Abstract
Abstract
BACKGROUND
Lynch syndrome (LS) and constitutional mismatch repair deficiency syndrome (CMMRD) are caused by germline mutations in mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2. LS patients have an inherited mono-allelic MMR defect, whereas CMMRD patients have a bi-allelic defect. MMR is critical to maintaining genomic integrity during DNA replication and these germline defects are known to produce microsatellite instability (MSI). Both LS and CMMRD have reported cases of increased primary brain cancer, namely glioblastoma multiforme (GBM). Given the shared pathophysiology of these syndromes, the large number of cases and registry studies published, and recent treatments of CNS tumors in CMMRD, a literature review has been conducted. OBJECTIVES: Review the pathophysiology of germline MMR deficiency and how it relates to brain tumor formation. Review the risk of developing primary CNS tumors with various MMR defects. Review the current management of CNS tumors in LS and CMMRD.
METHODS
Literature review of the most recent understanding of pathophysiology, all literature on CNS tumors in LS and CMMRD, and the current management of GBM including recent literature on CMMRD.
RESULTS
The lifetime risk of developing a primary malignant brain tumor or other CNS tumor in the United States has been calculated at 0.62%. Based on registry data, current estimates of the lifetime risk of developing a primary CNS tumor in LS is between 1–8.7%. Of the 146 genetically confirmed cases of CMMRD, 58 cases of high-grade gliomas were identified (including GBM). Most patients with CMMRD carry homozygous germline mutations in PMS2 (approximately 60%). Although primary CNS tumors appears to be a less common extra-colonic manifestation in LS, it is relatively common amongst CMMRD patients. Acknowledgement: Henry Lynch