Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations

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Abstract

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).

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Figure 1: A schematic view of the association results and LD structure in a region on chromosome 9q22.33.

References

  1. 1

    Goldgar, D.E., Easton, D.F., Cannon-Albright, L.A. & Skolnick, M.H. Systematic population-based assessment of cancer risk in first-degree relatives of cancer probands. J. Natl. Cancer Inst. 86, 1600–1608 (1994).

  2. 2

    Czene, K., Lichtenstein, P. & Hemminki, K. Environmental and heritable causes of cancer among 9.6 million individuals in the Swedish Family-Cancer Database. Int. J. Cancer 99, 260–266 (2002).

  3. 3

    Amundadottir, L.T. et al. Cancer as a complex phenotype: pattern of cancer distribution within and beyond the nuclear family. PLoS Med. 1, e65 (2004).

  4. 4

    Hrafnkelsson, J., Tulinius, H., Jonasson, J.G. & Sigvaldason, H. Familial non-medullary thyroid cancer in Iceland. J. Med. Genet. 38, 189–191 (2001).

  5. 5

    Baida, A. et al. Strong association of chromosome 1p12 loci with thyroid cancer susceptibility. Cancer Epidemiol. Biomarkers Prev. 17, 1499–1504 (2008).

  6. 6

    Jazdzewski, K. et al. Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma. Proc. Natl. Acad. Sci. USA 105, 7269–7274 (2008).

  7. 7

    Jazdzewski, K. et al. Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer. Proc. Natl. Acad. Sci. USA advance online publication, doi:10.1073/pnas.0812591106 (21 January 2009).

  8. 8

    He, H. et al. A susceptibility locus for papillary thyroid carcinoma on chromosome 8q24. Cancer Res. 69, 625–631 (2009).

  9. 9

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

  10. 10

    DeLellis, R.A. Pathology and genetics of thyroid carcinoma. J. Surg. Oncol. 94, 662–669 (2006).

  11. 11

    Marx, S.J. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat. Rev. Cancer 5, 367–375 (2005).

  12. 12

    Kebebew, E., Greenspan, F.S., Clark, O.H., Woeber, K.A. & McMillan, A. Anaplastic thyroid carcinoma. Treatment outcome and prognostic factors. Cancer 103, 1330–1335 (2005).

  13. 13

    Gudbjartsson, D.F. et al. Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609–615 (2008).

  14. 14

    Devlin, B. & Roeder, K. Genomic control for association studies. Biometrics 55, 997–1004 (1999).

  15. 15

    Kutyavin, I.V. et al. A novel endonuclease IV post-PCR genotyping system. Nucleic Acids Res. 34, e128 (2006).

  16. 16

    Dathan, N., Parlato, R., Rosica, A., De Felice, M. & Di Lauro, R. Distribution of the titf2/foxe1 gene product is consistent with an important role in the development of foregut endoderm, palate, and hair. Dev. Dyn. 224, 450–456 (2002).

  17. 17

    De Felice, M. et al. A mouse model for hereditary thyroid dysgenesis and cleft palate. Nat. Genet. 19, 395–398 (1998).

  18. 18

    Parlato, R. et al. An integrated regulatory network controlling survival and migration in thyroid organogenesis. Dev. Biol. 276, 464–475 (2004).

  19. 19

    Clifton-Bligh, R.J. et al. Mutation of the gene encoding human TTF-2 associated with thyroid agenesis, cleft palate and choanal atresia. Nat. Genet. 19, 399–401 (1998).

  20. 20

    Zhang, P. et al. Immunohistochemical analysis of thyroid-specific transcription factors in thyroid tumors. Pathol. Int. 56, 240–245 (2006).

  21. 21

    Sequeira, M.J. et al. Thyroid transcription factor-2 gene expression in benign and malignant thyroid lesions. Thyroid 11, 995–1001 (2001).

  22. 22

    Gulcher, J.R., Kristjansson, K., Gudbjartsson, H. & Stefansson, K. Protection of privacy by third-party encryption in genetic research in Iceland. Eur. J. Hum. Genet. 8, 739–742 (2000).

  23. 23

    Gretarsdottir, S. et al. The gene encoding phosphodiesterase 4D confers risk of ischemic stroke. Nat. Genet. 35, 131–138 (2003).

  24. 24

    Falk, C.T. & Rubinstein, P. Haplotype relative risks: an easy reliable way to construct a proper control sample for risk calculations. Ann. Hum. Genet. 51, 227–233 (1987).

  25. 25

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

  26. 26

    Gudmundsson, J. et al. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nat. Genet. 39, 977–983 (2007).

  27. 27

    Rafnar, T. et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat. Genet. 41, 221–227 (2009).

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Acknowledgements

We thank the study participants whose contribution made this work possible. This project was funded in part by the following contract numbers: US National Institutes of Health CA16058 and CA124570.

Author information

The study was designed and results were interpreted by J.G., P.S., D.F.G., J.T.B., A.K. and K.S. Statistical analysis was carried out by P.S., D.F.G., F.G., J.G., J.T.B., M.L.F. and A.K. Subject recruitment, biological material collection and handling was organized and carried out by J.G., J.G.J., J.T.B., S.N.S., H.He, R.N., E.A., E.F., E.P., B.S., M.M., G.I.E., U.S.B., H.Holm, K.K., H.K., J.R.G., T.J., T.R., H.Hjartarsson, J.I.M., A.d.l.C., J.H. and U.T. Genotyping was supervised and carried out by J.G, J.T.B., A.S., H.He, M.J., D.N.M., S.M., O.B.S., H.Helgadottir, W.L., T.B., A.d.l.C., T.R. and U.T. Authors J.G., P.S., D.F.G. and K.S. drafted the manuscript. All authors contributed to the final version of the paper. Principal collaborators for the replication case-control samples were J.I.M. (Spain) and A.d.l.C. (US).

Correspondence to Julius Gudmundsson or Kari Stefansson.

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The authors from deCODE are shareholders in deCODE genetics Inc.

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Supplementary Methods, Supplementary Figures 1 and 2, Supplementary Tables 1–5 (PDF 1061 kb)

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