A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Simon N. Stacey; Patrick Sulem; Aslaug Jonasdottir; Gisli Masson; Julius Gudmundsson; Daniel F. Gudbjartsson; Olafur T. Magnusson; Sigurjon A. Gudjonsson; Bardur Sigurgeirsson; Kristin Thorisdottir; Rafn Ragnarsson; Kristrun R. Benediktsdottir; Bjørn A. Nexø; Anne Tjønneland; Kim Overvad; Peter Rudnai; Eugene Gurzau; Kvetoslava Koppova; Kari Hemminki; Cristina Corredera; Victoria Fuentelsaz; Pilar Grasa; Sebastian Navarrete; Fernando Fuertes; Maria D. García-Prats; Enrique Sanambrosio; Angeles Panadero; Ana De Juan; Almudena Garcia; Fernando Rivera; Dolores Planelles; Virtudes Soriano; Celia Requena; Katja K. Aben; Michelle M. Van Rossum; Ruben G.H.M. Cremers; Inge M. Van Oort; Dick Johan Van Spronsen; Jack A. Schalken; Wilbert H.M. Peters; Brian T. Helfand; Jenny L. Donovan; Freddie C. Hamdy; Daniel Badescu; Ovidiu Codreanu; Mariana Jinga; Irma E. Csiki; Vali Constantinescu; Paula Badea; Ioan N. Mates; Daniela E. Dinu; Adrian Constantin; Dana Mates; Sjofn Kristjansdottir; Bjarni A. Agnarsson; Eirikur Jonsson; Rosa B. Barkardottir; Gudmundur V. Einarsson; Fridbjorn Sigurdsson; Pall H. Moller; Tryggvi Stefansson; Trausti Valdimarsson; Oskar T. Johannsson; Helgi Sigurdsson; Thorvaldur Jonsson; Jon G. Jonasson; Laufey Tryggvadottir; Terri Rice; Helen M. Hansen; Yuanyuan Xiao; Daniel H. Lachance; Brian Patrick O'Neill; Matthew L. Kosel; Paul A. Decker; Gudmar Thorleifsson; Hrefna Johannsdottir; Hafdis T. Helgadottir; Asgeir Sigurdsson; Valgerdur Steinthorsdottir; Annika Lindblom; Robert S. Sandler; Temitope O. Keku; Karina Banasik; Torben Jørgensen; Daniel R. Witte; Torben Hansen; Oluf Pedersen; Viorel Jinga; David E. Neal; William J. Catalona; Margaret Wrensch; John Wiencke; Robert B. Jenkins; Eduardo Nagore; Ulla Vogel; Lambertus A. Kiemeney; Rajiv Kumar; José I. Mayordomo; Jon H. Olafsson; Augustine Kong; Unnur Thorsteinsdottir; Thorunn Rafnar; Kari Stefansson

doi:10.1038/ng.926

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

Simon N. Stacey^*, Patrick Sulem, Aslaug Jonasdottir, Gisli Masson, Julius Gudmundsson, Daniel F. Gudbjartsson, Olafur T. Magnusson, Sigurjon A. Gudjonsson, Bardur Sigurgeirsson, Kristin Thorisdottir, Rafn Ragnarsson, Kristrun R. Benediktsdottir, Bjørn A. Nexø, Anne Tjønneland, Kim Overvad, Peter Rudnai, Eugene Gurzau, Kvetoslava Koppova, Kari Hemminki, Cristina CorrederaVictoria Fuentelsaz, Pilar Grasa, Sebastian Navarrete, Fernando Fuertes, Maria D. García-Prats, Enrique Sanambrosio, Angeles Panadero, Ana De Juan, Almudena Garcia, Fernando Rivera, Dolores Planelles, Virtudes Soriano, Celia Requena, Katja K. Aben, Michelle M. Van Rossum, Ruben G.H.M. Cremers, Inge M. Van Oort, Dick Johan Van Spronsen, Jack A. Schalken, Wilbert H.M. Peters, Brian T. Helfand, Jenny L. Donovan, Freddie C. Hamdy, Daniel Badescu, Ovidiu Codreanu, Mariana Jinga, Irma E. Csiki, Vali Constantinescu, Paula Badea, Ioan N. Mates, Daniela E. Dinu, Adrian Constantin, Dana Mates, Sjofn Kristjansdottir, Bjarni A. Agnarsson, Eirikur Jonsson, Rosa B. Barkardottir, Gudmundur V. Einarsson, Fridbjorn Sigurdsson, Pall H. Moller, Tryggvi Stefansson, Trausti Valdimarsson, Oskar T. Johannsson, Helgi Sigurdsson, Thorvaldur Jonsson, Jon G. Jonasson, Laufey Tryggvadottir, Terri Rice, Helen M. Hansen, Yuanyuan Xiao, Daniel H. Lachance, Brian Patrick O'Neill, Matthew L. Kosel, Paul A. Decker, Gudmar Thorleifsson, Hrefna Johannsdottir, Hafdis T. Helgadottir, Asgeir Sigurdsson, Valgerdur Steinthorsdottir, Annika Lindblom, Robert S. Sandler, Temitope O. Keku, Karina Banasik, Torben Jørgensen, Daniel R. Witte, Torben Hansen, Oluf Pedersen, Viorel Jinga, David E. Neal, William J. Catalona, Margaret Wrensch, John Wiencke, Robert B. Jenkins, Eduardo Nagore, Ulla Vogel, Lambertus A. Kiemeney, Rajiv Kumar, José I. Mayordomo, Jon H. Olafsson, Augustine Kong, Unnur Thorsteinsdottir, Thorunn Rafnar, Kari Stefansson

