2. Academic Validation
  3. A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

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

Affiliation

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).

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