Letter | Published:

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

Nature Genetics volume 41, pages 221227 (2009) | Download Citation

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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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.

Author information

Author notes

    • Thorunn Rafnar
    •  & Patrick Sulem

    These authors contributed equally to this work.

Affiliations

  1. deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.

    • Thorunn Rafnar
    • , Patrick Sulem
    • , Simon N Stacey
    • , Frank Geller
    • , Julius Gudmundsson
    • , Asgeir Sigurdsson
    • , Margret Jakobsdottir
    • , Hafdis Helgadottir
    • , Steinunn Thorlacius
    • , Thorarinn Blöndal
    • , Thorgeir E Thorgeirsson
    • , Gudmar Thorleifsson
    • , Kristleifur Kristjansson
    • , Hjordis Bjarnason
    • , Margret Asgeirsdottir
    • , Kari T Kristinsson
    • , Sigurborg Matthiasdottir
    • , Michael L Frigge
    • , Jeffrey R Gulcher
    • , Gisli Masson
    • , Daniel F Gudbjartsson
    • , Augustine Kong
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  2. Comprehensive Cancer Center East, 6501 BG Nijmegen, The Netherlands.

    • Katja K H Aben
    •  & Lambertus A Kiemeney
  3. Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.

    • Katja K H Aben
    • , Femmie de Vegt
    •  & Lambertus A Kiemeney
  4. Department of Dermatology, University of Iceland, 101 Reykjavik, Iceland.

    • Kristin Thorisdottir
    • , Bardur Sigurgeirsson
    •  & Jon H Olafsson
  5. Departments of Plastic Surgery, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Rafn Ragnarsson
  6. Medical Oncology, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Halla Skuladottir
  7. Surgery, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Tomas Gudbjartsson
    •  & Thorvaldur Jonsson
  8. Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.

    • Tomas Gudbjartsson
    • , Kristrun R Benediktsdottir
    • , Bjarni A Agnarsson
    • , Thorvaldur Jonsson
    • , Steinn Jonsson
    • , Jon H Olafsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  9. Departments of Pathology, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Helgi J Isaksson
    • , Kristrun R Benediktsdottir
    • , Bjarni A Agnarsson
    •  & Rosa B Barkardottir
  10. Urology, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Gudmundur V Einarsson
    •  & Eirikur Jonsson
  11. Obstetrics and Gynecology, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Karl Olafsson
    • , Anna Salvarsdottir
    •  & Hafsteinn Saemundsson
  12. Clinical Research Centre, Krokhals 5D, 110 Reykjavik, Iceland.

    • Steinunn G Sveinsdottir
  13. ISI Foundation (Institute for Scientific Interchange), 10133 Torino, Italy.

    • Silvia Polidoro
    • , Giuseppe Matullo
    •  & Paolo Vineis
  14. Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino, Italy.

    • Silvia Polidoro
    •  & Giuseppe Matullo
  15. Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna Stockholm, S-171 76, Sweden.

    • Veronica Höiom
    • , Gunnar Steineck
    •  & Johan Hansson
  16. Department of Dermatology, Instituto Valenciano de Oncologia, 46009, Valencia, Spain.

    • Rafael Botella-Estrada
    •  & Eduardo Nagore
  17. Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, D-69120, Germany.

    • Kari Hemminki
    •  & Rajiv Kumar
  18. National Institute of Environmental Health, H-1450 Budapest, Hungary.

    • Peter Rudnai
  19. Section of Epidemiology & Biostatistics, Leeds Institute of Molecular Medicine, St. James's University Hospital, LS9 7TF Leeds, UK.

    • D Timothy Bishop
  20. Department of Experimental and Applied Medicine - Section of Occupational Medicine and Industrial Hygiene, University of Brescia, 25125 Brescia, Italy.

    • Marcello Campagna
    •  & Stefano Porru
  21. Department of General Practice, Catholic University of Leuven, 3000 Leuven, Belgium.

    • Eliane Kellen
    •  & Frank Buntinx
  22. Leuven University Centre for Cancer Prevention (LUCK), 3000 Leuven, Belgium.

    • Eliane Kellen
  23. Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, B15 2TT Birmingham, UK.

    • Maurice P Zeegers
  24. Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, 6200 MD Maastricht, The Netherlands.

    • Maurice P Zeegers
  25. Department of Molecular Medicine and Surgery, Karolinska Institutet, S171 76 Stockholm, Sweden.

    • Petra de Verdier
    •  & Annika Lindblom
  26. Division of Medical Oncology, University Hospital, 50009 Zaragoza, Spain.

    • Ana Ferrer
    • , Dolores Isla
    • , Maria Jesus Vidal
    • , Raquel Andres
    • , Alejandro Tres
    •  & José I Mayordomo
  27. Health Science Institute, 50009 Zaragoza, Spain.

    • Berta Saez
  28. Division of Dermatology, University Hospital, 50009 Zaragoza, Spain.

    • Pablo Juberias
  29. Divisions of Nuclear Medicine, University Hospital, 50009 Zaragoza, Spain.

    • Javier Banzo
  30. Radiation Oncology, University Hospital, 50009 Zaragoza, Spain.

    • Sebastian Navarrete
  31. Health Science Institute, Nanotechnology Institute of Aragon, 50009, Zaragoza, Spain.

    • Alejandro Tres
    •  & José I Mayordomo
  32. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.

    • Donghui Kan
    •  & William J Catalona
  33. Environmental Health Center, 400166 Cluj Napoca, Romania.

    • Eugene Gurzau
  34. State Health Institute, SK-975 56 Banska Bystrica, Slovakia.

    • Kvetoslava Koppova
  35. Departments of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

    • Jack A Schalken
    • , Egbert Oosterwijk
    • , Onno van Hooij
    •  & Lambertus A Kiemeney
  36. Pulmonary Diseases, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

    • Henricus F M van der Heijden
  37. Department of Pulmonary Medicine, Rijnstate Hospital, Arnhem, The Netherlands.

    • Hans J Smit
  38. Department of Pulmonary Diseases, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands.

    • René A Termeer
  39. Department of Oncology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden.

    • Gunnar Steineck
  40. Department of General Practice, Maastricht University, 6200 MD Maastricht, The Netherlands.

    • Frank Buntinx
  41. Department of Epidemiology and Public Health, Imperial College, W2 1PG London, UK.

    • Paolo Vineis
  42. Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James's University Hospital, LS9 7TF Leeds, UK.

    • Anne E Kiltie
  43. Department of Medicine, Landspitali-University Hospital, 101 Reykjavik, Iceland.

    • Steinn Jonsson

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Contributions

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.

Competing interests

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

Corresponding authors

Correspondence to Thorunn Rafnar or Kari Stefansson.

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DOI

https://doi.org/10.1038/ng.296

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