Sex differences in GBM revealed by analysis of patient imaging, transcriptome, and survival data

Abstract

Male and female glioblastomas are biologically distinct, and improving outcomes may require sex-specific approaches to treatment. Brain tumors’ battle of the sexes In recent years, there has been increasing interest in personalized medicine for cancer, considering the unique biology of each tumor and patient to optimize therapeutic approaches. Sex differences play a role in patient outcomes, and Yang et al. determined that in the case of the brain tumor glioblastoma, these go beyond hormonal influences and appear to be intrinsic to the tumor cells themselves. The authors found that the sex of the patient correlates not only with prognosis but also with responses to different treatments, suggesting that it may be an important factor to consider when optimizing the therapeutic regimen for each patient. Sex differences in the incidence and outcome of human disease are broadly recognized but, in most cases, not sufficiently understood to enable sex-specific approaches to treatment. Glioblastoma (GBM), the most common malignant brain tumor, provides a case in point. Despite well-established differences in incidence and emerging indications of differences in outcome, there are few insights that distinguish male and female GBM at the molecular level or allow specific targeting of these biological differences. Here, using a quantitative imaging–based measure of response, we found that standard therapy is more effective in female compared with male patients with GBM. We then applied a computational algorithm to linked GBM transcriptome and outcome data and identified sex-specific molecular subtypes of GBM in which cell cycle and integrin signaling are the critical determinants of survival for male and female patients, respectively. The clinical relevance of cell cycle and integrin signaling pathway signatures was further established through correlations between gene expression and in vitro chemotherapy sensitivity in a panel of male and female patient-derived GBM cell lines. Together, these results suggest that greater precision in GBM molecular subtyping can be achieved through sex-specific analyses and that improved outcomes for all patients might be accomplished by tailoring treatment to sex differences in molecular mechanisms.