Department of oncogenetics and biochemistry, Paul Brousse University Hospital (APHP), 12 Av. Paul Vaillant Couturier, 94800 Villejuif, France.
Bioinformatics Core Facility, Gustave Roussy Cancer Campus, Villejuif, France.
Eur J Cancer. 2024 Oct;210:114256. doi: 10.1016/j.ejca.2024.114256. Epub 2024 Aug 3.
High-throughput sequencing techniques have revolutionized oncology. Paired germline-tumor DNA analysis has emerged as a comprehensive strategy to uncover actionable alterations in advanced cancer patients (ACP) enrolled in precision oncology trials. However, challenges persist in variant interpretation and managing incidental germline findings.
We conducted a study involving 288 ACP from MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials to assess germline variants impacting cancer-related genes. Germline DNA sequencing was performed using a panel of 250 cancer-related genes, and the results were discussed during tumor molecular board sessions.
Germline pathogenic variants (PV) were classified according to the ESCAT classification. Lung cancer (36.8 %), followed by prostate (18.4 %) and breast cancer (17.7 %), comprised the most prevalent tumor types. PVs were found in 12.5 % of patients. Most PVs were classified as ESCAT X (63.9 %), highlighting limited therapeutic actionability. Notably,2 % of patients had actionable variants (ESCAT I-A/II-A). Incidental findings included 7.3 % of patients with PVs in cancer-predisposition genes, with 2.4 % having very high-risk potential, necessitating mandatory oncogenetic counseling. Nearly one in five patients (21.9 %) had at least one VUS.
Our study underscores the significance of germline sequencing in identifying actionable alterations and the need for improved variant interpretation as well as pretest counseling plans in precision oncology trials.
高通量测序技术彻底改变了肿瘤学。对生殖系-肿瘤 DNA 的分析已成为一种全面的策略，可用于发现参与精准肿瘤学试验的晚期癌症患者（ACP）中的可操作改变。然而，在变异解释和管理偶然的种系发现方面仍存在挑战。
我们对来自 MOSCATO（NCT01566019）和 MATCHR（NCT02517892）试验的 288 名 ACP 进行了一项研究，以评估影响癌症相关基因的种系变异。使用包含 250 个癌症相关基因的面板对生殖系 DNA 进行测序，并在肿瘤分子委员会会议上讨论结果。
根据 ESCAT 分类对生殖系致病性变异（PV）进行分类。肺癌（36.8%）、前列腺癌（18.4%）和乳腺癌（17.7%）构成最常见的肿瘤类型。12.5%的患者发现了 PV。大多数 PV 被归类为 ESCAT X（63.9%），表明治疗作用有限。值得注意的是，2%的患者有可操作的变异（ESCAT I-A/II-A）。偶然发现包括 7.3%的患者存在癌症易感性基因中的 PV，其中 2.4%具有非常高的潜在风险，需要强制性肿瘤遗传学咨询。近五分之一的患者（21.9%）至少有一种 VUS。
我们的研究强调了生殖系测序在识别可操作改变方面的重要性，以及在精准肿瘤学试验中需要改进变异解释以及测试前咨询计划。
