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Common genetic variant on 14q13.3 contributes to thyroid cancer susceptibility: evidence based on 12 studies

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Abstract

Several genome-wide association studies on thyroid cancer (TC) have reported similar findings of a new susceptibility locus, 14q13.3. After that, a number of studies reported that rs944289 polymorphism at chromosome 14q13.3 has been implicated in TC risk. However, these studies have yielded inconsistent results. To investigate this inconsistency, we performed a meta-analysis of 12 studies involving a total of 7,598 TC cases, 53,613 controls, and 239 nuclear families for 14q13.3–rs944289 polymorphism to evaluate its effect on genetic susceptibility for TC. An overall random-effect per-allele OR of 1.30 (95 % CI 1.21–1.40, P < 10−5) was found for the polymorphism. Significant results were also observed for under dominant and recessive genetic models. In the subgroup analysis by ethnicity, we found similar significant results for both Caucasians (T allele: OR 1.29, 95 % CI 1.17–1.42, P < 10−5) and East Asians (T allele: OR 1.33, 95 % CI 1.18–1.49, P < 10−5). Further in stratified analyses according to study design and sample size, evidence of gene–disease association was also obtained. In addition, we found that rs944289 confers its risk, for both papillary thyroid carcinoma and follicular thyroid carcinoma when stratified by histological types of TC. Furthermore, our results on stratified analysis according to radiation exposure status showed an increased sporadic TC risk, while no associations were detected among radiation-related TCs for rs944289 polymorphism. Our result demonstrated that rs944289 polymorphism on 14q13.3 is a low penetrant risk factor for developing TC.

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References

  • Agate L, Lorusso L, Elisei R (2012) New and old knowledge on differentiated thyroid cancer epidemiology and risk factors. J Endocrinol Investig 35:3–9

    CAS  Google Scholar 

  • Ai L, Yu Y, Liu X, Wang C, Shi J, Sun H, Yu Q (2014) Are the SNPs of NKX2-1 associated with papillary thyroid carcinoma in the Han population of Northern China? Front Med 8:113–117

    Article  PubMed  Google Scholar 

  • Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50:1088–1101

    Article  CAS  PubMed  Google Scholar 

  • Bignell GR, Canzian F, Shayeghi M, Stark M, Shugart YY, Biggs P, Mangion J, Hamoudi R, Rosenblatt J, Buu P, Sun S, Stoffer SS, Goldgar DE, Romeo G, Houlston RS, Narod SA, Stratton MR, Foulkes WD (1997) Familial nontoxic multinodular thyroid goiter locus maps to chromosome 14q but does not account for familial nonmedullary thyroid cancer. Am J Hum Genet 61:1123–1130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bonora E, Rizzato C, Diquigiovanni C, Oudot-Mellakh T, Campa D, Vargiolu M, Guedj M, NMTC Consortium, McKay JD, Romeo G, Canzian F, Lesueur F (2014) The FOXE1 locus is a major genetic determinant for familial nonmedullary thyroid carcinoma. Int J Cancer 134:2098–2107

    Article  CAS  PubMed  Google Scholar 

  • Canzian F, Amati P, Harach HR, Kraimps JL, Lesueur F, Barbier J, Levillain P, Romeo G, Bonneau D (1998) A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2. Am J Hum Genet 63:1743–1748

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Cardis E, Kesminiene A, Ivanov V, Malakhova I, Shibata Y, Khrouch V, Drozdovitch V, Maceika E, Zvonova I, Vlassov O, Bouville A, Goulko G, Hoshi M, Abrosimov A, Anoshko J, Astakhova L, Chekin S, Demidchik E, Galanti R, Ito M, Korobova E, Lushnikov E, Maksioutov M, Masyakin V, Nerovnia A, Parshin V, Parshkov E, Piliptsevich N, Pinchera A, Polyakov S, Shabeka N, Suonio E, Tenet V, Tsyb A, Yamashita S, Williams D (2005) Risk of thyroid cancer after exposure to 131I in childhood. J Natl Cancer Inst 97:724–732

    Article  PubMed  Google Scholar 

  • Cavaco BM, Batista PF, Sobrinho LG, Leite V (2008) Mapping a new familial thyroid epithelial neoplasia susceptibility locus to chromosome 8p23.1–p22 by high-density single-nucleotide polymorphism genome-wide linkage analysis. J Clin Endocrinol Metab 93:4426–4430

