A germline variant in the TP53 polyadenylation signal confers cancer susceptibility

• Published in: Nature genetics Vol. 43; no. 11; pp. 1098 - 1103
• Main Authors: Stacey, Simon N, Stefansson, Kari, Sulem, Patrick, Jonasdottir, Aslaug, Masson, Gisli, Gudmundsson, Julius, Gudbjartsson, Daniel F, Magnusson, Olafur T, Gudjonsson, Sigurjon A, Thorisdottir, Kristin, Ragnarsson, Rafn, Benediktsdottir, Kristrun R, Nexø, Bjørn A, Tjønneland, Anne, Overvad, Kim, Rudnai, Peter, Gurzau, Eugene, Koppova, Kvetoslava, Corredera, Cristina, Fuentelsaz, Victoria, Grasa, Pilar, Navarrete, Sebastian, Fuertes, Fernando, García-Prats, Maria D, Sanambrosio, Enrique, Panadero, Angeles, Juan, Ana De, Garcia, Almudena, Rivera, Fernando, Planelles, Dolores, Soriano, Virtudes, Requena, Celia, Aben, Katja K, Rossum, Michelle M van, Cremers, Ruben G H M, Oort, Inge M van, van Spronsen, Dick-Johan, Schalken, Jack A, Peters, Wilbert H M, Helfand, Brian T, Donovan, Jenny L, Hamdy, Freddie C, Badescu, Daniel, Codreanu, Ovidiu, Jinga, Mariana, Csiki, Irma E, Constantinescu, Vali, Badea, Paula, Mates, Ioan N, Dinu, Daniela E, Constantin, Adrian, Mates, Dana, Kristjansdottir, Sjofn, Agnarsson, Bjarni A, Jonsson, Eirikur, Barkardottir, Rosa B, Einarsson, Gudmundur V, Sigurdsson, Fridbjorn, Moller, Pall H, Stefansson, Tryggvi, Valdimarsson, Trausti, Johannsson, Oskar T, Sigurdsson, Helgi, Jonsson, Thorvaldur, Jonasson, Jon G, Tryggvadottir, Laufey, Rice, Terri, Hansen, Helen M, Xiao, Yuanyuan, Lachance, Daniel H, Kosel, Matthew L, Decker, Paul A, Thorleifsson, Gudmar, Johannsdottir, Hrefna, Helgadottir, Hafdis T, Sigurdsson, Asgeir, Steinthorsdottir, Valgerdur, Lindblom, Annika, Sandler, Robert S, Keku, Temitope O, Banasik, Karina, Jørgensen, Torben, Witte, Daniel R, Hansen, Torben, Pedersen, Oluf, Jinga, Viorel, Neal, David E, Catalona, William J, Wrensch, Margaret, Wiencke, John, Jenkins, Robert B, Nagore, Eduardo, Vogel, Ulla, Kiemeney, Lambertus A, Kumar, Rajiv, Mayordomo, José I, Olafsson, Jon H, Kong, Augustine, Thorsteinsdottir, Unnur, Rafnar, Thorunn
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2011; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/2489/144/68; 631/208/727/2000; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical research; Biomedicine; Cancer Research; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Disease susceptibility; DNA sequencing; Fundamental and applied biological sciences. Psychology; Gene Function; Genealogy; Genetic aspects; Genetic Predisposition to Disease; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Genotypes; Germ-Line Mutation; Haplotypes; Human Genetics; Humans; letter; Medical research; Medical schools; Medicin och hälsovetenskap; Molecular and cellular biology; Neoplasms - genetics; Polymorphism, Single Nucleotide; Prostate cancer; Skin cancer; Tumor proteins; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Variant; Polyadenylation signal; TP53 Gene; Malignant tumor; Germ line; Cancer
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.926

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).