Table 1_Molecular characterization of gliomas and glioneuronal tumors amid Noonan syndrome: cancer predisposition examined.xlsx

IntroductionIn the setting of pediatric and adolescent young adult cancer, increased access to genomic profiling has enhanced the detection of genetic variation associated with cancer predisposition, including germline syndromic conditions. Noonan syndrome (NS) is associated with the germline RAS pathway activating alterations and increased risk of cancer. Herein, we describe our comprehensive molecular profiling approach, the association of NS with glioma and glioneuronal tumors, and the clinical and histopathologic characteristics associated with the disease.
MethodsWithin an institutional pediatric cancer cohort (n = 314), molecular profiling comprised of paired somatic disease–germline comparator exome analysis, RNA sequencing, and tumor classification by DNA methylation analysis was performed.
ResultsThrough the implementation of paired analysis, this study identified 4 of 314 (1.3%) individuals who harbored a germline PTPN11 variant associated with NS, of which 3 individuals were diagnosed with a glioma or glioneuronal tumor. Furthermore, we extend this study through collaboration with a peer institution to identify two additional individuals with NS and a glioma or glioneuronal tumor. Notably, in three of five (60%) individuals, paired genomic profiling led to a previously unrecognized diagnosis of Noonan syndrome despite an average age of cancer diagnosis of 16.8 years. The study of the disease-involved tissue identified signaling pathway dysregulation through somatic alteration of genes involved in cellular proliferation, survival, and differentiation.
DiscussionComparative pathologic findings are presented to enable an in-depth examination of disease characteristics. This comprehensive analysis highlights the association of gliomas and glioneuronal tumors with RASopathies and the potential therapeutic challenges and importantly demonstrates the utility of genomic profiling for the identification of germline cancer predisposition.

引言：在儿童、青少年及年轻成人癌症患者群体中，基因组测序（genomic profiling）可及性的提升，显著增强了与癌症易感相关的遗传变异的检出能力，其中包括胚系综合征性疾病。努南综合征（Noonan syndrome, NS）与胚系RAS通路激活变异及癌症风险升高密切相关。本文详述了本团队采用的综合性分子检测策略，探讨了努南综合征与胶质瘤及神经胶质瘤性肿瘤的关联，以及该疾病相关的临床与组织病理学特征。
方法：本研究纳入某机构的儿童癌症队列（n=314），采用配对体细胞疾病-胚系外显子组对照分析、RNA测序（RNA sequencing）及DNA甲基化分析完成肿瘤分型的分子检测方案。
结果：通过配对分析，本研究在314名受试者中鉴定出4名（1.3%）携带与努南综合征相关的胚系PTPN11变异者，其中3名被诊断为胶质瘤或神经胶质瘤性肿瘤。此外，本研究通过与合作机构的协作，额外鉴定出2名同时罹患努南综合征与胶质瘤或神经胶质瘤性肿瘤的受试者。值得注意的是，在5名受试者中的3名（60%）中，尽管癌症确诊时的平均年龄为16.8岁，配对基因组测序仍首次确诊了努南综合征。对受累病变组织的研究发现，细胞增殖、存活及分化相关基因发生体细胞变异，进而导致信号通路失调。
讨论：本文呈现了对比病理学结果，以支持对疾病特征的深入剖析。这项综合性分析明确了胶质瘤及神经胶质瘤性肿瘤与RAS病（RASopathies）的关联，以及潜在的治疗挑战，同时重要地证明了基因组测序在鉴定胚系癌症易感方面的应用价值。