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

Journal article

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).

Authors: Stacey, SN; Sulem, P; Jonasdottir, A; Masson, G; Gudmundsson, J

• Publication status: Published
• Journal: Nature genetics
• Volume: 43
• Issue: 11
• Pages: 1098-1103
• Publication date: 2011-11-01
• DOI: 10.1038/ng.926
• EISSN: 1546-1718
• ISSN: 1061-4036
• Language: English
• Keywords: Germ-Line Mutation; Tumor Suppressor Protein p53; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Humans; Swedish Low-risk Colorectal Cancer Study Group; Neoplasms