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

Research output: Contribution to journalArticle

159 Citations (Scopus)

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 languageEnglish
Pages (from-to)1098-1103
Number of pages6
JournalNature genetics
Volume43
Issue number11
DOIs
Publication statusPublished - Nov 1 2011

    Fingerprint

ASJC Scopus subject areas

  • Genetics

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