整个基因组中常见的遗传变异以及迄今为止发现的罕见编码变异解释了上皮性卵巢癌风险中大约一半的遗传成分。非编码基因组中的罕见变异很可能可以解释一些无法解释的遗传性，但识别此类变异具有挑战性。主要问题是缺乏通过关联来识别个体风险变异的统计功效，因为功效是样本大小、效应大小和等位基因频率的函数。可以通过使用负荷测试来提高功效，该测试测试特定基因组区域中任何变异携带者的关联。这具有增加假定效应等位基因频率的作用。 PAX8是一种转录因子，在肿瘤进展、迁移和侵袭中发挥着关键作用。此外，PAX8 靶基因附近的调控元件富含常见卵巢癌风险变异。我们假设 PAX8 结合位点的罕见变异也与卵巢癌风险相关，但不太可能与乳腺癌、结直肠癌或子宫内膜癌风险相关。我们使用来自英国 100,000 基因组计划的公开全基因组测序数据来评估整个基因组中 PAX8 结合位点的罕见变异的负担。可获得 522 例卵巢癌、2,984 例乳腺癌、2,696 例结直肠癌、836 例子宫内膜癌和 2253 例非癌症对照的数据。使用多个 PAX8 和 H3K27 ChIPseq 实验的数据定义活性结合位点。我们发现 PAX8 结合位点（以多种方式定义）的罕见变异负担与卵巢癌、乳腺癌或子宫内膜癌的风险之间没有关联。与结直肠癌的明显关联很可能是技术产物，因为在基因组随机区域的罕见变异中也检测到了类似的关联。尽管结果无效，但这项研究为使用负荷测试来识别与疾病相关的罕见非编码种系遗传变异提供了原理验证。大规模测序项目提供的更大样本量以及对非编码基因组功能的进一步了解将增加未来类似研究的潜力。© 作者 2024。由牛津大学出版社代表约翰霍普金斯大学彭博公共卫生学院。

Common genetic variation throughout the genome together with rare coding variants identified to date explain about a half of the inherited genetic component of epithelial ovarian cancer risk. It is likely that rare variation in the non-coding genome will explain some of the unexplained heritability, but identifying such variants is challenging. The primary problem is lack of statistical power to identifying individual risk variants by association as power is a function of sample size, effect size and allele frequency. Power can be increased by using burden tests which test for association of carriers of any variant in a specified genomic region. This has the effect of increasing the putative effect allele frequency. PAX8 is a transcription factor that plays a critical role in tumour progression, migration and invasion. Furthermore, regulatory elements proximal to target genes of PAX8 are enriched for common ovarian cancer risk variants. We hypothesised that rare variation in PAX8 binding sites are also associated with ovarian cancer risk, but unlikely to be associated with risk of breast, colorectal or endometrial cancer. We have used publicly available, whole-genome sequencing data from the UK 100,000 Genomes Project to evaluate the burden of rare variation in PAX8 binding sites across the genome. Data were available for 522 ovarian cancers, 2,984 breast cancers, 2,696 colorectal cancers, 836 endometrial cancers and 2253 non-cancer controls. Active binding sites were defined using data from multiple PAX8 and H3K27 ChIPseq experiments. We found no association between the burden of rare variation in PAX8 binding sites (defined in several ways) and risk of ovarian, breast or endometrial cancer. An apparent association with colorectal cancer was likely to be a technical artefact as a similar association was also detected for rare variation in random regions of the genome. Despite the null result this study provides a proof-of -principle for using burden testing to identify rare, non-coding germline genetic variation associated with disease. Larger sample sizes available from large-scale sequencing projects together with improved understanding of the function of the non-coding genome will increase the potential of similar studies in the future.© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.