Background: Many cancer types show considerable heritability, and extensive research has been done to identify germline susceptibility variants. Linkage studies have discovered many rare high-risk variants, and genome-wide association studies (GWAS) have discovered many common low-risk variants. However, it is believed that a considerable proportion of the heritability of cancer remains unexplained by known susceptibility variants. The “rare variant hypothesis” proposes that much of the missing heritability lies in rare variants that cannot reliably be detected by linkage analysis or GWAS. Until recently, high sequencing costs have precluded extensive surveys of rare variants, but technological advances have now made it possible to analyze rare variants on a much greater scale. Objectives: In this study, we investigated associations between rare variants and 14 cancer types. Methods: We ran association tests using whole-exome sequencing data from The Cancer Genome Atlas (TCGA) and validated the findings using data from the Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG). Results: We identified four significant associations in TCGA, only one of which was replicated in PCAWG (BRCA1 and ovarian cancer). Conclusions: Our results provide little evidence in favor of the rare variant hypothesis. Much larger sample sizes may be needed to detect undiscovered rare cancer variants.
Hum Hered

中文翻译：

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8,719 人种系变异的外显子组泛癌分析几乎没有发现罕见变异关联的证据

背景：许多癌症类型显示出相当大的遗传性，并且已经进行了广泛的研究来识别种系易感性变异。连锁研究发现了许多罕见的高风险变异，全基因组关联研究（GWAS）发现了许多常见的低风险变异。然而，据信，相当一部分癌症的遗传性仍未被已知的易感性变异解释。“稀有变异假说”提出，大部分缺失的遗传力在于无法通过连锁分析或 GWAS 可靠检测到的稀有变异。直到最近，高昂的测序成本还阻碍了对稀有变异的广泛调查，但技术进步现在使得在更大范围内分析稀有变异成为可能。目标：在这项研究中，我们调查了罕见变异与 14 种癌症类型之间的关联。方法：我们使用癌症基因组图谱 (TCGA) 的全外显子组测序数据进行关联测试，并使用全基因组联盟 (PCAWG) 的泛癌分析数据验证了这些发现。结果：我们确定了 TCGA 中的四个显着关联，其中只有一个在 PCAWG（BRCA1 和卵巢癌）中复制。结论：我们的结果几乎没有提供支持罕见变异假设的证据。可能需要更大的样本量来检测未发现的罕见癌症变异。
赫瑞德