Environmental and sex-specific molecular signatures of glioma causation. Issue 1 (4th May 2021)

• Record Type: Journal Article
• Authors: Claus, Elizabeth B; Cannataro, Vincent L; Gaffney, Stephen G; Townsend, Jeffrey P
• Is Part Of: Neuro-oncology. Volume 24:Issue 1(2022)
• Page Start: 29
• Page End: 36
• Publication Date: 2021-05-04
• Subjects: cancer effect -- glioma -- haloalkanes -- molecular signatures -- mutations; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab103
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: The relative importance of genetic and environmental risk factors in gliomagenesis remains uncertain. Methods: Using whole-exome sequencing data from 1105 adult gliomas, we evaluate the relative contribution to cancer cell lineage proliferation and survival of single-nucleotide mutations in tumors by IDH mutation subtype and sex. We also quantify the contributions of COSMIC cancer mutational signatures to these tumors, identifying possible risk exposures. Results: IDH -mutant tumors exhibited few unique recurrent substitutions—all in coding regions, while IDH wild-type tumors exhibited many substitutions in non-coding regions. The importance of previously reported mutations in IDH1/2, TP53, EGFR, PTEN, PIK3CA, and PIK3R1 was confirmed; however, the largest cancer effect in IDH wild-type tumors was associated with mutations in the low-prevalence BRAF V600E. Males and females exhibited mutations in a similar set of significantly overburdened genes, with some differences in variant sites—notably in the phosphoinositide 3-kinase (PI3K) pathway. In IDH -mutant tumors, PIK3CA mutations were located in the helical domain for females and the kinase domain for males; variants of import also differed by sex for PIK3R1 . Endogenous age-related mutagenesis was the primary molecular signature identified; a signature associated with exogenous exposure to haloalkanes was identified and noted more frequently in males. Conclusions: Cancer-causing mutations in glioma primarily originated as a consequence of endogenous rather than exogenous factors. Mutations in helical vs kinase domains of genes in the phosphoinositide 3-kinase (PI3K) pathway are differentially selected in males and females. Additionally, a rare environmental risk factor is suggested for some cases of glioma—particularly in males.