Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
JCO Precis Oncol. 2023 Aug;7:e2300070. doi: 10.1200/PO.23.00070.
Clonal hematopoiesis (CH), the expansion of clones in the hematopoietic system, has been linked to different internal and external features such as aging, genetic ancestry, smoking, and oncologic treatment. However, the interplay between mutations in known cancer predisposition genes and CH has not been thoroughly examined in patients with solid tumors.
We used prospective tumor-blood paired sequencing data from 46,906 patients who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) testing to interrogate the associations between CH and rare pathogenic or likely pathogenic (P/LP) germline variants.
We observed an enrichment of CH-positive patients among those carrying P/LP germline mutations and identified a significant association between P/LP germline variants in and CH. Germline and CH comutation patterns in , , and suggested biallelic inactivation as a potential mediator of clonal expansion. Moreover, we observed that CH- mutations, similar to somatic tumor-associated mutations, were depleted in patients with P/LP germline mutations in the DNA damage response (DDR) genes , , and . Patients with solid tumors and harboring P/LP germline mutations, CH mutations, and mosaicism chromosomal alterations might be at an increased risk of developing secondary leukemia while germline variants in were identified as an independent risk factor (hazard ratio, 36; < .001) for secondary leukemias.
Our results suggest a close relationship between inherited variants and CH mutations within the DDR genes in patients with solid tumors. Associations identified in this study might translate into enhanced clinical surveillance for CH and associated comorbidities in patients with cancer harboring these germline mutations.
克隆性造血（CH），即造血系统中克隆的扩增，与衰老、遗传背景、吸烟和肿瘤治疗等内部和外部特征有关。然而，在实体瘤患者中，已知癌症易感性基因的突变与 CH 之间的相互作用尚未得到彻底研究。
我们使用来自 46906 名接受 Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets（MSK-IMPACT）检测的患者的前瞻性肿瘤-血液配对测序数据，来探究 CH 与罕见致病性或可能致病性（P/LP）种系变异之间的关联。
我们观察到携带 P/LP 种系突变的患者中 CH 阳性患者增多，并发现 P/LP 种系变异与 CH 之间存在显著关联。在 、 、和 中，种系和 CH 共突变模式表明双等位基因失活可能是克隆扩增的潜在介导因素。此外，我们观察到 CH-突变与体细胞肿瘤相关的 突变相似，在携带 P/LP 种系突变的 DNA 损伤反应（DDR）基因 、 、和 中的突变缺失。携带 P/LP 种系突变、CH 突变和镶嵌性染色体改变的实体瘤患者可能会增加发生继发性白血病的风险，而 中的种系变异被确定为继发性白血病的独立危险因素（危险比，36；<0.001）。
我们的研究结果表明，在实体瘤患者中，DDR 基因中的遗传变异与 CH 突变之间存在密切关系。本研究中确定的关联可能会转化为增强对携带这些种系突变的癌症患者的 CH 监测和相关合并症的临床监测。
