文章：

在24,849名BRCA相关癌症患者中，生殖系DNA修复基因突变与克隆性造血（CH）的研究

Germline DNA Repair Gene Mutations and Clonal Hematopoiesis (CH) in 24,849 Patients with BRCA-Associated Cancers

原文发布日期：25 April 2025

DOI: 10.3390/cancers17091432

类型: Article

开放获取: 是

英文摘要：

Purpose: To determine if the risk of clonal hematopoiesis (CH) would be higher among those with germline alterations in homologous recombination repair genes (gHRR) in the fourBRCA-associated cancers (breast, ovarian, prostate, pancreas) compared to those without inherited predisposition (the sporadic group). Methods: We retrospectively analyzed deidentified data from 24,849 patient samples from the Tempus database with a primary diagnosis of breast, ovarian, prostate, and pancreatic cancers. Germline pathogenic or likely pathogenic variants inBRCA1,BRCA2,ATM,PALB2, andCHEK2were identified across all four cancer types. CH was determined based on the presence of pathogenic or likely pathogenic alterations in any one of 52 CH-associated genes with a variant allele fraction of at least 2% found in the normal match. Age-adjusted odds ratios were calculated for risk of CH across cancer types. Results: CH was identified in 14% of patients with BRCA-associated cancers.DNMT3A,PPM1D, andTET2were the most common CH gene alterations. After adjusting for age at time of biopsy, having any germline alteration in the breast cancer cohort was associated with a 41% increased likelihood of CH (OR 1.41; 95% CI 1.07–1.84,p= 0.014). An increase in CH prevalence was not seen in the three other cancer types. Conclusions: When accounting for age at time of testing, pathogenic germline alterations in DNA repair genes were associated with an increased risk of CH only among patients with breast cancer, but not in those with ovarian, pancreatic, or prostate cancers.

摘要翻译： 

目的：旨在比较四种BRCA相关癌症（乳腺癌、卵巢癌、前列腺癌、胰腺癌）患者中，携带同源重组修复基因胚系突变（gHRR）者与无遗传易感性（散发组）患者之间克隆性造血（CH）风险的差异。方法：我们回顾性分析了Tempus数据库中24,849例确诊为乳腺癌、卵巢癌、前列腺癌和胰腺癌患者的匿名数据。在所有四种癌症类型中，识别出BRCA1、BRCA2、ATM、PALB2和CHEK2基因的胚系致病性或可能致病性变异。CH的判定基于52个CH相关基因中任一基因存在致病性或可能致病性变异，且在正常对照样本中检测到变异等位基因频率不低于2%。计算了各癌症类型中CH风险的年龄校正比值比。结果：在BRCA相关癌症患者中，14%检测到CH。DNMT3A、PPM1D和TET2是最常见的CH基因变异。经活检时年龄校正后，乳腺癌队列中携带任何胚系突变与CH发生可能性增加41%相关（OR 1.41；95% CI 1.07–1.84，p=0.014）。其他三种癌症类型中未观察到CH患病率增加。结论：在考虑检测时年龄因素后，DNA修复基因的致病性胚系突变仅与乳腺癌患者的CH风险增加相关，而在卵巢癌、胰腺癌或前列腺癌患者中未发现此关联。

原文链接：

Germline DNA Repair Gene Mutations and Clonal Hematopoiesis (CH) in 24,849 Patients with BRCA-Associated Cancers