Department of Endocrinology, Diabetology and Metabolism, University Hospital Basel, Basel, Switzerland.
Department of Clinical Research, University of Basel, Basel, Switzerland.
Clin Endocrinol (Oxf). 2022 Oct;97(4):448-459. doi: 10.1111/cen.14639. Epub 2021 Dec 6.
Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours with malignant potential and a hereditary basis in almost 40% of patients. Germline genetic testing has transformed the management of PPGL enabling stratification of surveillance approaches, earlier diagnosis and predictive testing of at-risk family members. Recent studies have identified somatic mutations in a further subset of patients, indicating that molecular drivers at either a germline or tumour level can be identified in up to 80% of PPGL cases. The aim of this study was to investigate the clinical utility of somatic sequencing in a large cohort of patients with PPGL in the United Kingdom.
Prospectively collected matched germline and tumour samples (development cohort) and retrospectively collected tumour samples (validation cohort) of patients with PPGL were investigated.
Clinical characteristics of patients were assessed and tumour and germline DNA was analysed using a next-generation sequencing strategy. A screen for variants within 'mutation hotspots' in 68 human cancer genes was performed.
Of 141 included patients, 45 (32%) had a germline mutation. In 37 (26%) patients one or more driver somatic variants were identified including 26 likely pathogenic or pathogenic variants and 19 variants of uncertain significance. Pathogenic somatic variants, observed in 25 (18%) patients, were most commonly identified in the VHL, NF1, HRAS and RET genes. Pathogenic somatic variants were almost exclusively identified in patients without a germline mutation (all but one), suggesting that somatic sequencing is likely to be most informative for those patients with negative germline genetic test results.
Somatic sequencing may further stratify surveillance approaches for patients without a germline genetic driver and may also inform targeted therapeutic strategies for patients with metastatic disease.
嗜铬细胞瘤和副神经节瘤（PPGL）是罕见的神经内分泌肿瘤，具有恶性潜能，近 40%的患者存在遗传基础。种系基因检测改变了 PPGL 的管理方式，能够对监测方法进行分层，更早地诊断，并对高危家族成员进行预测性检测。最近的研究在进一步的亚组患者中发现了体细胞突变，表明在多达 80%的 PPGL 病例中，可以在种系或肿瘤水平上确定分子驱动因素。本研究旨在调查体细胞测序在英国大型 PPGL 患者队列中的临床应用。
前瞻性收集匹配的种系和肿瘤样本（开发队列）和回顾性收集的肿瘤样本（验证队列），用于研究 PPGL 患者。
评估患者的临床特征，并使用下一代测序策略分析肿瘤和种系 DNA。对 68 个人类癌症基因中的“突变热点”内的变体进行了筛选。
在纳入的 141 名患者中，45 名（32%）存在种系突变。在 37 名（26%）患者中，发现了一个或多个驱动体突变，包括 26 个可能致病性或致病性变异和 19 个意义不明的变异。在 25 名（18%）患者中观察到致病性体细胞突变，最常见于 VHL、NF1、HRAS 和 RET 基因。致病性体细胞突变几乎仅在无种系基因突变的患者中（除 1 例外）被发现，这表明体细胞测序可能对那些种系基因检测结果为阴性的患者最具信息性。
体细胞测序可能进一步分层无种系遗传驱动的患者的监测方法，也可能为转移性疾病患者提供靶向治疗策略。
