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Common genetic variants on FOXE1 contributes to thyroid cancer susceptibility: evidence based on 16 studies

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Tumor Biology

Abstract

Genome-wide association studies have identified polymorphisms at chromosome 9q22.23 as a new thyroid cancer (TC) susceptibility locus in populations of European descent. Since then, the relationship between three common variations (rs965513, rs1867277, and rs71369530) of FOXE1 and TC has been reported in various ethnic groups; however, the results have been inconclusive. To derive a more precise estimation of the relationship as well as to quantify the between-study heterogeneity and potential bias, a meta-analysis including 120,258 individuals from 16 studies was performed. An overall random-effect per-allele odds ratio (OR) of 1.74 (95 % confidence interval (95 % CI), 1.62–1.86, P < 10−5) and 1.62 (95 % CI, 1.50–1.76, P < 10−5) was found for the rs965513 and rs1867277 polymorphisms, respectively. In addition, we also detected significant association of FOXE1 polyalanine tract (rs71369530) with TC risk (OR = 2.01; 95 % CI, 1.66–2.44, P < 10−5). Significant associations were also detected under dominant and recessive genetic models. In the subgroup analysis by ethnicity, significantly increased risks were found for the rs965513 polymorphism among Caucasians (OR = 1.79; 95 % CI, 1.69–1.91, P < 10−5) and Asians (OR = 1.42; 95 % CI, 1.12–1.81, P = 0.004). Ethnicity was identified as a potential source of between-study heterogeneity for rs965513. When stratified by sample size, study design, histological types of TC, and radiation exposure status, significantly increased risks were found for the rs965513 polymorphism. This meta-analysis demonstrated that the three common variations on FOXE1 is a risk factor associated with increased TC susceptibility, but these associations vary in different ethnic populations.

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References

  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71–96.

    Article  PubMed  Google Scholar 

  2. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol. 2001;13:44–51.

    Article  CAS  PubMed  Google Scholar 

  3. Nikiforov YE, Fagin JA. Risk factors for thyroid cancer. Trends Endocrinol Metab. 1997;8:20–5.

    Article  CAS  PubMed  Google Scholar 

  4. Agate L, Lorusso L, Elisei R. New and old knowledge on differentiated thyroid cancer epidemiology and risk factors. J Endocrinol Invest. 2012;35:3–9.

    CAS  PubMed  Google Scholar 

  5. Williams D. Cancer after nuclear fallout: lessons from the Chernobyl accident. Nat Rev Cancer. 2002;2:543–9.

    Article  CAS  PubMed  Google Scholar 

  6. Goldgar DE, Easton DF, Cannon-Albright LA, Skolnick MH. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J Natl Cancer Inst. 1994;86:1600–8.

    Article  CAS  PubMed  Google Scholar 

  7. Canzian F, Amati P, Harach HR, Kraimps JL, Lesueur F, Barbier J, et al. A gene predisposing to familial thyroid tumors with cell oxyphilia maps to chromosome 19p13.2. Am J Hum Genet. 1998;63:1743–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. McKay JD, Lesueur F, Jonard L, Pastore A, Williamson J, Hoffman L, et al. Localization of a susceptibility gene for familial nonmedullary thyroid carcinoma to chromosome 2q21. Am J Hum Genet. 2001;69:440–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Eng C. Familial papillary thyroid cancer—many syndromes, too many genes? J Clin Endocrinol Metab. 2000;85:1755–7.

    CAS  PubMed  Google Scholar 

  10. Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Sigurdsson A, Bergthorsson JT, et al. Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nat Genet. 2009;41:460–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Takahashi M, Saenko VA, Rogounovitch TI, Kawaguchi T, Drozd VM, Takigawa-Imamura H, et al. The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Hum Mol Genet. 2010;19:2516–23.

    Article  CAS  PubMed  Google Scholar 

  12. Parlato R, Rosica A, Rodriguez-Mallon A, Affuso A, Postiglione MP, Arra C, et al. An integrated regulatory network controlling survival and migration in thyroid organogenesis. Dev Biol. 2004;276:464–75.

    Article  CAS  PubMed  Google Scholar 

  13. Zannini M, Avantaggiato V, Biffali E, Arnone MI, Sato K, Pischetola M, et al. TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO J. 1997;16:3185–97.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. McClellan J, King MC. Genetic heterogeneity in human disease. Cell. 2010;141:210–7.

    Article  CAS  PubMed  Google Scholar 

  15. Chen Q, Shi R, Liu W, Jiang D. Assessing interactions between the association of common genetic variant at 1p11 (rs11249433) and hormone receptor status with breast cancer risk. PLoS One. 2013;8:e72487.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Woolf B. On estimating the relation between blood group and disease. Ann Hum Genet. 1955;19:251–3.

    Article  CAS  PubMed  Google Scholar 

  17. Cochran WG. The combination of estimates from different experiments. Biometrics. 1954;10:101–29.

    Article  Google Scholar 

  18. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.

    Article  PubMed Central  PubMed  Google Scholar 

  19. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  20. Thompson SG, Sharp SJ. Explaining heterogeneity in meta-analysis: a comparison of methods. Stat Med. 1999;18:2693–708.

    Article  CAS  PubMed  Google Scholar 

  21. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.

    Article  CAS  PubMed  Google Scholar 

  22. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Penna-Martinez M, Epp F, Kahles H, Ramos-Lopez E, Hinsch N, Hansmann ML, Selkinski I, et al. FOXE1 association with differentiated thyroid cancer and its progression. Thyroid. 2014; doi:10.1089/thy.2013.0274

  24. Köhler A, Chen B, Gemignani F, Elisei R, Romei C, Figlioli G, et al. Genome-wide association study on differentiated thyroid cancer. J Clin Endocrinol Metab. 2013;98:E1674–81.

