文章：

在两个遗传性前列腺癌队列中进行的DNA损伤修复基因种系测序揭示了新的疾病风险相关基因变异

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants

原文发布日期：7 July 2024

DOI: 10.3390/cancers16132482

类型: Article

开放获取: 是

英文摘要：

Rare, inherited variants in DNA damage repair (DDR) genes have a recognised role in prostate cancer (PrCa) susceptibility. In addition, these genes are therapeutically targetable. While rare variants are informing clinical management in other common cancers, defining the rare disease-associated variants in PrCa has been challenging. Here, whole-genome and -exome sequencing data from two independent, high-risk Australian and North American familial PrCa datasets were interrogated for novel DDR risk variants. Rare DDR gene variants (predicted to be damaging and present in two or more family members) were identified and subsequently genotyped in 1963 individuals (700 familial and 459 sporadic PrCa cases, 482 unaffected relatives, and 322 screened controls), and association analyses accounting for relatedness (MQLS) undertaken. In the combined datasets, rareERCC3(rs145201970,p= 2.57 × 10−4) andBRIP1(rs4988345,p= 0.025) variants were significantly associated with PrCa risk. APARP2(rs200603922,p= 0.028) variant in the Australian dataset and aMUTYH(rs36053993,p= 0.031) variant in the North American dataset were also associated with risk. Evaluation of clinicopathological characteristics provided no evidence for a younger age or higher-grade disease at diagnosis in variant carriers, which should be taken into consideration when determining genetic screening eligibility criteria for targeted, gene-based treatments in the future. This study adds valuable knowledge to our understanding of PrCa-associated DDR genes, which will underpin effective clinical screening and treatment strategies.

摘要翻译： 

DNA损伤修复（DDR）基因中的罕见遗传性变异在前列腺癌（PrCa）易感性中具有公认的作用。此外，这些基因可作为治疗靶点。尽管罕见变异在其他常见癌症的临床管理中已发挥作用，但在前列腺癌中确定与疾病相关的罕见变异一直具有挑战性。本研究通过对两个独立的高风险澳大利亚和北美家族性前列腺癌数据集的全基因组和外显子组测序数据进行分析，以探寻新的DDR风险变异。我们识别出罕见的DDR基因变异（预测为有害且在两名或以上家族成员中出现），随后在1963名个体（包括700例家族性病例、459例散发病例、482名未患病亲属及322名筛查对照）中进行基因分型，并基于亲缘关系（MQLS）进行关联分析。在合并数据集中，罕见的ERCC3（rs145201970，p=2.57×10⁻⁴）和BRIP1（rs4988345，p=0.025）变异与前列腺癌风险显著相关。澳大利亚数据集中的PARP2（rs200603922，p=0.028）变异及北美数据集中的MUTYH（rs36053993，p=0.031）变异也与风险相关。对临床病理特征的评估显示，变异携带者在诊断时并未表现出更年轻或更高分级的疾病特征，这一发现应在未来制定基于靶向基因治疗的遗传筛查资格标准时予以考虑。本研究为理解前列腺癌相关DDR基因增添了重要知识，将为有效的临床筛查和治疗策略提供支撑。

原文链接：

Germline Sequencing of DNA Damage Repair Genes in Two Hereditary Prostate Cancer Cohorts Reveals New Disease Risk-Associated Gene Variants