Prospective characterization of germline variants in patients with gliomas and glioneuronal tumors

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY
Subhiksha Nandakumar, Miika Mehine, Yelena Kemel, Chaitanya Bandlamudi, Diana Mandelker, Marc K. Rosenblum, Tejus Bale, Matthias A. Karajannis, Sameer Farouk Sait, Kevin B. Elmore, Kate E. Therkelsen, Walid K. Chatila, Daniel Muldoon, Robert J. Young, Brandon S. Imber, Cameron Brennan, Nelson S. Moss, Kenny K. H. Yu, Viviane Tabar, Shahiba Ogilvie, Anita Bowman, Pallavi Akella, Yun-Te Lin, Igor T. Gavrilovic, Elena Pentsova, Lauren Schaff, Jacqueline Stone, Craig Nolan, Adrienne Boire, Christian Grommes, Bianca D. Santomasso, Eli L. Diamond, Jessica Wilcox, Anna Piotrowski, Thomas J. Kaley, Lisa M. DeAngelis, Ingo K. Mellinghoff, Michael Berger, Nikolaus Schultz, Zsofia K. Stadler, Andrew L. Lin
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Abstract

Several tumor predisposition syndromes have been linked to the development of gliomas and glioneuronal tumors (glioma/GNT). For many pathogenic germline variants, the prevalence and clinical significance remain unclear. Germline variants and copy-number variants affecting 76–90 well-established cancer predisposing genes were identified in 2,187 patients with gliomas/GNT, who underwent prospective sequencing of their tumor and a matched normal sample. A germline pathogenic or likely pathogenic (P/LP) mutation was identified in 11% (250/2187, 95% CI 10.1–12.8%). Affected high- and moderate-penetrance genes included BRCA2 (n = 11; 0.5%), TP53 (n = 8; 0.4%), NF1 (n = 8; 0.4%), CHEK2 (n = 21, 0.9% excluding common variant I157T), and the mismatch repair (MMR) genes (n = 22, 1.0%). Biallelic inactivation was identified in 8/8 tumors with a germline NF1 mutation, 7/8 tumors with a germline TP53 alteration, and 10/19 tumors with a heterozygous germline MMR defect. Gliomas/GNT with biallelic inactivation of an MMR gene were characterized by hypermutation, microsatellite instability, and a distinct clinical phenotype. Assessment of zygosity identifies biallelic inactivation of DNA double-strand break repair alterations in a minority of tumors, including BRCA2-deficient gliomas with increased genomic scarring attributable to homologous recombination deficiency, and refutes the contribution of the most common P/LP germline variants. Irrespective of gene, tumors with biallelic inactivation were diagnosed at a younger age than tumors without a germline variant (p = 3.5 × 10–6) and tumors with a monoallelic alteration (p = 0.00014). In conclusion, germline sequencing identifies a P/LP variant in a high proportion of patients with glioma/GNT. Biallelic inactivation was common in younger patients with germline variants and patients with neurofibromatosis type 1/Li-Fraumeni, but was only present in half of the patients with Lynch syndrome.

神经胶质瘤和神经胶质细胞肿瘤患者种系变异的前瞻性特征。
一些肿瘤易感综合征与胶质瘤和神经胶质细胞肿瘤(胶质瘤/GNT)的发展有关。对于许多致病种系变异,患病率和临床意义尚不清楚。在2187例胶质瘤/GNT患者中发现了影响76-90个已知癌症易感基因的生殖系变异和拷贝数变异,这些患者对其肿瘤和匹配的正常样本进行了前瞻性测序。11%的人发现种系致病性或可能致病性(P/LP)突变(250/2187,95% CI 10.1-12.8%)。受影响的高外显率和中等外显率基因包括BRCA2 (n = 11, 0.5%)、TP53 (n = 8, 0.4%)、NF1 (n = 8, 0.4%)、CHEK2 (n = 21, 0.9%,排除常见变异I157T)和错配修复(MMR)基因(n = 22, 1.0%)。在8/8种系NF1突变的肿瘤中发现双等位基因失活,7/8种系TP53改变的肿瘤中发现双等位基因失活,10/19种系MMR杂合缺陷的肿瘤中发现双等位基因失活。MMR基因双等位基因失活的胶质瘤/GNT具有高突变、微卫星不稳定性和独特的临床表型。合子性评估确定了少数肿瘤中DNA双链断裂修复改变的双等位基因失活,包括同源重组缺陷导致基因组疤痕增加的brca2缺陷胶质瘤,并驳斥了最常见的P/LP种系变异的贡献。与基因无关,双等位基因失活的肿瘤比无种系变异的肿瘤(p = 3.5 × 10-6)和单等位基因改变的肿瘤(p = 0.00014)的诊断年龄更小。总之,种系测序在很大比例的胶质瘤/GNT患者中发现了P/LP变异。双等位基因失活在年轻的种系变异患者和1型/Li-Fraumeni神经纤维瘤病患者中很常见,但仅在半数Lynch综合征患者中存在。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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