^*Corresponding author for this work

Urology

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

221 Scopus citations

Abstract

To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 ×-10 ^-17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 ×-10 ^-20). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 ×-10 ^-6), glioma (OR = 2.35, P = 1.0 ×-10 ^-5) and colorectal adenoma (OR = 1.39, P = 1.6 ×-10 ^-4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

Original language	English (US)
Pages (from-to)	1098-1103
Number of pages	6
Journal	Nature Genetics
Volume	43
Issue number	11
DOIs	https://doi.org/10.1038/ng.926
State	Published - Nov 2011

ASJC Scopus subject areas

Genetics

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Cite this

Stacey, S. N., Sulem, P., Jonasdottir, A., Masson, G., Gudmundsson, J., Gudbjartsson, D. F., Magnusson, O. T., Gudjonsson, S. A., Sigurgeirsson, B., Thorisdottir, K., Ragnarsson, R., Benediktsdottir, K. R., Nexø, B. A., Tjønneland, A., Overvad, K., Rudnai, P., Gurzau, E., Koppova, K., Hemminki, K., ... Stefansson, K. (2011). A germline variant in the TP53 polyadenylation signal confers cancer susceptibility. Nature Genetics, 43(11), 1098-1103. https://doi.org/10.1038/ng.926

@article{ebca04922470432a919dc7ae603afaae,

title = "A germline variant in the TP53 polyadenylation signal confers cancer susceptibility",

abstract = "To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 ×-10 -17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 ×-10 -20). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 ×-10 -6), glioma (OR = 2.35, P = 1.0 ×-10 -5) and colorectal adenoma (OR = 1.39, P = 1.6 ×-10 -4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).",

