in 838 PTCs, 495 patients with thyroid benign tumors (BNs) and 1006 controls in a Chinese Han population. Clinicopathological data was collected and compared. The expression level of mature mir-149 was examined in 55 normal thyroid tissue samples; (3) RESULTS: The CC genotype of rs2292832 was significantly associated with an increased risk of PTC compared with TT homozygote (OR = 1.60, 95% CI: 1.72-2.20, p = 0.003) and TT/TC combined genotype (OR = 1.54, 95% CI: 1.14-2.09, p = 0.005). Rs2292832 is an independent risk factor correlated with tumor invasion (p = 0.006) and higher T stage in PTC patients (p = 0.007), but uncorrelated with short-term disease persistence of PTC. PTC subjects carrying CC genotype have lower mir-149-5p expression than those with TC genotype (p = 0.002). Twelve predicted target genes have been identified by collaboratively using computational tools; (4) CONCLUSION: Rs2292832 was possibly involved in the susceptibility and local progression of PTC in Chinese patients, by altering the expression level of mir-149-5p and its target genes.

Liu S, Zhang B, Zhao Y, et al.
Association of BRAFV600E mutation with clinicopathological features of papillary thyroid carcinoma: a study on a Chinese population.
Int J Clin Exp Pathol. 2014; 7(10):6922-8 [PubMed] Article available free on PMC after 23/10/2015 Related Publications
BACKGROUND: The new finding of the heterogeneous distribution of BRAF(V600E) mutation in primary papillary thyroid carcinoma suggested the percentage of BRAF(V600E) alleles should be taken into consideration when evaluating its association with clinicopathological features of papillary thyroid carcinoma. The aim of this study was to detect both the presence and the percentage of BRAF(V600E) alleles in fine-needle aspiration biopsy samples and to assess its association with clinicopathological characteristics of papillary thyroid carcinoma in a Chinese population.
MATERIALS AND METHODS: Fine needle aspiration samples were collected in a total of 182 patients (132 conventional papillary thyroid carcinomas and 50 goiters). The associations of the presence and percentage of BRAF(V600E) alleles genotyped by pyrosequencing with clinicopathological characteristics were evaluated in papillary thyroid carcinomas.
RESULTS: 80 (60.61%) of papillary thyroid carcinomas exhibited BRAF(V600E) mutation in a range of 7.7% to 46.3% of the total BRAF alleles. The presence of BRAF(V600E) mutation was significantly associated with extrathyroidal invasion. There was no significant difference between the presence of BRAF(V600E) mutation and other clinicopathological features. It was not found that the significant relationship between percentage of BRAF(V600E) alleles and clinicopathological characteristics.
CONCLUSION: We concluded that the presence of BRAF(V600E) could be preoperatively predictive of extrathyroidal invasion in a Chinese population.

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