Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.
Investigating the role of somatic sequencing platforms for phaeochromocytoma and paraganglioma in a large UK cohort.
复制标题
DOI：
10.1111/cen.14639
复制
发表时间：
2022-10
影响因子：
3.2
通讯作者：
中科院分区：
文献类型：
--
作者：
嗜铬细胞瘤和副神经节瘤(PPGL)是一种罕见的具有恶性潜能的神经内分泌肿瘤，在几乎40%的患者中具有遗传基础。生殖系基因检测改变了PPGL的管理，使监测方法能够分层，对高危家庭成员进行早期诊断和预测性检测。最近的研究已经在另一组患者中发现了体细胞突变，这表明在高达80%的PPGL病例中可以确定胚系或肿瘤水平的分子驱动因素。这项研究的目的是在英国的一大群PPGL患者中调查体细胞测序的临床应用。前瞻性收集匹配的PPGL患者的种系和肿瘤样本(发展队列)和回溯性收集的肿瘤样本(验证队列)进行调查。评估了患者的临床特征，并使用下一代测序策略分析了肿瘤和生殖系DNA。对68个人类癌症基因的“突变热点”内的变异进行了筛查。在纳入的141名患者中，45名(32%)有生殖系突变。在37例(26%)患者中，发现了一个或多个驱动体细胞变异，包括26个可能的致病或致病变异和19个不确定意义的变异。在VHL、NF1、HRAS和RET基因中最常见的致病体细胞变异发生在25例(18%)患者中。致病的体细胞变异几乎只在没有种系突变的患者中被发现(除一个外)，这表明体细胞测序可能对那些种系基因测试结果为阴性的患者提供最大的信息。体细胞测序可能会进一步对没有胚系遗传驱动因素的患者的监测方法进行分层，也可能为转移性疾病患者的有针对性的治疗策略提供信息。
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.
登录
查看更多内容
影响因子：
8.4
作者：
Eisenhofer, Graeme;Lenders, Jacques W. M.;Siegert, Gabriele;Bornstein, Stefan R.;Friberg, Peter;Milosevic, Dragana;Mannelli, Massimo;Linehan, W. Marston;Adams, Karen;Timmers, Henri J.;Pacak, Karel
通讯作者：
Pacak, Karel
影响因子：
50.3
作者：
Fishbein L;Leshchiner I;Walter V;Danilova L;Robertson AG;Johnson AR;Lichtenberg TM;Murray BA;Ghayee HK;Else T;Ling S;Jefferys SR;de Cubas AA;Wenz B;Korpershoek E;Amelio AL;Makowski L;Rathmell WK;Gimenez-Roqueplo AP;Giordano TJ;Asa SL;Tischler AS;Cancer Genome Atlas Research Network;Pacak K;Nathanson KL;Wilkerson MD
通讯作者：
Wilkerson MD
影响因子：
16.6
作者：
Castro-Vega, Luis Jaime;Letouze, Eric;Burnichon, Nelly;Buffet, Alexandre;Disderot, Pierre-Helie;Khalifa, Emmanuel;Loriot, Celine;Elarouci, Nabila;Morin, Aurelie;Menara, Melanie;Lepoutre-Lussey, Charlotte;Badoual, Cecile;Sibony, Mathilde;Dousset, Bertrand;Libe, Rossella;Zinzindohoue, Franck;Plouin, Pierre Francois;Bertherat, Jerome;Amar, Laurence;de Reynies, Aurelien;Favier, Judith;Gimenez-Roqueplo, Anne-Paule
通讯作者：
Gimenez-Roqueplo, Anne-Paule
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
5.2
作者：
Coppin, Lucie;Grutzmacher, Claudine;Pigny, Pascal
通讯作者：
Pigny, Pascal