    Article  CAS  PubMed  Google Scholar 

  • Cochran WG (1954) The combination of estimates from different experiments. Biometrics 10:101–129

    Article  Google Scholar 

  • Damiola F, Byrnes G, Moissonnier M, Pertesi M, Deltour I, Fillon A, Le Calvez-Kelm F, Tenet V, McKay-Chopin S, McKay JD, Malakhova I, Masyakin V, Cardis E, Lesueur F, Kesminiene A (2014) Contribution of ATM and FOXE1 (TTF2) to risk of papillary thyroid carcinoma in Belarusian children exposed to radiation. Int J Cancer 134:1659–1668

    Article  CAS  PubMed  Google Scholar 

  • DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    Article  CAS  PubMed  Google Scholar 

  • Egger M, Davey Smith G, Schneider M (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Fallah M, Pukkala E, Tryggvadottir L, Olsen JH, Tretli S, Sundquist K, Hemminki K (2013) Risk of thyroid cancer in first-degree relatives of patients with non-medullary thyroid cancer by histology type and age at diagnosis: a joint study from five Nordic countries. J Med Genet 50:373–382

    Article  CAS  PubMed  Google Scholar 

  • Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH (1994) Systematic population based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst 86:1600–1608

    Article  CAS  PubMed  Google Scholar 

  • Gu X, Zhang W, Xu L, Cai D (2014) Quantitative assessment of the influence of prostate stem cell antigen polymorphisms on gastric cancer risk. Tumour Biol 35:2167–2174

    Article  CAS  PubMed  Google Scholar 

  • Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Sigurdsson A, Bergthorsson JT, He H, Blondal T, Geller F, Jakobsdottir M, Magnusdottir DN, Matthiasdottir S, Stacey SN, Skarphedinsson OB, Helgadottir H, Li W, Nagy R, Aguillo E, Faure E, Prats E, Saez B, Martinez M, Eyjolfsson GI, Bjornsdottir US, Holm H, Kristjansson K, Frigge ML, Kristvinsson H, Gulcher JR, Jonsson T, Rafnar T, Hjartarsson H, Mayordomo JI, de la Chapelle A, Hrafnkelsson J, Thorsteinsdottir U, Kong A, Stefansson K (2009) Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet 41:460–464

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Masson G, He H, Jonasdottir A, Sigurdsson A, Stacey SN, Johannsdottir H, Helgadottir HT, Li W, Nagy R, Ringel MD, Kloos RT, de Visser MC, Plantinga TS, den Heijer M, Aguillo E, Panadero A, Prats E, Garcia-Castaño A, De Juan A, Rivera F, Walters GB, Bjarnason H, Tryggvadottir L, Eyjolfsson GI, Bjornsdottir US, Holm H, Olafsson I, Kristjansson K, Kristvinsson H, Magnusson OT, Thorleifsson G, Gulcher JR, Kong A, Kiemeney LA, Jonsson T, Hjartarson H, Mayordomo JI, Netea-Maier RT, de la Chapelle A, Hrafnkelsson J, Thorsteinsdottir U, Rafnar T, Stefansson K (2012) Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet 44:319–322

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • He H, Nagy R, Liyanarachchi S, Jiao H, Li W, Suster S, Kere J, de la Chapelle A (2009) A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24. Cancer Res 69:625–631

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Hinds DA, Stuve LL, Nilsen GB, Halperin E, Eskin E, Ballinger DG, Frazer KA, Cox DR (2005) Whole-genome patterns of common DNA variation in three human populations. Science 307:1072–1079

