Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

Abstract

The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma1, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 × 10−12). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 × 10−8) and urinary bladder, prostate and cervix cancer (ORs = 1.07−1.31, all P < 4 × 10−4). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 × 10−4). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

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Figure 1: A schematic view of the association results and LD structure in a region on chromosome 5p15.33.

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Acknowledgements

We thank the individuals that participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE's participant recruitment center and the personnel at deCODE's core facilities. We acknowledge the Icelandic Cancer Registry for assistance in the ascertainment of the Icelandic subjects with cancer. The project was funded in part by the European Commission (POLYGENE: LSHC-CT-2005-018827 and GENADDICT: LSHM-CT-2004-005166), the National Institutes of Health (R01-DA017932) and a research investment grant of the Radboud University Nijmegen Medical Centre. The Leeds Bladder Cancer Study was funded by Cancer Research UK and Yorkshire Cancer Research. Torino Bladder Cancer Case Control Study was supported by a grant to ECNIS (Environmental Cancer Risk, Nutrition and Individual Susceptibility), a network of excellence operating within the European Union 6th Framework Program, Priority 5: “Food Quality and Safety” (Contract No 513943); and by a grant of the compagnia di San Paolo, the Italian Association for Cancer Research, Italy and the Piedmont Region Progetti di Ricerca Sanitaria Finalizzata. J.H. is supported by the Swedish Cancer Society, The Radiumhemmet Research Funds, The Swedish Research Council and the Karolinska Institutet Research Funds.

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The study was designed and results were interpreted by T.R., P.S., S.N.S., F.G., J.G., J.R.G., D.F.G., A.K., S.T., U.T. and K.S. Statistical analysis was carried out by P.S., F.G., D.F.G., M.L.F., G.T. and A.K. Subject ascertainment, recruitment, biological material collection and collection of clinical and lifestyle information was organized and carried out by T.E.T., K. Kristjansson, S.G.S., R.R., B. Sigurgeirsson, K.T., J.H.O., S.J., H.H., T.G., H.J.I., E.J., T.J., G.V.E., R.B.B., K.R.B., B.A.A., H. Skuladottir, K.O., A. Salvarsdottir, H. Saemundsson, J.H., V.H., E.N., S. Polidoro, S. Porru, R.B.-E., R.K., K.H., P.R., K. Koppova, E.G., G.S., D.T.B., A.E.K., M.C., E.K., M.P.Z., P.V., P.d.V., G. Matullo, A.F., D.I., M.J.V., R.A., B. Saez, P.J., J.B., S.N., A.T., D.K., A.L., F.d.V., F.B., W.J.C., J.A.S., H.F.M.v.d.H., H.J.S., R.A.T., E.O., O.v.H., K.K.H.A., J.I.M., L.A.K. Principal collaborators for the non-Icelandic populations were L.A.K. (The Netherlands), J.I.M. (Zaragoza, Spain), A.E.K. (UK), G. Matullo and P.V. (Torino), S.P. (Brescia), M.P.Z. and F.B. (Belgium), R.K. (Eastern Europe), G.S. (bladder cancer, Sweden), J.H. (melanoma, Sweden), E.N. (Valencia, Spain) and W.J.C. (Chicago, USA). Genotyping and laboratory experiments were carried out by A. Sigurdsson, T.B., M.J., H.H., H.B., M.A., K.T.K. and S.M. Bioinformatic analysis was carried out by P.S., T.R., A. Sigurdsson, T.E.T., G. Masson, T.B. and G.T. Authors T.R., P.S., D.F.G., A.K., U.T. and K.S. drafted the manuscript. All authors contributed to the final version of the paper.

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Correspondence to Thorunn Rafnar or Kari Stefansson.

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The authors from deCODE Genetics are shareholders in deCODE Genetics Inc. and therefore declare competing financial interest.

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Supplementary Methods, Supplementary Note, Supplementary Tables 1–11 and Supplementary Figures 1 and 2 (PDF 229 kb)

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Rafnar, T., Sulem, P., Stacey, S. et al. Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nat Genet 41, 221–227 (2009). https://doi.org/10.1038/ng.296

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