Comprehensive Characterization of Molecular Differences in Cancer between Male and Female Patients

Abstract

Summary An individual’s sex has been long recognized as a key factor affecting cancer incidence, prognosis and treatment responses. However, the molecular basis for sex disparities in cancer remains poorly understood. We performed a comprehensive analysis of molecular differences between male and female patients in 13 cancer types of The Cancer Genome Atlas and revealed two sex-effect groups associated with distinct incidence and mortality profiles. One group contains a small number of sex-affected genes, whereas the other shows much more extensive sex-biased molecular signatures. Importantly, 53% of clinically actionable genes (60/114) show sex-biased signatures. Our study provides a systematic molecular-level understanding of sex effects in diverse cancers and suggests a pressing need to develop sex-specific therapeutic strategies in certain cancer types.

Sexual dimorphism in glioma glycolysis underlies sex differences in survival

“…Hexokinase 1 (HK1), conversely, was slightly increased in females relative to males (1.1-fold, P = 0.02). Together, this was consistent with previous findings of a weak sex effect on transcript expression in the TCGA LGG dataset (13). However, we were interested in whether there might be glycolytic subtypes within each sex that correlated with survival, specifically.…”

“…a recent multidimensional analysis of molecular differences in cancer between males and females determined strong sex effects in the presence of mutations, DNA methylation, transcript, and protein expression among renal, bladder, liver, lung, head and neck squamous, and thyroid cancers, but a weak sex effect in low-grade and high-grade gliomas (13). These findings suggest that there are alternative molecular mechanisms, perhaps related to metabolism, that may explain the sex disparity seen in brain cancers that are otherwise invisible to global molecular profiling studies.…”

Gender Dimorphism Creates Divergent Cancer Susceptibilities

“…Recently, the first pan-cancer study investigating these molecular signatures was reported [6]. In this study, Yuan et al performed a comprehensive characterization of common and unique molecular features in male and female patients across 13 major tumor types.…”

“…In this study, Yuan et al performed a comprehensive characterization of common and unique molecular features in male and female patients across 13 major tumor types. They integrated The Cancer Genome Atlas (TCGA) pan-omics profiles of six molecular data types: somatic mutations, somatic copy-number alterations, DNA methylation, mRNA expression, microRNA expression, and protein expression [6]. Using a propensity score, they extracted two sex-effect groups with molecular features from their analysis [6], which was consistent with patient gender as a prognostic factor in cancer according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline in Oncology.…”

“…They integrated The Cancer Genome Atlas (TCGA) pan-omics profiles of six molecular data types: somatic mutations, somatic copy-number alterations, DNA methylation, mRNA expression, microRNA expression, and protein expression [6]. Using a propensity score, they extracted two sex-effect groups with molecular features from their analysis [6], which was consistent with patient gender as a prognostic factor in cancer according to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline in Oncology. In a particular case of lung adenocarcinoma, Yuan et al identified 11 sex-biased genes, including STK11, a gene encoding a kinase that activates the energy-sensing AMPK pathway, which suggested that sexual dimorphism might play important roles in reprogramming pathways that mediate the cellular metabolism of cancer [7,8].…”