    Article  CAS  PubMed  Google Scholar 

  • International HapMap Consortium, Frazer KA, Ballinger DG, Cox DR, Hinds DA, Stuve LL, Gibbs RA, Belmont JW, Boudreau A, Hardenbol P, Leal SM, Pasternak S, Wheeler DA, Willis TD, Yu F, Yang H, Zeng C, Gao Y, Hu H, Hu W, Li C, Lin W, Liu S, Pan H, Tang X, Wang J, Wang W, Yu J, Zhang B, Zhang Q, Zhao H, Zhao H, Zhou J, Gabriel SB, Barry R, Blumenstiel B, Camargo A, Defelice M, Faggart M, Goyette M, Gupta S, Moore J, Nguyen H, Onofrio RC, Parkin M, Roy J, Stahl E, Winchester E, Ziaugra L, Altshuler D, Shen Y, Yao Z, Huang W, Chu X, He Y, Jin L, Liu Y, Shen Y, Sun W, Wang H, Wang Y, Wang Y, Xiong X, Xu L, Waye MM, Tsui SK, Xue H, Wong JT, Galver LM, Fan JB, Gunderson K, Murray SS, Oliphant AR, Chee MS, Montpetit A, Chagnon F, Ferretti V, Leboeuf M, Olivier JF, Phillips MS, Roumy S, Sallée C, Verner A, Hudson TJ, Kwok PY, Cai D, Koboldt DC, Miller RD, Pawlikowska L, Taillon-Miller P, Xiao M, Tsui LC, Mak W, Song YQ, Tam PK, Nakamura Y, Kawaguchi T, Kitamoto T, Morizono T, Nagashima A, Ohnishi Y, Sekine A, Tanaka T, Tsunoda T, Deloukas P, Bird CP, Delgado M, Dermitzakis ET, Gwilliam R, Hunt S, Morrison J, Powell D, Stranger BE, Whittaker P, Bentley DR, Daly MJ, de Bakker PI, Barrett J, Chretien YR, Maller J, McCarroll S, Patterson N, Pe’er I, Price A, Purcell S, Richter DJ, Sabeti P, Saxena R, Schaffner SF, Sham PC, Varilly P, Altshuler D, Stein LD, Krishnan L, Smith AV, Tello-Ruiz MK, Thorisson GA, Chakravarti A, Chen PE, Cutler DJ, Kashuk CS, Lin S, Abecasis GR, Guan W, Li Y, Munro HM, Qin ZS, Thomas DJ, McVean G, Auton A, Bottolo L, Cardin N, Eyheramendy S, Freeman C, Marchini J, Myers S, Spencer C, Stephens M, Donnelly P, Cardon LR, Clarke G, Evans DM, Morris AP, Weir BS, Tsunoda T, Mullikin JC, Sherry ST, Feolo M, Skol A, Zhang H, Zeng C, Zhao H, Matsuda I, Fukushima Y, Macer DR, Suda E, Rotimi CN, Adebamowo CA, Ajayi I, Aniagwu T, Marshall PA, Nkwodimmah C, Royal CD, Leppert MF, Dixon M, Peiffer A, Qiu R, Kent A, Kato K, Niikawa N, Adewole IF, Knoppers BM, Foster MW, Clayton EW, Watkin J, Gibbs RA, Belmont JW, Muzny D, Nazareth L, Sodergren E, Weinstock GM, Wheeler DA, Yakub I, Gabriel SB, Onofrio RC, Richter DJ, Ziaugra L, Birren BW, Daly MJ, Altshuler D, Wilson RK, Fulton LL, Rogers J, Burton J, Carter NP, Clee CM, Griffiths M, Jones MC, McLay K, Plumb RW, Ross MT, Sims SK, Willey DL, Chen Z, Han H, Kang L, Godbout M, Wallenburg JC, L’Archevêque P, Bellemare G, Saeki K, Wang H, An D, Fu H, Li Q, Wang Z, Wang R, Holden AL, Brooks LD, McEwen JE, Guyer MS, Wang VO, Peterson JL, Shi M, Spiegel J, Sung LM, Zacharia LF, Collins FS, Kennedy K, Jamieson R, Stewart J (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861

    Article  Google Scholar 

  • Ioannidis JP, Boffetta P, Little J, O’Brien TR, Uitterlinden AG, Vineis P, Balding DJ, Chokkalingam A, Dolan SM, Flanders WD, Higgins JP, McCarthy MI, McDermott DH, Page GP, Rebbeck TR, Seminara D, Khoury MJ (2008) Assessment of cumulative evidence on genetic associations: interim guidelines. Int J Epidemiol 37:120–132

    Article  PubMed  Google Scholar 

  • Jendrzejewski J, He H, Radomska HS, Li W, Tomsic J, Liyanarachchi S, Davuluri RV, Nagy R, de la Chapelle A (2012) The polymorphism rs944289 predisposes to papillary thyroid carcinoma through a large intergenic noncoding RNA gene of tumor suppressor type. Proc Natl Acad Sci USA 109:8646–8651

