Environmental and sex-specific molecular signatures of glioma causation

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.

Keywords: cancer effect; glioma; haloalkanes; molecular signatures; mutations.

Fig. 1

Cancer effect sizes of recurrent somatic substitutions for IDH-mutant and IDH wild-type tumors by sex.

Fig. 2

Cancer effect size of the genes with dndsCV Q < 0.1 and 2 or more substitutions, sorted by IDH mutation status, gene, and then sex. Variant mutations in (A) TP53, with variants, typically exhibiting slightly higher estimated scaled selection coefficients in IDH-mutant males than females and slightly lower estimated scaled selection coefficients in IDH wild-type males than females, (B) EGFR, in which strong selection occurs on variants only in IDH wild-type tumors (C) PTEN, in which strong selection occurs on variants only in IDH wild-type tumors (D) PIK3CA, in which strong selection occurs only on helical variants in females and almost exclusively on kinase domain mutations in males, (E, F) CIC and IDH1, in which strong selection occurs on variants only in IDH-mutant tumors, and (G–L) ATRX, PIK3R1, IDH2, NF1, PTPN11, and TRAT1, showing evidence of additional patterns among IDH wild-type and IDH-mutant tumors of males and females with lower numbers of variants under strong selection.

Fig. 3

Cancer effect sizes of recurrent somatic substitutions (non-synonymous amino acid changing, red; non-coding single-nucleotide variant, blue) for IDH-mutant and IDH wild-type tumors by sex.

Fig. 4

COSMIC signatures name and numbers, ordered by their contribution to cancer effect, for IDH-mutant and IDH wild-type glioma by sex. (A) IDH-mutant tumors in females, (B) IDH-mutant tumors in males, (C) IDH wild-type tumors in females, and (D) IDH wild-type tumors in males.