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Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.
乳腺癌风险受易感基因中的罕见编码变异（如BRCA1）以及许多常见的、大多为非编码变异的影响。然而，对乳腺癌风险的大部分遗传贡献仍不清楚。在此，我们报告了一项针对欧洲血统的122977例病例和105974例对照以及东亚血统的14068例病例和13104例对照的乳腺癌全基因组关联研究结果。我们在P < 5×10时鉴定出65个与总体乳腺癌风险相关的新位点。这些位点中大多数可信的风险单核苷酸多态性位于远端调控元件中，通过整合计算机数据以预测每个位点乳腺细胞中的靶基因，我们证明了候选靶基因与乳腺肿瘤中的体细胞驱动基因之间存在强烈重叠。我们还发现，相对于全基因组平均水平，调控特征中所有单核苷酸多态性导致的乳腺癌遗传度富集了2至5倍，特定转录因子结合位点有强烈富集。这些结果为乳腺癌遗传易感性提供了进一步的见解，并将改善遗传风险评分在个体化筛查和预防中的应用。
