Germline analysis of an international cohort of pediatric diffuse midline glioma patients

Abstract

Background Factors that drive the development of diffuse midline gliomas (DMG) are unknown. Our study aimed to determine the prevalence of pathogenic/likely pathogenic (P/LP) germline variants in pediatric patients with DMG. Methods We assembled an international cohort of 252 pediatric patients with DMG, including diffuse intrinsic pontine glioma (n = 153), with germline whole genome or whole exome sequencing. Results We identified P/LP germline variants in cancer predisposition genes in 7.5% (19/252) of patients. Tumor profiles differed, with the absence of somatic drivers in the PI3K/mTOR pathway in patients with germline P/LP variants versus those without (P = .023). P/LP germline variants were recurrent in homologous recombination (n = 9; BRCA1, BRCA2, PALB2) and Fanconi anemia genes (n = 4). Somatic findings established that the germline variants definitively contributed to tumorigenesis in at least 1% of cases. One patient with recurrent DMG and pathogenic germline variants (BRCA2, FANCE) showed a near-complete radiological response to PARP and immune checkpoint inhibition. Conclusions Our study determined the prevalence of pathogenic germline variants in pediatric DMG and suggests a role in tumorigenesis for a subset of patients.