背景:前列腺癌(PrCa)是全球男性死亡的主要原因。BRCA2中罕见的种系突变已被有力地验证为增加侵袭性形式的风险,预后较差;然而,其他基因的证据仍然不那么确定。
目的:检测与PrCa侵袭性相关的基因,通过对英国遗传性前列腺癌研究(UKGPCS)先前报道的六项研究的罕见变异测序数据进行汇总分析。
方法:我们积累了6805例PrCa病例,其中一组10个候选基因已在所有样本中进行了测序。
方法:我们检查了每个基因中罕见的推定功能丧失(pLOF)变异与侵袭性分类(定义为PrCa死亡,转移性疾病,T4阶段,或T3阶段和格里森评分均≥8)。次要分析分别检查了分期表型。Cox比例风险模型和Kaplan-Meier生存分析用于进一步检查突变状态和生存之间的关系。
结论:我们观察到ATM中PrCa侵袭性和pLOF突变之间的关联,BRCA2、MSH2和NBN(比值比=2.67-18.9)。这四个基因和MLH1另外与一个或多个二级分析表型相关。与非携带者相比,这些基因中种系突变的携带者的PrCa特异性生存期较短(风险比=2.15,95%置信区间1.79-2.59,p=4×10-16)。
结论:这项研究提供了进一步的支持,即特定基因中的罕见pLOF变异可能会增加PrCa的侵袭性风险,并可能有助于确定筛选和治疗考虑因素的信息性基因组。
结果:通过结合先前几项研究的数据,我们已经能够增强有关基因的知识,在这些基因中,遗传突变预计会增加更具侵袭性的PrCa的风险.这可能,在未来,帮助识别患有PrCa死亡风险较高的男性。
BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes.
OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS).
METHODS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples.
METHODS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival.
CONCLUSIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers.
CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations.
RESULTS: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.