Foley Georgea R, Marthick James R, Lucas Sionne E, Raspin Kelsie, Banks Annette, Stanford Janet L, Ostrander Elaine A, FitzGerald Liesel M, Dickinson Joanne L
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS 7000, Australia.
Fred Hutchinson Cancer Center, 1100 Fairview Ave. N., M4-B874, Seattle, WA 98109, USA.
Cancers (Basel). 2024 Jul 7;16(13):2482. doi: 10.3390/cancers16132482.
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 (M) undertaken. In the combined datasets, rare (rs145201970, = 2.57 × 10) and (rs4988345, = 0.025) variants were significantly associated with PrCa risk. A (rs200603922, = 0.028) variant in the Australian dataset and a (rs36053993, = 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.
DNA损伤修复（DDR）基因中的罕见遗传变异在前列腺癌（PrCa）易感性中具有公认作用。此外，这些基因是可治疗靶向的。虽然罕见变异在其他常见癌症的临床管理中具有指导意义，但确定PrCa中与罕见疾病相关的变异一直具有挑战性。在此，对来自两个独立的澳大利亚和北美高风险家族性PrCa数据集的全基因组和外显子组测序数据进行分析，以寻找新的DDR风险变异。鉴定出罕见的DDR基因变异（预测具有损害性且存在于两个或更多家庭成员中），随后在1963名个体（700名家族性和459名散发性PrCa病例、482名未受影响的亲属以及322名筛查对照）中进行基因分型，并进行考虑亲缘关系（M）的关联分析。在合并数据集中，罕见变异（rs145201970，P = 2.57 × 10⁻⁶）和（rs4988345，P = 0.025）与PrCa风险显著相关。澳大利亚数据集中的一个变异（rs200603922，P = 0.028）和北美数据集中的一个变异（rs36053993，P = 0.031）也与风险相关。对临床病理特征的评估未发现变异携带者在诊断时年龄较小或疾病分级较高的证据，这在未来确定基于基因的靶向治疗的遗传筛查资格标准时应予以考虑。本研究为我们对PrCa相关DDR基因的理解增添了宝贵知识，这将为有效的临床筛查和治疗策略奠定基础。
