760 名 CHEK2 种系突变女性携带者的乳腺癌多基因风险评分表现。

Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.

机构信息

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.

出版信息

J Natl Cancer Inst. 2021 Jul 1;113(7):893-899. doi: 10.1093/jnci/djaa203.

DOI:10.1093/jnci/djaa203

PMID:33372680

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8246885/

Abstract

BACKGROUND

Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.

METHODS

A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided.

RESULTS

Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26).

CONCLUSIONS

PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.

摘要

背景

全基因组关联研究表明，乳腺癌（BC）相关单核苷酸多态性（SNP）的综合效应可以通过多基因风险评分（PRS）提高 BC 风险分层。在携带中度外显率 BC 易感性基因（如 CHEK2）突变的个体中，PRS 在全基因组关联研究以外的临床队列中的表现研究甚少。

方法

共纳入 760 名女性 CHEK2 突变携带者；其中 561 名女性患有 BC，其中 74 名发生了对侧 BC（mCBC）。为了计算 PRS，使用了 2 个包含 77 个（SNP 集 1，用于未选择其 BRCA1/2 种系突变状态的女性的 BC 风险分层）和 88 个（SNP 集 2，用于 BC 风险分层在女性 BRCA1/2 突变携带者中）BC 相关 SNP 的 SNP 集。所有统计检验均为双侧检验。

结果

在个体水平上，两个 SNP 集都提供了一致的 PRS 结果（r=0.91，P<2.20×10-16）。加权队列 Cox 回归分析显示，PRS 与首次 BC 风险呈统计学显著相关。对于 SNP 集 1，观察到 PRS 每标准差的风险比为 1.71（95%置信区间为 1.36 至 2.15，P=3.87×10-6）。PRS 确定了一组 CHEK2 突变携带者，他们的一生中首次发生 BC 的风险预测超过了国际指南定义的监测阈值。通过 Cox 回归分析检查了 PRS 与 mCBC 的相关性（SNP 集 1 风险比=1.23，95%置信区间为 0.86 至 1.78，P=0.26）。