Atypical germline mutations and primary cns tumors: a single-center case series and literature review

Abstract A growing spectrum of germline mutations and their association with primary CNS tumors has been described over the last decade. These germline mutations are implicated in regulation of DNA integrity and repair, telomere maintenance, and cell cycle regulation resulting in aberrant cellular proliferation and immune surveillance evasion. To date, there are no well-defined guidelines for primary CNS tumor surveillance for these patients. Moreover, the exact role of traditional chemotherapy, immunotherapy, and radiation is unclear. We present a single-institution case series of adult patients with primary CNS tumors with atypical germline mutations and literature review. The most common germline mutations encountered involved heterozygous mutations of one of the mismatch repair (MMR) genes (MSH2, PMS2, MLH1). All patients developed high-grade gliomas defined as astrocytoma or glioblastoma WHO grade 4 based on the WHO 2021 classification. Germline mutations involving RAD51C, POT1, IDH1/2, MutyH, NTHL1, PALB2, and CHEK2 were associated with gliomas of variable grades and molecular subtypes. Non-glial tumors, including atypical rhabdoid tumors, medulloblastomas, hemangioblastomas, and meningiomas were found in association with germline SMARCB1, ATM, BRCA1, and CHEK2 mutations respectively. Review of the existing literature and knowledge obtained from our case series suggests several important concepts: (1) there is an increased risk of both glioma and non-glial tumor types in several atypical germline mutations, (2) multiple risk genes or variants of unknown significance likely contribute to primary brain tumor formation, (3) germline MMR mutations associated with high-grade glioma may be MMR gene-specific with potential increased risk of resistance and/or disease progression in the presence of alkylating agents such as temozolomide, (4) several germline mutations may increase risk of secondary tumor development after radiation, and (5) the role of screening for atypical germline mutations and subsequent disease surveillance remain unanswered.