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

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.