A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

• DOI: 10.1038/ng.926
• Publication Date: 2011-09-25T18:34:16Z
• Authors: Simon N Stacey; Patrick Sulem; Aslaug Jonasdottir; Gisli Masson; Julius Gudmundsson; Daniel F Gudbjart...; Olafur T Magnusson; Sigurjon A Gudjon...; Bardur Sigurgeirsson; Kristin Thorisdottir; Rafn Ragnarsson; Kristrun R Benedi...; 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 Ro...; Ruben G H M Cremers; Inge M van Oort; Dick-Johan van Sp...; 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 Kristjansdo...; Bjarni A Agnarsson; Eirikur Jonsson; Rosa B Barkardottir; Gudmundur V Einar...; 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′N...; Matthew L Kosel; Paul A Decker; Gudmar Thorleifsson; Hrefna Johannsdottir; Hafdis T Helgadottir; Asgeir Sigurdsson; Valgerdur Steinth...; 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 Thorsteinsd...; Thorunn Rafnar; Kari Stefansson
• Keywords: 0301 basic medicine; NCEBP 1: Molecular epidemiology ONCOL 5: Aetiology, screening and detection; N4i 1: Pathogenesis and modulation of inflammation ONCOL 1: Hereditary cancer and cancer-related syndromes; IGMD 2: Molecular gastro-enterology and hepatology ONCOL 3: Translational research; NCEBP 1: Molecular epidemiology; NCMLS 6: Genetics and epigenetic pathways of disease; Polymorphism, Single Nucleotide; 3. Good health; 03 medical and health sciences; Neoplasms; Humans; Genetic Predisposition to Disease; Tumor Suppressor Protein p53; Germ-Line Mutation

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).