Letter abstract

Nature Genetics 41, 221 - 227 (2009)
Published online: 18 January 2009 | doi:10.1038/ng.296

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

Thorunn Rafnar1,44, Patrick Sulem1,44, Simon N Stacey1, Frank Geller1, Julius Gudmundsson1, Asgeir Sigurdsson1, Margret Jakobsdottir1, Hafdis Helgadottir1, Steinunn Thorlacius1, Katja K H Aben2,3, Thorarinn Blöndal1, Thorgeir E Thorgeirsson1, Gudmar Thorleifsson1, Kristleifur Kristjansson1, Kristin Thorisdottir4, Rafn Ragnarsson5, Bardur Sigurgeirsson4, Halla Skuladottir6, Tomas Gudbjartsson7,8, Helgi J Isaksson9, Gudmundur V Einarsson10, Kristrun R Benediktsdottir8,9, Bjarni A Agnarsson8,9, Karl Olafsson11, Anna Salvarsdottir11, Hjordis Bjarnason1, Margret Asgeirsdottir1, Kari T Kristinsson1, Sigurborg Matthiasdottir1, Steinunn G Sveinsdottir12, Silvia Polidoro13,14, Veronica Höiom15, Rafael Botella-Estrada16, Kari Hemminki17, Peter Rudnai18, D Timothy Bishop19, Marcello Campagna20, Eliane Kellen21,22, Maurice P Zeegers23,24, Petra de Verdier25, Ana Ferrer26, Dolores Isla26, Maria Jesus Vidal26, Raquel Andres26, Berta Saez27, Pablo Juberias28, Javier Banzo29, Sebastian Navarrete30, Alejandro Tres26,31, Donghui Kan32, Annika Lindblom25, Eugene Gurzau33, Kvetoslava Koppova34, Femmie de Vegt3, Jack A Schalken35, Henricus F M van der Heijden36, Hans J Smit37, René A Termeer38, Egbert Oosterwijk35, Onno van Hooij35, Eduardo Nagore16, Stefano Porru20, Gunnar Steineck15,39, Johan Hansson15, Frank Buntinx21,40, William J Catalona32, Giuseppe Matullo13,14, Paolo Vineis13,41, Anne E Kiltie42, José I Mayordomo26,31, Rajiv Kumar17, Lambertus A Kiemeney2,3,35, Michael L Frigge1, Thorvaldur Jonsson7,8, Hafsteinn Saemundsson11, Rosa B Barkardottir9, Eirikur Jonsson10, Steinn Jonsson8,43, Jon H Olafsson4,8, Jeffrey R Gulcher1, Gisli Masson1, Daniel F Gudbjartsson1, Augustine Kong1, Unnur Thorsteinsdottir1,8 & Kari Stefansson1,8

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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 times 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 times 10-8) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 times 10-4). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 times 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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  1. deCODE Genetics, Sturlugata 8, 101 Reykjavik, Iceland.
  2. Comprehensive Cancer Center East, 6501 BG Nijmegen, The Netherlands.
  3. Department of Epidemiology, Biostatistics and HTA, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands.
  4. Department of Dermatology, University of Iceland, 101 Reykjavik, Iceland.
  5. Departments of Plastic Surgery, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  6. Medical Oncology, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  7. Surgery, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  8. Faculty of Medicine, University of Iceland, 101 Reykjavik, Iceland.
  9. Departments of Pathology, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  10. Urology, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  11. Obstetrics and Gynecology, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  12. Clinical Research Centre, Krokhals 5D, 110 Reykjavik, Iceland.
  13. ISI Foundation (Institute for Scientific Interchange), 10133 Torino, Italy.
  14. Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino, Italy.
  15. Department of Oncology-Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital Solna Stockholm, S-171 76, Sweden.
  16. Department of Dermatology, Instituto Valenciano de Oncologia, 46009, Valencia, Spain.
  17. Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, D-69120, Germany.
  18. National Institute of Environmental Health, H-1450 Budapest, Hungary.
  19. Section of Epidemiology & Biostatistics, Leeds Institute of Molecular Medicine, St. James's University Hospital, LS9 7TF Leeds, UK.
  20. Department of Experimental and Applied Medicine - Section of Occupational Medicine and Industrial Hygiene, University of Brescia, 25125 Brescia, Italy.
  21. Department of General Practice, Catholic University of Leuven, 3000 Leuven, Belgium.
  22. Leuven University Centre for Cancer Prevention (LUCK), 3000 Leuven, Belgium.
  23. Unit of Genetic Epidemiology, Department of Public Health and Epidemiology, University of Birmingham, B15 2TT Birmingham, UK.
  24. Department of Complex Genetics, Cluster of Genetics and Cell Biology, Nutrition and Toxicology Research Institute, Maastricht University, 6200 MD Maastricht, The Netherlands.
  25. Department of Molecular Medicine and Surgery, Karolinska Institutet, S171 76 Stockholm, Sweden.
  26. Division of Medical Oncology, University Hospital, 50009 Zaragoza, Spain.
  27. Health Science Institute, 50009 Zaragoza, Spain.
  28. Division of Dermatology, University Hospital, 50009 Zaragoza, Spain.
  29. Divisions of Nuclear Medicine, University Hospital, 50009 Zaragoza, Spain.
  30. Radiation Oncology, University Hospital, 50009 Zaragoza, Spain.
  31. Health Science Institute, Nanotechnology Institute of Aragon, 50009, Zaragoza, Spain.
  32. Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
  33. Environmental Health Center, 400166 Cluj Napoca, Romania.
  34. State Health Institute, SK-975 56 Banska Bystrica, Slovakia.
  35. Departments of Urology, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
  36. Pulmonary Diseases, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
  37. Department of Pulmonary Medicine, Rijnstate Hospital, Arnhem, The Netherlands.
  38. Department of Pulmonary Diseases, Canisius-Wilhelmina Hospital, Weg door Jonkerbos 100, 6532 SZ, Nijmegen, The Netherlands.
  39. Department of Oncology, Sahlgrenska University Hospital, S-413 45 Goteborg, Sweden.
  40. Department of General Practice, Maastricht University, 6200 MD Maastricht, The Netherlands.
  41. Department of Epidemiology and Public Health, Imperial College, W2 1PG London, UK.
  42. Section of Experimental Oncology, Leeds Institute of Molecular Medicine, St. James's University Hospital, LS9 7TF Leeds, UK.
  43. Department of Medicine, Landspitali-University Hospital, 101 Reykjavik, Iceland.
  44. These authors contributed equally to this work.

Correspondence to: Kari Stefansson1,8 e-mail: kstefans@decode.is

Correspondence to: Thorunn Rafnar1,44 e-mail: thorunn.rafnar@decode.is



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