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

Thorunn Rafnar; Patrick Sulem; Simon N. Stacey; Frank Geller; Julius Gudmundsson; Asgeir Sigurdsson; Margret Jakobsdottir; Hafdis Helgadottir; Steinunn Thorlacius; Katja K.H. Aben; Thorarinn Blöndal; Thorgeir E. Thorgeirsson; Gudmar Thorleifsson; Kristleifur Kristjansson; Kristin Thorisdottir; Rafn Ragnarsson; Bardur Sigurgeirsson; Halla Skuladottir; Tomas Gudbjartsson; Helgi J. Isaksson; Gudmundur V. Einarsson; Kristrun R. Benediktsdottir; Bjarni A. Agnarsson; Karl Olafsson; Anna Salvarsdottir; Hjordis Bjarnason; Margret Asgeirsdottir; Kari T. Kristinsson; Sigurborg Matthiasdottir; Steinunn G. Sveinsdottir; Silvia Polidoro; Veronica Höiom; Rafael Botella-Estrada; Kari Hemminki; Peter Rudnai; D. Timothy Bishop; Marcello Campagna; Eliane Kellen; Maurice P. Zeegers; Petra De Verdier; Ana Ferrer; Dolores Isla; Maria Jesus Vidal; Raquel Andres; Berta Saez; Pablo Juberias; Javier Banzo; Sebastian Navarrete; Alejandro Tres; Donghui Kan; Annika Lindblom; Eugene Gurzau; Kvetoslava Koppova; Femmie De Vegt; Jack A. Schalken; Henricus F.M. Van Der Heijden; Hans J. Smit; René A. Termeer; Egbert Oosterwijk; Onno Van Hooij; Eduardo Nagore; Stefano Porru; Gunnar Steineck; Johan Hansson; Frank Buntinx; William J. Catalona; Giuseppe Matullo; Paolo Vineis; Anne E. Kiltie; José I. Mayordomo; Rajiv Kumar; Lambertus A. Kiemeney; Michael L. Frigge; Thorvaldur Jonsson; Hafsteinn Saemundsson; Rosa B. Barkardottir; Eirikur Jonsson; Steinn Jonsson; Jon H. Olafsson; Jeffrey R. Gulcher; Gisli Masson; Daniel F. Gudbjartsson; Augustine Kong; Unnur Thorsteinsdottir; Kari Stefansson

doi:10.1038/ng.296

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

Thorunn Rafnar^*, Patrick Sulem, Simon N. Stacey, Frank Geller, Julius Gudmundsson, Asgeir Sigurdsson, Margret Jakobsdottir, Hafdis Helgadottir, Steinunn Thorlacius, Katja K.H. Aben, Thorarinn Blöndal, Thorgeir E. Thorgeirsson, Gudmar Thorleifsson, Kristleifur Kristjansson, Kristin Thorisdottir, Rafn Ragnarsson, Bardur Sigurgeirsson, Halla Skuladottir, Tomas Gudbjartsson, Helgi J. IsakssonGudmundur V. Einarsson, Kristrun R. Benediktsdottir, Bjarni A. Agnarsson, Karl Olafsson, Anna Salvarsdottir, Hjordis Bjarnason, Margret Asgeirsdottir, Kari T. Kristinsson, Sigurborg Matthiasdottir, Steinunn G. Sveinsdottir, Silvia Polidoro, Veronica Höiom, Rafael Botella-Estrada, Kari Hemminki, Peter Rudnai, D. Timothy Bishop, Marcello Campagna, Eliane Kellen, Maurice P. Zeegers, Petra De Verdier, Ana Ferrer, Dolores Isla, Maria Jesus Vidal, Raquel Andres, Berta Saez, Pablo Juberias, Javier Banzo, Sebastian Navarrete, Alejandro Tres, Donghui Kan, Annika Lindblom, Eugene Gurzau, Kvetoslava Koppova, Femmie De Vegt, Jack A. Schalken, Henricus F.M. Van Der Heijden, Hans J. Smit, René A. Termeer, Egbert Oosterwijk, Onno Van Hooij, Eduardo Nagore, Stefano Porru, Gunnar Steineck, Johan Hansson, Frank Buntinx, William J. Catalona, Giuseppe Matullo, Paolo Vineis, Anne E. Kiltie, José I. Mayordomo, Rajiv Kumar, Lambertus A. Kiemeney, Michael L. Frigge, Thorvaldur Jonsson, Hafsteinn Saemundsson, Rosa B. Barkardottir, Eirikur Jonsson, Steinn Jonsson, Jon H. Olafsson, Jeffrey R. Gulcher, Gisli Masson, Daniel F. Gudbjartsson, Augustine Kong, Unnur Thorsteinsdottir, Kari Stefansson

^*Corresponding author for this work

The Rowett Institute of Nutrition and Health

Research output: Contribution to journal › Article › peer-review

508 Citations (Scopus)

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 carcinoma, 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.