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Jones AM, Howarth KM, Martin L, Gorman M, Mihai R, Moss L, Auton A, Lemon C, Mehanna H, Mohan H, Clarke SE, Wadsley J, Macias E, Coatesworth A, Beasley M, Roques T, Martin C, Ryan P, Gerrard G, Power D, Bremmer C, TCUKIN Consortium, Tomlinson I, Carvajal-Carmona LG (2012) Thyroid cancer susceptibility polymorphisms: confirmation of loci on chromosomes 9q22 and 14q13, validation of a recessive 8q24 locus and failure to replicate a locus on 5q24. J Med Genet 49:158–163

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kimura S, Hara Y, Pineau T, Fernandez-Salguero P, Fox CH, Ward JM, Gonzalez FJ (1996) The T/ebp null mouse: thyroid-specific enhancer-binding protein is essential for the organogenesis of the thyroid, lung, ventral forebrain, and pituitary. Genes Dev 10:60–69

    Article  CAS  PubMed  Google Scholar 

  • Köhler A, Chen B, Gemignani F, Elisei R, Romei C, Figlioli G, Cipollini M, Cristaudo A, Bambi F, Hoffmann P, Herms S, Kalemba M, Kula D, Harris S, Broderick P, Houlston R, Pastor S, Marcos R, Velázquez A, Jarzab B, Hemminki K, Landi S, Försti A (2013) Genome-wide association study on differentiated thyroid cancer. J Clin Endocrinol Metab 98:E1674–E1681

    Article  PubMed  Google Scholar 

  • Kondo T, Ezzat S, Asa SL (2006) Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6:292–306

    Article  CAS  PubMed  Google Scholar 

  • Li M, Gu Y (2014) Quantitative assessment of the influence of common variation rs16892766 at 8q23.3 with colorectal adenoma and cancer susceptibility. Mol Genet Genomics. doi:10.1007/s00438-014-0928-z

  • Liyanarachchi S, Wojcicka A, Li W, Czetwertynska M, Stachlewska E, Nagy R, Hoag K, Wen B, Ploski R, Ringel MD, Kozłowicz-Gudzinska I, Gierlikowski W, Jazdzewski K, He H, de la Chapelle A (2013) Cumulative risk impact of five genetic variants associated with papillary thyroid carcinoma. Thyroid 23:1532–1540

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Malchoff CD, Sarfarazi M, Tendler B, Forouhar F, Whalen G, Joshi V, Arnold A, Malchoff DM (2000) Papillary thyroid carcinoma associated with papillary renal neoplasia: genetic linkage analysis of a distinct heritable tumor syndrome. J Clin Endocrinol Metab 85:1758–1764

    CAS  PubMed  Google Scholar 

  • Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748

    CAS  PubMed  Google Scholar 

  • Matsuse M, Takahashi M, Mitsutake N, Nishihara E, Hirokawa M, Kawaguchi T, Rogounovitch T, Saenko V, Bychkov A, Suzuki K, Matsuo K, Tajima K, Miyauchi A, Yamada R, Matsuda F, Yamashita S (2011) The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population. J Med Genet 48:645–648

    Article  CAS  PubMed  Google Scholar 

  • McClellan J, King MC (2010) Genetic heterogeneity in human disease. Cell 141:210–217

    Article  CAS  PubMed  Google Scholar 

  • McKay JD, Lesueur F, Jonard L, Pastore A, Williamson J, Hoffman L, Burgess J, Duffield A, Papotti M, Stark M, Sobol H, Maes B, Murat A, Kääriäinen H, Bertholon-Grégoire M, Zini M, Rossing MA, Toubert ME, Bonichon F, Cavarec M, Bernard AM, Boneu A, Leprat F, Haas O, Lasset C, Schlumberger M, Canzian F, Goldgar DE, Romeo G (2001) Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21. Am J Hum Genet 69:440–446

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Munafo MR, Flint J (2004) Meta-analysis of genetic association studies. Trends Genet 20:439–444