    Article  PubMed  Google Scholar 

  25. Damiola F, Byrnes G, Moissonnier M, Pertesi M, Deltour I, Fillon A, et al. Contribution of ATM and FOXE1 (TTF2) to risk of papillary thyroid carcinoma in Belarusian children exposed to radiation. Int J Cancer. 2014;134:1659–68.

    Article  CAS  PubMed  Google Scholar 

  26. Wang YL, Feng SH, Guo SC, Wei WJ, Li DS, Wang Y, et al. 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. 2013;50:689–95.

    Article  CAS  PubMed  Google Scholar 

  27. Bonora E, Rizzato C, Diquigiovanni C, Oudot-Mellakh T, Campa D, Vargiolu M, et al. The FOXE1 locus is a major genetic determinant for familial nonmedullary thyroid carcinoma. Int J Cancer. 2014;134:2098–107.

    Article  CAS  PubMed  Google Scholar 

  28. Liyanarachchi S, Wojcicka A, Li W, Czetwertynska M, Stachlewska E, Nagy R, et al. Cumulative risk impact of five genetic variants associated with papillary thyroid carcinoma. Thyroid. 2013;23:1532–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Tomaz RA, Sousa I, Silva JG, Santos C, Teixeira MR, Leite V, et al. FOXE1 polymorphisms are associated with familial and sporadic nonmedullary thyroid cancer susceptibility. Clin Endocrinol (Oxf). 2012;77:926–33.

    Article  CAS  PubMed  Google Scholar 

  30. Bullock M, Duncan EL, O’Neill C, Tacon L, Sywak M, Sidhu S, et al. Association of FOXE1 polyalanine repeat region with papillary thyroid cancer. J Clin Endocrinol Metab. 2012;97:E1814–9.

    Article  CAS  PubMed  Google Scholar 

  31. Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Masson G, He H, et al. Discovery of common variants associated with low TSH levels and thyroid cancer risk. Nat Genet. 2012;44:319–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Jones AM, Howarth KM, Martin L, Gorman M, Mihai R, Moss L, et al. 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. 2012;49:158–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, Bradford Y, et al. Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. Am J Hum Genet. 2011;89:529–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Matsuse M, Takahashi M, Mitsutake N, Nishihara E, Hirokawa M, Kawaguchi T, et al. The FOXE1 and NKX2-1 loci are associated with susceptibility to papillary thyroid carcinoma in the Japanese population. J Med Genet. 2011;48:645–8.

    Article  CAS  PubMed  Google Scholar 

  35. Kallel R, Belguith-Maalej S, Akdi A, Mnif M, Charfeddine I, Galofré P, et al. Genetic Investigation of FOXE1 polyalanine tract in thyroid diseases: new insight on the role of FOXE1 in thyroid carcinoma. Cancer Biomarkers. 2010;8:43–51.

    CAS  PubMed  Google Scholar 

  36. Landa I, Ruiz-Llorente S, Montero-Conde C, Inglada-Pérez L, Schiavi F, Leskelä S, et al. The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLoS Genet. 2009;5:e1000637.

    Article  PubMed Central  PubMed  Google Scholar 

  37. Hishinuma A, Ohyama Y, Kuribayashi T, Nagakubo N, Namatame T, Shibayama K, et al. Polymorphism of the polyalanine tract of thyroid transcription factor-2 gene in patients with thyroid dysgenesis. Eur J Endocrinol. 2001;145:385–9.

    Article  CAS  PubMed  Google Scholar 

  38. Carré A, Castanet M, Sura-Trueba S, Szinnai G, Van Vliet G, Trochet D, et al. Polymorphic length of FOXE1 alanine stretch: evidence for genetic susceptibility to thyroid dysgenesis. Hum Genet. 2007;122:467–76.

    Article  PubMed  Google Scholar 

  39. Ardlie KG, Lunetta KL, Seielstad M. Testing for population subdivision and association in four case–control studies. Am J Hum Genet. 2002;71:304–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Song Y, Niu T, Manson JE, Kwiatkowski DJ, Liu S. Are variants in the CAPN10 gene related to risk of type 2 diabetes? A quantitative assessment of population and family-based association studies. Am J Hum Genet. 2004;74:208–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, Koskenvuo M, et al. Environmental and heritable factors in the causation of cancer-analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000;343:78–85.

    Article  CAS  PubMed  Google Scholar 

  42. Albores-Saavedra J, Henson DE, Glazer E, Schwartz AM. Changing patterns in the incidence and survival of thyroid cancer with follicular phenotype-papillary, follicular, and anaplastic: a morphological and epidemiological study. Endocr Pathol. 2007;18:1–7.

    Article  PubMed  Google Scholar 

  43. Williams ED, Abrosimov A, Bogdanova T, Demidchik EP, Ito M, LiVolsi V, et al. Morphologic characteristics of Chernobyl-related childhood papillary thyroid carcinomas are independent of radiation exposure but vary with iodine intake. Thyroid. 2008;18:847–52.

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

This work was supported by National Natural Science Foundation of China (No. 81272722).

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Correspondence to Weixin Shen.

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Yixin Zhuang, Weixin Wu and Han Liu contributed equally to this work.

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Zhuang, Y., Wu, W., Liu, H. et al. Common genetic variants on FOXE1 contributes to thyroid cancer susceptibility: evidence based on 16 studies. Tumor Biol. 35, 6159–6166 (2014). https://doi.org/10.1007/s13277-014-1896-y

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  • DOI: https://doi.org/10.1007/s13277-014-1896-y

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