Open AccessA germline variant in the TP53 polyadenylation signal confers cancer susceptibility
Author(s) -
Simon Stacey,
Patrick Sulem,
Áslaug Jónasdóttir,
Gísli Másson,
Jūlı́us Guðmundsson,
Daníel F. Guðbjartsson,
Ólafur Þ. Magnússon,
Sigurjon A. Gudjonsson,
Bárður Sigurgeirsson,
Kristin Thorisdottir,
Rafn Ragnarsson,
Kristrún R. Benediktsdóttir,
Bjørn A. Nexø,
Anne Tjønneland,
Kim Overvad,
Péter Rudnai,
Eugen Gurzău,
Kvetoslava Koppová,
Kari Hemminki,
Cristina Corredera,
Victoria Fuentelsaz,
Pilar Grasa,
Sebastián Navarrete,
Fernando Fuertes,
María Dolores García-Prats,
Enrique Sanambrosio,
Angeles Panadero,
Ana De Juan,
A M Arnáiz García,
Fernando Rivera,
Dolores Planelles,
Vincent Soriano,
Celia Requena,
Katja K.H. Aben,
Michelle M. van Rossum,
R.G.H.M. Cremers,
Inge M. van Oort,
D.J. van Spronsen,
Jack A. Schalken,
Wilbert H. M. Peters,
Brian T. Helfand,
Jenny Donovan,
Freddie C. Hamdy,
D. Badescu,
O. Codreanu,
Mariana Jinga,
Irma Eva Csiki,
Vali Constantinescu,
P Badea,
Ioan Nicolae Mateș,
Daniela Dinu,
Adrian Constantin,
Dana Mateș,
Sjöfn Kristjánsdóttir,
Bjarni A. Agnarsson,
Eiríkur Jónsson,
Rósa B. Barkardóttir,
Guðmundur Einarsson,
Fridbjörn Sigurdsson,
Páll Helgi Möller,
Tryggvi Stefánsson,
Trausti Valdimarsson,
Óskar T. Jóhannsson,
Helgi Sigurðsson,
Þorvaldur Jónsson,
Jón G. Jonasson,
Laufey Tryggvadóttír,
Terri Rice,
Helen M. Hansen,
Yuanyuan Xiao,
Daniel H. Lachance,
Brian P. O’Neill,
Matthew L. Kosel,
Paul A. Decker,
Guðmar Þorleifsson,
Hrefna Johannsdottir,
Hafdís T. Helgadottir,
Ásgeir Sigurðsson,
Valgerður Steinthórsdóttir,
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. Catàlona,
Margaret Wrensch,
John K. Wiencke,
Robert B. Jenkins,
Eduardo Nagore,
Ulla Vogel,
Lambertus A. Kiemeney,
Rajiv Kumar,
José Ignacio Mayordomo,
Jón Ólafsson,
Augustine Kong,
Unnur Þorsteinsdóttir,
Thorunn Rafnar,
Kāri Stefánsson
Publication year - 2011
Publication title -
nature genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 18.861
H-Index - 573
eISSN - 1546-1718
pISSN - 1061-4036
DOI - 10.1038/ng.926
Subject(s) - biology , genetics , single nucleotide polymorphism , polyadenylation , cancer , odds ratio , snp , genotype , microbiology and biotechnology , medicine , gene , gene expression
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).