The germline genetic landscape of paediatric central nervous sysetem tumours

Abstract

Central nervous system (CNS) cancers represent the most prevalent solid tumours in children and are among the leading causes of cancer-related deaths in this population. Inherited germline variants in cancer-predisposing genes (CPG), elevate the risk of cancer development during childhood. In South Africa, there is a scarcity of research on the prevalence of paediatric cancers and the influence of inherited genetic factors that heighten the risk of early cancer development in children. Next- generation sequencing technologies have played a pivotal role in identifying and understanding the contribution of germline variants to the development of paediatric cancers, advancing both research and diagnostic efforts globally. Through the design and analysis of a virtual panel including 56 CPGs, this study aimed to identify germline genetic variants in CPGs in a subset of paediatric patients with CNS tumours. Whole-exome sequencing (WES) data from 13 individuals diagnosed with CNS tumours, including medulloblastoma, astrocytoma, optic nerve glioma, craniopharyngioma, and pineoblastoma, and unspecified brain tumours were analysed. The workflow included annotation, filtering, prioritisation, and rigorous quality control of the candidate variants. Eleven candidate variants were subsequently classified in accordance with the guidelines established by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP). Pathogenic variants were detected in the ATM (c.2200dup; p.Val734GlyfsTer4; c.8911C>T; p.Gln2971Ter), and NF1 ( c.625C>T; p.Gln209Ter) genes. These variants were identified in individuals with medulloblastoma and optic nerve glioma, respectively. The positive pick-up rate of this study was 15,38%, which is in-keeping with international published oncology research. This underscores the role of ATM and NF1 variants in contributing to cancer susceptibility in individuals with paediatric CNS tumours. This study contributes to our understanding of the germline genetic landscape underlying paediatric CNS tumours in South Africa.