author = "Stacey, {Simon N.} and Patrick Sulem and Aslaug Jonasdottir and Gisli Masson and Julius Gudmundsson and Gudbjartsson, {Daniel F.} and Magnusson, {Olafur T.} and Gudjonsson, {Sigurjon A.} and Bardur Sigurgeirsson and Kristin Thorisdottir and Rafn Ragnarsson and Benediktsdottir, {Kristrun R.} and Nex{\o}, {Bj{\o}rn A.} and Anne Tj{\o}nneland and Kim Overvad and Peter Rudnai and Eugene Gurzau and Kvetoslava Koppova and Kari Hemminki and Cristina Corredera and Victoria Fuentelsaz and Pilar Grasa and Sebastian Navarrete and Fernando Fuertes and Garc{\'i}a-Prats, {Maria D.} and Enrique Sanambrosio and Angeles Panadero and {De Juan}, Ana and Almudena Garcia and Fernando Rivera and Dolores Planelles and Virtudes Soriano and Celia Requena and Aben, {Katja K.} and {Van Rossum}, {Michelle M.} and Cremers, {Ruben G.H.M.} and {Van Oort}, {Inge M.} and {Van Spronsen}, {Dick Johan} and Schalken, {Jack A.} and Peters, {Wilbert H.M.} and Helfand, {Brian T.} and Donovan, {Jenny L.} and Hamdy, {Freddie C.} and Daniel Badescu and Ovidiu Codreanu and Mariana Jinga and Csiki, {Irma E.} and Vali Constantinescu and Paula Badea and Mates, {Ioan N.} and Dinu, {Daniela E.} and Adrian Constantin and Dana Mates and Sjofn Kristjansdottir and Agnarsson, {Bjarni A.} and Eirikur Jonsson and Barkardottir, {Rosa B.} and Einarsson, {Gudmundur V.} and Fridbjorn Sigurdsson and Moller, {Pall H.} and Tryggvi Stefansson and Trausti Valdimarsson and Johannsson, {Oskar T.} and Helgi Sigurdsson and Thorvaldur Jonsson and Jonasson, {Jon G.} and Laufey Tryggvadottir and Terri Rice and Hansen, {Helen M.} and Yuanyuan Xiao and Lachance, {Daniel H.} and O'Neill, {Brian Patrick} and Kosel, {Matthew L.} and Decker, {Paul A.} and Gudmar Thorleifsson and Hrefna Johannsdottir and Helgadottir, {Hafdis T.} and Asgeir Sigurdsson and Valgerdur Steinthorsdottir and Annika Lindblom and Sandler, {Robert S.} and Keku, {Temitope O.} and Karina Banasik and Torben J{\o}rgensen and Witte, {Daniel R.} and Torben Hansen and Oluf Pedersen and Viorel Jinga and Neal, {David E.} and Catalona, {William J.} and Margaret Wrensch and John Wiencke and Jenkins, {Robert B.} and Eduardo Nagore and Ulla Vogel and Kiemeney, {Lambertus A.} and Rajiv Kumar and Mayordomo, {Jos{\'e} I.} and Olafsson, {Jon H.} and Augustine Kong and Unnur Thorsteinsdottir and Thorunn Rafnar and Kari Stefansson",

note = "Funding Information: The work at deCODE genetics was funded in part by contract number 202059 (PROMARK) from the 7th Framework Program of the European Union. The Danish study {\textquoteleft}Diet, Cancer and Health{\textquoteright} was supported by grants from the Danish Cancer Society and {\textquoteleft}Europe against cancer{\textquoteright}: European Prospective Investigation into Cancer and Nutrition (EPIC). The Inter99 study {\textquoteleft}A population-based primary prevention study on cardiovascular disease and type 2 diabetes{\textquoteright} was initiated by T. J{\o}rgensen (principal investigator), K. Borch-Johnsen (co-principal investigator), H. Ibsen and T.F. Thomsen. The steering committee comprises the former two individuals and C. Pisinger. The establishment of the cohort was financially supported by research grants from the Danish Research Council, The Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, the Ministry of Internal Affairs and Health, The Danish Heart Foundation, The Danish Pharmaceutical Association, The Augustinus Foundation, The Ib Henriksen Foundation and the Becket Foundation. The University of California, San Francisco (UCSF) Adult Glioma Study also acknowledges the people who have made substantial contributions to subject recruitment, specimen processing, pathology review and data analysis, including L.S. McCoy, I. Smirnov, J.S. Patoka, M.D. Prados, S.M. Chang and M.S. Berger (Department of Neurological Surgery, UCSF), J.L. Wiemels (Department of Epidemiology and Biostatistics, UCSF) and T. Tihan (Department of Pathology, UCSF). Work at the University of California, San Francisco has been supported by US National Institutes of Health (NIH) grants R01CA52689 and UCSF Brain Tumor SPORE, P50CA097257, as well as by grants from the National Brain Tumor Foundation, the UCSF Lewis Chair in Brain Tumor Research and by donations from families and friends of J. Berardi, H. Glaser, E. Olsen, R.E. Cooper and W. Martinusen. Work at the Mayo Clinic has been supported by the Mayo Clinic Brain Tumor SPORE (NIH P50 CA108961), the Mayo Clinic Comprehensive Cancer Center (NIH P30 CA15083) and an American Recovery and Reinvestment Act (ARRA) Recovery grant (NIH NS068222). Members of the Swedish Low-risk Colorectal Cancer Study Group are: D. Edler, Karolinska Universitetssjukhuset, Solna, Stockholm, Sweden; C. Lenander, Mag-tarm-centrum, Ersta sjukhus, Stockholm, Sweden; J. Dal{\'e}n, St G{\"o}rans sjukhus, Stockholm, Sweden; F. Hjern, Danderyds sjukhus, Danderyd, Sweden; N. Lundqvist, Norrt{\"a}lje sjukhus, Norrt{\"a}lje, Sweden; U. Lindforss, S{\"o}dert{\"a}lje sjukhus, S{\"o}dert{\"a}lje, Sweden; L. P{\aa}hlman, Akademiska sjukhuset, Uppsala, Sweden; K. Smedh, Centrallasarettet, V{\"a}ster{\aa}s, Sweden; A. T{\"o}rnqvist, Centralsjukhuset, Karlstad, Sweden; J. Holm, L{\"a}nssjukhuset G{\"a}vle-Sandviken, G{\"a}vle. Sweden; M. Janson, Karolinska Universitetssjukhuset, Huddinge, Huddinge, Sweden; M. Andersson, Universitetssjukhuset, {\"O}rebro, Sweden; S. Ekelund, S{\"o}dersjukhuset, Stockholm, Sweden; and E. Olsson, M{\"a}larsjukhuset, Eskilstuna, Sweden. Work on the US Prostate Cancer sample set was supported in part by the Urological Research Foundation, Prostate SPORE grant (P50 CA90386-05S2) and the Robert H. Lurie Comprehensive Cancer Center grant (P30 CA60553). For the UK Prostate Cancer sample set, the UK Department of Health funded the ProtecT study through the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 96/20/06, 96/20/99). We acknowledge the contribution of all members of the ProtecT study research group. We acknowledge the support of the NIHR Cambridge Biomedical Research Centre and the National Cancer Research Institute (ProMPT) Prostate Cancer Collaborative. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the UK Department of Health. Sample collection in Romania was supported in part by the Romanian National Council For Scientific Research (CNCSIS-UEFISCSU), grant PNII-IDEI 1184/2008. In Spain, J.I.M. is funded by Red Tematica de Investigacion Cooperative en Cancer RD06/0020/1054.",