    Article  CAS  PubMed  Google Scholar 

  • Penna-Martinez M, Epp F, Kahles H, Ramos-Lopez E, Hinsch N, Hansmann ML, Selkinski I, Grünwald F, Holzer K, Bechstein WO, Zeuzem S, Vorländer C, Badenhoop K (2014) FOXE1 association with differentiated thyroid cancer and its progression. Thyroid 24:845–851

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Rio Frio T, Bahubeshi A, Kanellopoulou C, Hamel N, Niedziela M, Sabbaghian N, Pouchet C, Gilbert L, O’Brien PK, Serfas K, Broderick P, Houlston RS, Lesueur F, Bonora E, Muljo S, Schimke RN, Bouron-Dal Soglio D, Arseneau J, Schultz KA, Priest JR, Nguyen VH, Harach HR, Livingston DM, Foulkes WD, Tischkowitz M (2011) DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli–Leydig cell tumors. JAMA 305:68–77

    Article  CAS  PubMed  Google Scholar 

  • Ron E, Lubin JH, Shore RE, Mabuchi K, Modan B, Pottern LM, Schneider AB, Tucker MA, Boice JD Jr (1995) Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res 141:259–277

    Article  CAS  PubMed  Google Scholar 

  • Schlumberger MJ (1998) Papillary and follicular thyroid carcinoma. N Engl J Med 338:297–306

    Article  CAS  PubMed  Google Scholar 

  • Siegel R, Naishadham D, Jemal A (2013) Cancer statistics, 2013. CA Cancer J Clin 63:11–30

    Article  PubMed  Google Scholar 

  • Stang A (2010) Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25:603–605

    Article  PubMed  Google Scholar 

  • Suh I, Filetti S, Vriens MR, Guerrero MA, Tumino S, Wong M, Shen WT, Kebebew E, Duh QY, Clark OH (2009) Distinct loci on chromosome 1q21 and 6q22 predispose to familial nonmedullary thyroid cancer: a SNP array-based linkage analysis of 38 families. Surgery 146:1073–1080

    Article  PubMed  Google Scholar 

  • Takahashi M, Saenko VA, Rogounovitch TI, Kawaguchi T, Drozd VM, Takigawa-Imamura H, Akulevich NM, Ratanajaraya C, Mitsutake N, Takamura N, Danilova LI, Lushchik ML, Demidchik YE, Heath S, Yamada R, Lathrop M, Matsuda F, Yamashita S (2010) The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum Mol Genet 19:2516–2523

    Article  CAS  PubMed  Google Scholar 

  • Tang K, Li Y, Zhang Z, Gu Y, Xiong Y, Feng G, He L, Qin S (2010) The PstI/RsaI and DraI polymorphisms of CYP2E1 and head and neck cancer risk: a meta-analysis based on 21 case–control studies. BMC Cancer 10:575

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wacholder S, Chanock S, Garcia-Closas M, El Ghormli L, Rothman N (2004) Assessing the probability that a positive report is false: an approach for molecular epidemiology studies. J Natl Cancer Inst 96:434–442

    Article  PubMed  Google Scholar 

  • Wang YL, Feng SH, Guo SC, Wei WJ, Li DS, Wang Y, Wang X, Wang ZY, Ma YY, Jin L, Ji QH, Wang JC (2013) Confirmation of papillary thyroid cancer susceptibility loci identified by genome-wide association studies of chromosomes 14q13, 9q22, 2q35 and 8p12 in a Chinese population. J Med Genet 50:689–695

    Article  CAS  PubMed  Google Scholar 

  • Williams D (2002) Cancer after nuclear fallout: lessons from the Chernobyl accident. Nat Rev Cancer 2:543–549

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (81272722).

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The authors declare that they have no conflict of interest.

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  1. Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, People’s Republic of China

    JiaoJiao Zheng, Chen Li, Cong Wang & Zhilong Ai

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  1. JiaoJiao Zheng
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  2. Chen Li
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  3. Cong Wang
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  4. Zhilong Ai
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Correspondence to Zhilong Ai.

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Communicated by S. Hohmann.

J. Zheng, C. Li, and C. Wang have contributed equally to this work.

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Zheng, J., Li, C., Wang, C. et al. Common genetic variant on 14q13.3 contributes to thyroid cancer susceptibility: evidence based on 12 studies. Mol Genet Genomics 290, 1125–1133 (2015). https://doi.org/10.1007/s00438-014-0981-7

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