A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
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为了确定皮肤基底细胞癌的新风险变异，我们对通过 457 名冰岛人的全基因组测序确定的 1600 万个 SNP 进行了全基因组关联研究。我们对 41,675 名 Illumina SNP 芯片型冰岛人及其亲属的基因型进行了估算。在发现阶段，最强的信号来自rs78378222[C]（优势比（OR）= 2.36，P = 5.2 × 10−17），其在冰岛人群中的频率为0.0192。然后，我们在非冰岛样本中证实了这种关联（OR = 1.75，P = 0.0060；总体 OR = 2.16，P = 2.2 × 10−20）。 rs78378222 位于 TP53 的 3' 非翻译区，将 AATAAA 多腺苷酸化信号更改为 AATACA，导致 TP53 mRNA 3' 端加工受损。对其他肿瘤类型的调查发现该 SNP 与前列腺癌 (OR = 1.44，P = 2.4 × 10−6)、神经胶质瘤 (OR = 2.35，P = 1.0 × 10−5) 和结直肠腺瘤 (OR = 1.39，P = 1.6 × 10−4) 之间的关联。然而，我们观察到对乳腺癌（一种常见的 Li-Fraumeni 综合征肿瘤）没有影响（OR = 1.06，P = 0.57，95% 置信区间 0.88–1.27）。
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).