year = "2011",

month = nov,

doi = "10.1038/ng.926",

language = "English (US)",

volume = "43",

pages = "1098--1103",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "11",

}

Stacey, SN, Sulem, P, Jonasdottir, A, Masson, G, Gudmundsson, J, Gudbjartsson, DF, Magnusson, OT, Gudjonsson, SA, Sigurgeirsson, B, Thorisdottir, K, Ragnarsson, R, Benediktsdottir, KR, Nexø, BA, Tjønneland, A, Overvad, K, Rudnai, P, Gurzau, E, Koppova, K, Hemminki, K, Corredera, C, Fuentelsaz, V, Grasa, P, Navarrete, S, Fuertes, F, García-Prats, MD, Sanambrosio, E, Panadero, A, De Juan, A, Garcia, A, Rivera, F, Planelles, D, Soriano, V, Requena, C, Aben, KK, Van Rossum, MM, Cremers, RGHM, Van Oort, IM, Van Spronsen, DJ, Schalken, JA, Peters, WHM, Helfand, BT, Donovan, JL, Hamdy, FC, Badescu, D, Codreanu, O, Jinga, M, Csiki, IE, Constantinescu, V, Badea, P, Mates, IN, Dinu, DE, Constantin, A, Mates, D, Kristjansdottir, S, Agnarsson, BA, Jonsson, E, Barkardottir, RB, Einarsson, GV, Sigurdsson, F, Moller, PH, Stefansson, T, Valdimarsson, T, Johannsson, OT, Sigurdsson, H, Jonsson, T, Jonasson, JG, Tryggvadottir, L, Rice, T, Hansen, HM, Xiao, Y, Lachance, DH, O'Neill, BP, Kosel, ML, Decker, PA, Thorleifsson, G, Johannsdottir, H, Helgadottir, HT, Sigurdsson, A, Steinthorsdottir, V, Lindblom, A, Sandler, RS, Keku, TO, Banasik, K, Jørgensen, T, Witte, DR, Hansen, T, Pedersen, O, Jinga, V, Neal, DE, Catalona, WJ, Wrensch, M, Wiencke, J, Jenkins, RB, Nagore, E, Vogel, U, Kiemeney, LA, Kumar, R, Mayordomo, JI, Olafsson, JH, Kong, A, Thorsteinsdottir, U, Rafnar, T & Stefansson, K 2011, 'A germline variant in the TP53 polyadenylation signal confers cancer susceptibility', Nature Genetics, vol. 43, no. 11, pp. 1098-1103. https://doi.org/10.1038/ng.926

TY - JOUR

T1 - A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

AU - Stacey, Simon N.