Original language	English
Pages (from-to)	221-227
Number of pages	7
Journal	Nature Genetics
Volume	41
Issue number	2
DOIs	https://doi.org/10.1038/ng.296
Publication status	Published - Feb 2009

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Rafnar, T., Sulem, P., Stacey, S. N., Geller, F., Gudmundsson, J., Sigurdsson, A., Jakobsdottir, M., Helgadottir, H., Thorlacius, S., Aben, K. K. H., Blöndal, T., Thorgeirsson, T. E., Thorleifsson, G., Kristjansson, K., Thorisdottir, K., Ragnarsson, R., Sigurgeirsson, B., Skuladottir, H., Gudbjartsson, T., ... Stefansson, K. (2009). Sequence variants at the TERT-CLPTM1L locus associate with many cancer types. Nature Genetics, 41(2), 221-227. https://doi.org/10.1038/ng.296

Rafnar, T, Sulem, P, Stacey, SN, Geller, F, Gudmundsson, J, Sigurdsson, A, Jakobsdottir, M, Helgadottir, H, Thorlacius, S, Aben, KKH, Blöndal, T, Thorgeirsson, TE, Thorleifsson, G, Kristjansson, K, Thorisdottir, K, Ragnarsson, R, Sigurgeirsson, B, Skuladottir, H, Gudbjartsson, T, Isaksson, HJ, Einarsson, GV, Benediktsdottir, KR, Agnarsson, BA, Olafsson, K, Salvarsdottir, A, Bjarnason, H, Asgeirsdottir, M, Kristinsson, KT, Matthiasdottir, S, Sveinsdottir, SG, Polidoro, S, Höiom, V, Botella-Estrada, R, Hemminki, K, Rudnai, P, Bishop, DT, Campagna, M, Kellen, E, Zeegers, MP, De Verdier, P, Ferrer, A, Isla, D, Vidal, MJ, Andres, R, Saez, B, Juberias, P, Banzo, J, Navarrete, S, Tres, A, Kan, D, Lindblom, A, Gurzau, E, Koppova, K, De Vegt, F, Schalken, JA, Van Der Heijden, HFM, Smit, HJ, Termeer, RA, Oosterwijk, E, Van Hooij, O, Nagore, E, Porru, S, Steineck, G, Hansson, J, Buntinx, F, Catalona, WJ, Matullo, G, Vineis, P, Kiltie, AE, Mayordomo, JI, Kumar, R, Kiemeney, LA, Frigge, ML, Jonsson, T, Saemundsson, H, Barkardottir, RB, Jonsson, E, Jonsson, S, Olafsson, JH, Gulcher, JR, Masson, G, Gudbjartsson, DF, Kong, A, Thorsteinsdottir, U & Stefansson, K 2009, 'Sequence variants at the TERT-CLPTM1L locus associate with many cancer types', Nature Genetics, vol. 41, no. 2, pp. 221-227. https://doi.org/10.1038/ng.296

@article{aca9d81a65cd49e4ae57b76e5a1cb519,

title = "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 carcinoma, 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.",

author = "Thorunn Rafnar and Patrick Sulem and Stacey, {Simon N.} and Frank Geller and Julius Gudmundsson and Asgeir Sigurdsson and Margret Jakobsdottir and Hafdis Helgadottir and Steinunn Thorlacius and Aben, {Katja K.H.} and Thorarinn Bl{\"o}ndal and Thorgeirsson, {Thorgeir E.} and Gudmar Thorleifsson and Kristleifur Kristjansson and Kristin Thorisdottir and Rafn Ragnarsson and Bardur Sigurgeirsson and Halla Skuladottir and Tomas Gudbjartsson and Isaksson, {Helgi J.} and Einarsson, {Gudmundur V.} and Benediktsdottir, {Kristrun R.} and Agnarsson, {Bjarni A.} and Karl Olafsson and Anna Salvarsdottir and Hjordis Bjarnason and Margret Asgeirsdottir and Kristinsson, {Kari T.} and Sigurborg Matthiasdottir and Sveinsdottir, {Steinunn G.} and Silvia Polidoro and Veronica H{\"o}iom and Rafael Botella-Estrada and Kari Hemminki and Peter Rudnai and Bishop, {D. Timothy} and Marcello Campagna and Eliane Kellen and Zeegers, {Maurice P.} and {De Verdier}, Petra and Ana Ferrer and Dolores Isla and Vidal, {Maria Jesus} and Raquel Andres and Berta Saez and Pablo Juberias and Javier Banzo and Sebastian Navarrete and Alejandro Tres and Donghui Kan and Annika Lindblom and Eugene Gurzau and Kvetoslava Koppova and {De Vegt}, Femmie and Schalken, {Jack A.} and {Van Der Heijden}, {Henricus F.M.} and Smit, {Hans J.} and Termeer, {Ren{\'e} A.} and Egbert Oosterwijk and {Van Hooij}, Onno and Eduardo Nagore and Stefano Porru and Gunnar Steineck and Johan Hansson and Frank Buntinx and Catalona, {William J.} and Giuseppe Matullo and Paolo Vineis and Kiltie, {Anne E.} and Mayordomo, {Jos{\'e} I.} and Rajiv Kumar and Kiemeney, {Lambertus A.} and Frigge, {Michael L.} and Thorvaldur Jonsson and Hafsteinn Saemundsson and Barkardottir, {Rosa B.} and Eirikur Jonsson and Steinn Jonsson and Olafsson, {Jon H.} and Gulcher, {Jeffrey R.} and Gisli Masson and Gudbjartsson, {Daniel F.} and Augustine Kong and Unnur Thorsteinsdottir and Kari Stefansson",

