Sex difference of mutation clonality in diffuse glioma evolution.

Background: x differences in glioma incidence and outcome have been previously reported but remain poorly understood. Many sex differencesthat affect the cancer risk were thought to be associated with cancer evolution.

Material/Methods: In this study, we used an integrated framework to infer the timing and clonal status of mutations in ~600 diffuse gliomas from The Cancer Genome Atlas including glioblastomas (GBM) and low grade gliomas (LGG), and investigated the sex difference of mutation clonality.

Results: We observed higher overall and subclonal mutation burden in female patients with different grades of gliomas, which could be largely explained by the mutations of X-chromosome. Some well-established drivers were identified showing sex-biased clonality, such as CDH18 and ATRX. Focusing on glioma subtypes, we further found a higher subclonal mutation burden in females than males in the majority of glioma subtypes, and observed opposite clonal tendency of several drivers between male and female patients in a specific subtype. Moreover, analysis of clinically actionable genes revealed that mutations in genes of mitogen-activated protein kinase (MAPK) signaling pathway were more likely to be clonal in female patients with GBM, whereas mutations in genes involved in receptor tyrosine kinase (RTK) signaling pathway were more likely to be clonal in male patients with LGG.

Conclusions: The patients with diffuse glioma showed sex-biased mutation clonality (e.g. different subclonal mutation number and different clonal tendency of cancer genes), highlighting the need to consider sex as an important variable for improving glioma therapy and clinical care.