AU - Sulem, Patrick

AU - Jonasdottir, Aslaug

AU - Masson, Gisli

AU - Gudmundsson, Julius

AU - Gudbjartsson, Daniel F.

AU - Magnusson, Olafur T.

AU - Gudjonsson, Sigurjon A.

AU - Sigurgeirsson, Bardur

AU - Thorisdottir, Kristin

AU - Ragnarsson, Rafn

AU - Benediktsdottir, Kristrun R.

AU - Nexø, Bjørn A.

AU - Tjønneland, Anne

AU - Overvad, Kim

AU - Rudnai, Peter

AU - Gurzau, Eugene

AU - Koppova, Kvetoslava

AU - Hemminki, Kari

AU - Corredera, Cristina

AU - Fuentelsaz, Victoria

AU - Grasa, Pilar

AU - Navarrete, Sebastian

AU - Fuertes, Fernando

AU - García-Prats, Maria D.

AU - Sanambrosio, Enrique

AU - Panadero, Angeles

AU - De Juan, Ana

AU - Garcia, Almudena

AU - Rivera, Fernando

AU - Planelles, Dolores

AU - Soriano, Virtudes

AU - Requena, Celia

AU - Aben, Katja K.

AU - Van Rossum, Michelle M.

AU - Cremers, Ruben G.H.M.

AU - Van Oort, Inge M.

AU - Van Spronsen, Dick Johan

AU - Schalken, Jack A.

AU - Peters, Wilbert H.M.

AU - Helfand, Brian T.

AU - Donovan, Jenny L.

AU - Hamdy, Freddie C.

AU - Badescu, Daniel

AU - Codreanu, Ovidiu

AU - Jinga, Mariana

AU - Csiki, Irma E.

AU - Constantinescu, Vali

AU - Badea, Paula

AU - Mates, Ioan N.

AU - Dinu, Daniela E.

AU - Constantin, Adrian

AU - Mates, Dana

AU - Kristjansdottir, Sjofn

AU - Agnarsson, Bjarni A.

AU - Jonsson, Eirikur

AU - Barkardottir, Rosa B.

AU - Einarsson, Gudmundur V.

AU - Sigurdsson, Fridbjorn

AU - Moller, Pall H.

AU - Stefansson, Tryggvi

AU - Valdimarsson, Trausti

AU - Johannsson, Oskar T.

AU - Sigurdsson, Helgi

AU - Jonsson, Thorvaldur

AU - Jonasson, Jon G.

AU - Tryggvadottir, Laufey

AU - Rice, Terri

AU - Hansen, Helen M.

AU - Xiao, Yuanyuan

AU - Lachance, Daniel H.

AU - O'Neill, Brian Patrick

AU - Kosel, Matthew L.

AU - Decker, Paul A.

AU - Thorleifsson, Gudmar

AU - Johannsdottir, Hrefna

AU - Helgadottir, Hafdis T.

AU - Sigurdsson, Asgeir

AU - Steinthorsdottir, Valgerdur

AU - Lindblom, Annika

AU - Sandler, Robert S.

AU - Keku, Temitope O.

AU - Banasik, Karina

AU - Jørgensen, Torben

AU - Witte, Daniel R.

AU - Hansen, Torben

AU - Pedersen, Oluf

AU - Jinga, Viorel

AU - Neal, David E.

AU - Catalona, William J.

AU - Wrensch, Margaret

AU - Wiencke, John

AU - Jenkins, Robert B.

AU - Nagore, Eduardo

AU - Vogel, Ulla

AU - Kiemeney, Lambertus A.

AU - Kumar, Rajiv

AU - Mayordomo, José I.

AU - Olafsson, Jon H.

