利用多基因风险评分和遗传性癌症易感基因进行致命性前列腺癌的遗传风险评估。

Genetic risk assessment of lethal prostate cancer using polygenic risk score and hereditary cancer susceptibility genes.

机构信息

Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.

Division of Urology, Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China.

出版信息

J Transl Med. 2023 Jul 6;21(1):446. doi: 10.1186/s12967-023-04316-y.

DOI:10.1186/s12967-023-04316-y

PMID:37415201

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10327136/

Abstract

BACKGROUND

The genetic risk of aggressive prostate cancer (PCa) is hard to be assessed due to the lack of aggressiveness-related single-nucleotide polymorphisms (SNPs). Prostate volume (PV) is a potential well-established risk factor for aggressive PCa, we hypothesize that polygenic risk score (PRS) based on benign prostate hyperplasia (BPH) or PV-related SNPs may also predict the risk of aggressive PCa or PCa death.

METHODS

We evaluated a PRS using 21 BPH/PV-associated SNPs, two established PCa risk-related PRS and 10 guideline-recommended hereditary cancer risk genes in the population-based UK Biobank cohort (N = 209,502).

RESULTS

The BPH/PV PRS was significantly inversely associated with the incidence of lethal PCa as well as the natural progress in PCa patients (hazard ratio, HR = 0.92, 95% confidence interval [CI]: 0.87-0.98, P = 0.02; HR = 0.92, 95% CI 0.86-0.98, P = 0.01). Compared with men at the top 25th PRS, PCa patients with bottom 25 PRS would have a 1.41-fold (HR, 95% CI 1.16-1.69, P = 0.001) increased PCa fatal risk and shorter survival time at 0.37 yr (95% CI 0.14-0.61, P = 0.002). In addition, patients with BRCA2 or PALB2 pathogenic mutations would also have a high risk of PCa death (HR = 3.90, 95% CI 2.34-6.51, P = 1.79 × 10; HR = 4.29, 95% CI 1.36-13.50, P = 0.01, respectively). However, no interactive but independent effects were detected between this PRS and pathogenic mutations.

CONCLUSIONS

Our findings provide a new measurement of PCa patients' natural disease outcomes via genetic risk ways.

摘要

背景

由于缺乏与侵袭性相关的单核苷酸多态性（SNP），侵袭性前列腺癌（PCa）的遗传风险难以评估。前列腺体积（PV）是侵袭性 PCa 的一个潜在的既定风险因素，我们假设基于良性前列腺增生（BPH）或 PV 相关 SNP 的多基因风险评分（PRS）也可能预测侵袭性 PCa 或 PCa 死亡的风险。

方法

我们在基于人群的英国生物库队列中（N=209502），评估了 21 个与 BPH/PV 相关的 SNP、两个已建立的 PCa 风险相关的 PRS 和 10 个指南推荐的遗传性癌症风险基因的 PRS。

结果

BPH/PV PRS 与致命性 PCa 的发生以及 PCa 患者的自然病程呈显著负相关（危险比，HR=0.92，95%置信区间[CI]：0.87-0.98，P=0.02；HR=0.92，95%CI 0.86-0.98，P=0.01）。与 PRS 处于第 25 个百分位数的男性相比，PRS 处于最低 25%的 PCa 患者的 PCa 致命风险增加 1.41 倍（HR，95%CI 1.16-1.69，P=0.001），0.37 年（95%CI 0.14-0.61，P=0.002）的生存时间更短。此外，BRCA2 或 PALB2 致病性突变的患者也有很高的 PCa 死亡风险（HR=3.90，95%CI 2.34-6.51，P=1.79×10；HR=4.29，95%CI 1.36-13.50，P=0.01）。然而，没有检测到该 PRS 与致病性突变之间存在交互但独立的影响。