Integrative multi-omics characterization reveals sex differences in glioblastoma.

in Biology of sex differences by Byunghyun Jang, Dayoung Yoon, Ji Yoon Lee, Jiwon Kim, Jisoo Hong, Harim Koo, Jason K Sa

TLDR

  • The study looked at the differences between male and female GBM patients using big data from different sources. They found that female GBM patients had more MGMT promoter methylation, which is good for their overall and post-recurrence survival and response to chemotherapy. They also found that female GBMs had more genomic instability, which means they had more changes in their DNA. They also found that each sex-specific GBM has its own unique pathway and molecular subtypes. The study suggests that these differences can help doctors develop personalized treatment plans for male and female GBM patients.

Abstract

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, with limited treatment modalities and poor prognosis. Recent studies have highlighted the importance of considering sex differences in cancer incidence, prognosis, molecular disparities, and treatment outcomes across various tumor types, including colorectal adenocarcinoma, lung adenocarcinoma, and GBM. We performed comprehensive analyses of large-scale multi-omics data (genomic, transcriptomic, and proteomic data) from TCGA, GLASS, and CPTAC to investigate the genetic and molecular determinants that contribute to the unique clinical properties of male and female GBM patients. Our results revealed several key differences, including enrichments of MGMT promoter methylation, which correlated with increased overall and post-recurrence survival and improved response to chemotherapy in female patients. Moreover, female GBM exhibited a higher degree of genomic instability, including aneuploidy and tumor mutational burden. Integrative proteomic and phosphor-proteomic characterization uncovered sex-specific protein abundance and phosphorylation activities, including EGFR activation in males and SPP1 hyperphosphorylation in female patients. Lastly, the identified sex-specific biomarkers demonstrated prognostic significance, suggesting their potential as therapeutic targets. Collectively, our study provides unprecedented insights into the fundamental modulators of tumor progression and clinical outcomes between male and female GBM patients and facilitates sex-specific treatment interventions. Highlights Female GBM patients were characterized by increased MGMT promoter methylation and favorable clinical outcomes compared to male patients. Female GBMs exhibited higher levels of genomic instability, including aneuploidy and TMB. Each sex-specific GBM is characterized by unique pathway dysregulations and molecular subtypes. EGFR activation is prevalent in male patients, while female patients are marked by SPP1 hyperphosphorylation.

Overview

  • The study investigates the genetic and molecular determinants that contribute to the unique clinical properties of male and female GBM patients using comprehensive analyses of large-scale multi-omics data from TCGA, GLASS, and CPTAC. The study aims to provide insights into the fundamental modulators of tumor progression and clinical outcomes between male and female GBM patients and facilitate sex-specific treatment interventions. The hypothesis being tested is that there are sex differences in the genetic and molecular determinants of GBM that can inform personalized treatment strategies.

Comparative Analysis & Findings

  • The study reveals several key differences between male and female GBM patients, including enrichments of MGMT promoter methylation, which correlated with increased overall and post-recurrence survival and improved response to chemotherapy in female patients. Female GBM also exhibited a higher degree of genomic instability, including aneuploidy and tumor mutational burden. Integrative proteomic and phosphor-proteomic characterization uncovered sex-specific protein abundance and phosphorylation activities, including EGFR activation in males and SPP1 hyperphosphorylation in female patients. The identified sex-specific biomarkers demonstrated prognostic significance, suggesting their potential as therapeutic targets.

Implications and Future Directions

  • The study's findings highlight the importance of considering sex differences in cancer incidence, prognosis, molecular disparities, and treatment outcomes across various tumor types, including GBM. The study suggests that each sex-specific GBM is characterized by unique pathway dysregulations and molecular subtypes. The identified sex-specific biomarkers demonstrate prognostic significance and suggest their potential as therapeutic targets. Future research directions could include validation of the identified sex-specific biomarkers in clinical settings, development of sex-specific treatment interventions, and exploration of the underlying mechanisms of sex differences in GBM.
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