Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes
Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes
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DOI：
10.1038/s41431-019-0346-0
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发表时间：
2019-05-01
影响因子：
5.2
通讯作者：
Daly, Mark J.
中科院分区：
文献类型：
--
作者：
Artomov, Mykyta;Joseph, Vijai;Daly, Mark J.
沿着传统的衰老和致癌物质的影响，遗传的DNA变异对癌症风险有很大的贡献。使用GWAS方法分析常见变异取得的非凡进展并不能提供足够的分辨率来理解罕见变异。为了满足罕见种系变异的缺失分类，我们收集了来自>2000名患者的全外显子组序列数据集（选定的候选基因检测阴性的病例和阴性病例）（乳腺癌，结肠癌，皮肤和眼部黑色素瘤）与7000多名非癌症控制和分析已知癌症易感基因的生殖系变异，以鉴定疾病相关DNA变异的共同特性，并帮助未来寻找新的癌症易感基因。根据相关癌症综合征的遗传模式或已知的肿瘤抑制活性，将癌症易感基因分为非重叠类。在所有类别中，只有与显性综合征相关的基因在病例中呈现显著的罕见种系变异富集。对该基因列表中的蛋白质截短和错义变异的单独分析证实了蛋白质截短变体仅在功能丧失耐受基因（pLI < 0.1）的情况下显著流行，而超罕见错义变体仅在限制基因（pLI > 0.9）的情况下显著过度表达。除了在基因富集病例中的发现外，我们还观察到在癌症病例中罕见变异的显著负担，这表明即使在相对晚期的癌症表现中，遗传变异也具有重要作用。总之，我们的研究结果为遗传易感性的DNA变异的分布和类型提供了参考。
Along with traditional effects of aging and carcinogen exposure-inherited DNA variation has substantial contribution to cancer risk. Extraordinary progress made in analysis of common variation with GWAS methodology does not provide sufficient resolution to understand rare variation. To fulfill missing classification for rare germline variation we assembled dataset of whole exome sequences from>2000 patients (selected cases tested negative for candidate genes and unselected cases) with different types of cancers (breast cancer, colon cancer, and cutaneous and ocular melanomas) matched to more than 7000 non-cancer controls and analyzed germline variation in known cancer predisposing genes to identify common properties of disease-associated DNA variation and aid the future searches for new cancer susceptibility genes. Cancer predisposing genes were divided into non-overlapping classes according to the mode of inheritance of the related cancer syndrome or known tumor suppressor activity. Out of all classes only genes linked to dominant syndromes presented significant rare germline variants enrichment in cases. Separate analysis of protein-truncating and missense variation in this list of genes confirmed significant prevalence of protein-truncating variants in cases only in loss-of-function tolerant genes (pLI < 0.1), while ultra-rare missense variants were significantly overrepresented in cases only in constrained genes (pLI > 0.9). In addition to findings in genetically enriched cases, we observed significant burden of rare variation in unselected cases, suggesting substantial role of inherited variation even in relatively late cancer manifestation. Taken together, our findings provide reference for distribution and types of DNA variation underlying inherited predisposition to some common cancer types.