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-wildtype 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 wildtype 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 versus 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.

Evaluating hematologic parameters in newly diagnosed and recurrent glioblastoma: Prognostic utility and clinical trial implications of myelosuppression

“… 32 Of note, in agreement with prior findings by Le Rhun et al, 24 females were more likely to develop lymphopenia relative to males. These findings support recent work demonstrating broad-based sex differences in GBM, 33 as well as sex-based differences in hematologic adverse events in oncology patients. 34 …”

Multimodal-based machine learning strategy for accurate and non-invasive prediction of intramedullary glioma grade and mutation status of molecular markers: a retrospective study

“…TRA T2WI scans usually have smaller slice spacing, have the advantage of accurately constructing a 3D tumor ROI, and may allow for more accurate delineation of the tumor contour during segmentation. Additionally, previous research has confirmed that clinical features such as age and sex are related to glioma type [ 32 , 33 ]. Wu et al [ 34 ] developed a nomogram strategy to adopt clinical features in radiomics-based prediction models.…”

Development of preoperative and postoperative models to predict recurrence in postoperative glioma patients: a longitudinal cohort study

“…In addition, gliomas showed a male predominance, with males accounting for 58.21% (1492/2563) of the total study population and 64.56% (612/948) of glioblastomas. Sex-specific genetic signatures [ 26 ] have been found to predispose men to a 50% higher risk of being diagnosed with glioma than women [ 27 ]. In our study, we found that this difference was weakly correlated in WHO grade 3 tumors.…”