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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.

Stacey S.N., Sulem P., Jonasdottir A., Masson G., Gudmundsson J., Gudbjartsson D.F., Magnusson O.T., Gudjonsson S.A., Sigurgeirsson B., Thorisdottir K., Ragnarsson R., Benediktsdottir K.R., Nexo B.A., Tjonneland A., Overvad K., Rudnai P., Gurzau E., Koppova K., Hemminki K., Corredera C., Fuentelsaz V., Grasa P., Navarrete S., Fuertes F., Garcia-Prats M.D., Sanambrosio E., Panadero A., De Juan A., Garcia A., Rivera F., Planelles D., Soriano V., Requena C., Aben K.K., van Rossum M.M., Cremers R.G., van Oort I.M., van Spronsen D.J., Schalken J.A., Peters W.H., Helfand B.T., Donovan J.L., Hamdy F.C., Badescu D., Codreanu O., Jinga M., Csiki I.E., Constantinescu V., Badea P., Mates I.N., Dinu D.E., Constantin A., Mates D., Kristjansdottir S., Agnarsson B.A., Jonsson E., Barkardottir R.B., Einarsson G.V., Sigurdsson F., Moller P.H., Stefansson T., Valdimarsson T., Johannsson O.T., Sigurdsson H., Jonsson T., Jonasson J.G., Tryggvadottir L., Rice T., Hansen H.M., Xiao Y., Lachance D.H., O'Neill B.P., Kosel M.L., Decker P.A., Thorleifsson G., Johannsdottir H., Helgadottir H.T., Sigurdsson A., Steinthorsdottir V., Lindblom A., Sandler R.S., Keku T.O., Banasik K., Jorgensen T., Witte D.R., Hansen T., Pedersen O., Jinga V., Neal D.E., Catalona W.J., Wrensch M., Wiencke J., Jenkins R.B., Nagore E., Vogel U., Kiemeney L.A., Kumar R., Mayordomo J.I., Olafsson J.H., Kong A., Thorsteinsdottir U., Rafnar T., Stefansson K.

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).

Nat. Genet. 43:1098-1103(2011) [PubMed] [Europe PMC]

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