Genetic alterations in non-syndromic, familial gliomas in first degree relatives: a systematic review

Abstract Objective Despite numerous reports in syndromic gliomas, the underlying genetic and molecular basis of familial, non-syndromic gliomas, in first degree relatives, remains unclear. This rare cohort of patients harboring invasive primary brain tumors with poor prognosis may provide a potential substrate of understanding the complex genetic cascade triggering tumorigenesis. Methods A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) 2015 and The Cochrane Handbook of Systematic Reviews of Interventions. PubMed/MEDLINE, Embase and CENTRAL databases were accessed with set inclusion and exclusion criteria. Results Following returns of 6756 articles, systematic analysis resulted in 48 papers, with 18 case series, 4 linkage analyses, 3 case-control studies, 1 cohort study, and 22 case reports. A total of 164 first degree relatives of 72 families were analyzed. The most common genetic alterations associated with non-syndromic familial gliomas reported to affect chromosomes 17 (51.1% germline and 9.3% tumor mutations), 22 (15.6% germline and 6% tumor mutations) and 1 and 19 (4.4% germline and 9.3% tumor mutations), with the most commonly affected genes TP53 (8.5%) and NF2 (3.7%). Tumor suppressors or cell-cycle regulators, cell signaling and transcription regulation or methylation were the most common gene function categories. Conclusion Four specific chromosomes (17, 22, 1 and 19) and two specific genes (TP53 and NF2) appear to be most commonly involved. This appears to be the first systematic review of genetic factors underlying non-syndromic glioma clustering in families. The defined list of genetic abnormalities, linked to familial gliomas, may facilitate therapeutic targets and future treatment design.