note = "Funding Information: We thank the individuals that participated in the study and whose contribution made this work possible. We also thank the nurses at deCODE{\textquoteright}s participant recruitment center and the personnel at deCODE{\textquoteright}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: {\textquoteleft}{\textquoteleft}Food Quality and Safety{\textquoteright}{\textquoteright} (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.",

year = "2009",

month = feb,

doi = "10.1038/ng.296",

language = "English",

volume = "41",

pages = "221--227",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Sequence variants at the TERT-CLPTM1L locus associate with many cancer types

AU - Rafnar, Thorunn

AU - Sulem, Patrick

AU - Stacey, Simon N.

AU - Geller, Frank

AU - Gudmundsson, Julius

AU - Sigurdsson, Asgeir

AU - Jakobsdottir, Margret

AU - Helgadottir, Hafdis

AU - Thorlacius, Steinunn

AU - Aben, Katja K.H.

AU - Blöndal, Thorarinn

AU - Thorgeirsson, Thorgeir E.

AU - Thorleifsson, Gudmar

AU - Kristjansson, Kristleifur

AU - Thorisdottir, Kristin

AU - Ragnarsson, Rafn

AU - Sigurgeirsson, Bardur

AU - Skuladottir, Halla

AU - Gudbjartsson, Tomas

AU - Isaksson, Helgi J.

AU - Einarsson, Gudmundur V.

AU - Benediktsdottir, Kristrun R.

AU - Agnarsson, Bjarni A.

AU - Olafsson, Karl

AU - Salvarsdottir, Anna

AU - Bjarnason, Hjordis

AU - Asgeirsdottir, Margret

AU - Kristinsson, Kari T.

AU - Matthiasdottir, Sigurborg

AU - Sveinsdottir, Steinunn G.

AU - Polidoro, Silvia

AU - Höiom, Veronica

AU - Botella-Estrada, Rafael

AU - Hemminki, Kari

AU - Rudnai, Peter

AU - Bishop, D. Timothy

AU - Campagna, Marcello

AU - Kellen, Eliane

AU - Zeegers, Maurice P.

AU - De Verdier, Petra

AU - Ferrer, Ana

AU - Isla, Dolores

AU - Vidal, Maria Jesus

AU - Andres, Raquel

AU - Saez, Berta

AU - Juberias, Pablo

AU - Banzo, Javier

AU - Navarrete, Sebastian

AU - Tres, Alejandro

AU - Kan, Donghui

AU - Lindblom, Annika

AU - Gurzau, Eugene

AU - Koppova, Kvetoslava

AU - De Vegt, Femmie

AU - Schalken, Jack A.

AU - Van Der Heijden, Henricus F.M.

AU - Smit, Hans J.

AU - Termeer, René A.

AU - Oosterwijk, Egbert

AU - Van Hooij, Onno

AU - Nagore, Eduardo

AU - Porru, Stefano

AU - Steineck, Gunnar

AU - Hansson, Johan

AU - Buntinx, Frank

AU - Catalona, William J.

AU - Matullo, Giuseppe

AU - Vineis, Paolo

AU - Kiltie, Anne E.

AU - Mayordomo, José I.

AU - Kumar, Rajiv

AU - Kiemeney, Lambertus A.

AU - Frigge, Michael L.

AU - Jonsson, Thorvaldur

AU - Saemundsson, Hafsteinn

AU - Barkardottir, Rosa B.

AU - Jonsson, Eirikur

AU - Jonsson, Steinn

AU - Olafsson, Jon H.

AU - Gulcher, Jeffrey R.

AU - Masson, Gisli

AU - Gudbjartsson, Daniel F.

AU - Kong, Augustine

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

N1 - Funding Information: 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.

PY - 2009/2

Y1 - 2009/2

N2 - 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 carcinoma, 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.

AB - 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 carcinoma, 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.

UR - http://www.scopus.com/inward/record.url?scp=59149091340&partnerID=8YFLogxK

U2 - 10.1038/ng.296

DO - 10.1038/ng.296

M3 - Article

C2 - 19151717

AN - SCOPUS:59149091340

VL - 41

SP - 221

EP - 227

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -

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

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