Belcaid Laila, Bertelsen Birgitte, Wadt Karin, Tuxen Ida, Spanggaard Iben, Højgaard Martin, Benn Sørensen Jens, Ravn Jesper, Lassen Ulrik, Cilius Nielsen Finn, Rohrberg Kristoffer, Westmose Yde Christina
Dept. of Oncology, Copenhagen University Hospital, Rigshospitalet, Denmark.
Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Denmark.
Lung Cancer. 2023 May;179:107172. doi: 10.1016/j.lungcan.2023.03.008. Epub 2023 Mar 15.
Mesothelioma (MM) is associated with asbestos exposure, tumor heterogeneity and aggressive clinical behavior. Identification of germline pathogenic variants (PVs) in mesothelioma is relevant for identifying potential actionable targets and genetic counseling.
44 patients underwent whole exome sequencing (WES) or whole genome sequencing (WGS). Germline variants were selected according to association with inherited cancer using a 168-gene in silico panel, and variants classified according to ACMG/AMP classification as pathogenic (class 5) or likely pathogenic (class 4).
In total, 16 patients (36%) were found to carry pathogenic or likely pathogenic variants in 13 cancer associated genes (ATM, BAP1, BRCA2, CDKN2A, FANCA, FANCC, FANCD2, FANCM, MUTYH, NBN, RAD51B, SDHA and XPC). The germline PVs occurred in DNA repair pathways, including homologous recombination repair (HRR) (75%), nucleotide excision repair (6%), cell cycle regulatory (7%), base excision repair (6%), and hypoxic pathway (6%). Five (31%) patients with a germline PV had a first or second degree relative with mesothelioma compared to none for patients without a germline PV. Previously undiagnosed BRCA2 germline PVs were identified in two patients. Potential actionable targets based on the germline PVs were found in four patients (9%).
This study revealed a high frequency of germline PVs in patients with mesothelioma. Furthermore, we identified germline PVs in two genes (NBN & RAD51B) not previously associated with mesothelioma. The data support germline testing in mesothelioma and provide a rationale for additional investigation of the HRR pathway as a potential actionable target.
间皮瘤（MM）与石棉暴露、肿瘤异质性及侵袭性临床行为相关。鉴定间皮瘤中的种系致病变异（PVs）对于确定潜在的可操作靶点及遗传咨询具有重要意义。
44例患者接受了全外显子测序（WES）或全基因组测序（WGS）。使用168个基因的电子面板根据与遗传性癌症的关联选择种系变异，并根据ACMG/AMP分类将变异分类为致病性（5类）或可能致病性（4类）。
总共16例患者（36%）被发现携带13个癌症相关基因（ATM、BAP1、BRCA2、CDKN2A、FANCA、FANCC、FANCD2、FANCM、MUTYH、NBN、RAD51B、SDHA和XPC）中的致病性或可能致病性变异。种系PVs出现在DNA修复途径中，包括同源重组修复（HRR）（75%）、核苷酸切除修复（6%）、细胞周期调节（7%）、碱基切除修复（6%）和缺氧途径（6%）。5例（31%）有种系PV的患者有一级或二级亲属患有间皮瘤，而没有种系PV的患者则无此情况。在两名患者中鉴定出先前未诊断出的BRCA2种系PVs。4例患者（9%）中发现了基于种系PVs的潜在可操作靶点。
本研究揭示了间皮瘤患者中种系PVs的高频率。此外，我们在两个先前与间皮瘤无关的基因（NBN和RAD51B）中鉴定出种系PVs。这些数据支持对间皮瘤进行种系检测，并为进一步研究HRR途径作为潜在可操作靶点提供了理论依据。