AU - Kong, Augustine

AU - Thorsteinsdottir, Unnur

AU - Rafnar, Thorunn

AU - Stefansson, Kari

N1 - Funding Information: The work at deCODE genetics was funded in part by contract number 202059 (PROMARK) from the 7th Framework Program of the European Union. The Danish study ‘Diet, Cancer and Health’ was supported by grants from the Danish Cancer Society and ‘Europe against cancer’: European Prospective Investigation into Cancer and Nutrition (EPIC). The Inter99 study ‘A population-based primary prevention study on cardiovascular disease and type 2 diabetes’ was initiated by T. Jørgensen (principal investigator), K. Borch-Johnsen (co-principal investigator), H. Ibsen and T.F. Thomsen. The steering committee comprises the former two individuals and C. Pisinger. The establishment of the cohort was financially supported by research grants from the Danish Research Council, The Danish Centre for Health Technology Assessment, Novo Nordisk Inc., Research Foundation of Copenhagen County, the Ministry of Internal Affairs and Health, The Danish Heart Foundation, The Danish Pharmaceutical Association, The Augustinus Foundation, The Ib Henriksen Foundation and the Becket Foundation. The University of California, San Francisco (UCSF) Adult Glioma Study also acknowledges the people who have made substantial contributions to subject recruitment, specimen processing, pathology review and data analysis, including L.S. McCoy, I. Smirnov, J.S. Patoka, M.D. Prados, S.M. Chang and M.S. Berger (Department of Neurological Surgery, UCSF), J.L. Wiemels (Department of Epidemiology and Biostatistics, UCSF) and T. Tihan (Department of Pathology, UCSF). Work at the University of California, San Francisco has been supported by US National Institutes of Health (NIH) grants R01CA52689 and UCSF Brain Tumor SPORE, P50CA097257, as well as by grants from the National Brain Tumor Foundation, the UCSF Lewis Chair in Brain Tumor Research and by donations from families and friends of J. Berardi, H. Glaser, E. Olsen, R.E. Cooper and W. Martinusen. Work at the Mayo Clinic has been supported by the Mayo Clinic Brain Tumor SPORE (NIH P50 CA108961), the Mayo Clinic Comprehensive Cancer Center (NIH P30 CA15083) and an American Recovery and Reinvestment Act (ARRA) Recovery grant (NIH NS068222). Members of the Swedish Low-risk Colorectal Cancer Study Group are: D. Edler, Karolinska Universitetssjukhuset, Solna, Stockholm, Sweden; C. Lenander, Mag-tarm-centrum, Ersta sjukhus, Stockholm, Sweden; J. Dalén, St Görans sjukhus, Stockholm, Sweden; F. Hjern, Danderyds sjukhus, Danderyd, Sweden; N. Lundqvist, Norrtälje sjukhus, Norrtälje, Sweden; U. Lindforss, Södertälje sjukhus, Södertälje, Sweden; L. Påhlman, Akademiska sjukhuset, Uppsala, Sweden; K. Smedh, Centrallasarettet, Västerås, Sweden; A. Törnqvist, Centralsjukhuset, Karlstad, Sweden; J. Holm, Länssjukhuset Gävle-Sandviken, Gävle. Sweden; M. Janson, Karolinska Universitetssjukhuset, Huddinge, Huddinge, Sweden; M. Andersson, Universitetssjukhuset, Örebro, Sweden; S. Ekelund, Södersjukhuset, Stockholm, Sweden; and E. Olsson, Mälarsjukhuset, Eskilstuna, Sweden. Work on the US Prostate Cancer sample set was supported in part by the Urological Research Foundation, Prostate SPORE grant (P50 CA90386-05S2) and the Robert H. Lurie Comprehensive Cancer Center grant (P30 CA60553). For the UK Prostate Cancer sample set, the UK Department of Health funded the ProtecT study through the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 96/20/06, 96/20/99). We acknowledge the contribution of all members of the ProtecT study research group. We acknowledge the support of the NIHR Cambridge Biomedical Research Centre and the National Cancer Research Institute (ProMPT) Prostate Cancer Collaborative. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the UK Department of Health. Sample collection in Romania was supported in part by the Romanian National Council For Scientific Research (CNCSIS-UEFISCSU), grant PNII-IDEI 1184/2008. In Spain, J.I.M. is funded by Red Tematica de Investigacion Cooperative en Cancer RD06/0020/1054.

PY - 2011/11

Y1 - 2011/11

N2 - To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 ×-10 -17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 ×-10 -20). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 ×-10 -6), glioma (OR = 2.35, P = 1.0 ×-10 -5) and colorectal adenoma (OR = 1.39, P = 1.6 ×-10 -4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

AB - To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 ×-10 -17), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 ×-10 -20). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 ×-10 -6), glioma (OR = 2.35, P = 1.0 ×-10 -5) and colorectal adenoma (OR = 1.39, P = 1.6 ×-10 -4). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).

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C2 - 21946351

AN - SCOPUS:80055009292

SN - 1061-4036

VL - 43

SP - 1098

EP - 1103

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

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