A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

  • Nat Genet. 2011 Sep 25;43(11):1098-103. doi: 10.1038/ng.926.
Simon N Stacey  1 ,  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 ,  Swedish Low-risk Colorectal Cancer Study Group ,  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
Affiliations
PMID: 21946351 DOI: 10.1038/ng.926
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).