Genome-Wide Sex and Gender Differences in Cancer

Abstract

Despite their known importance in clinical medicine, differences based on sex and gender are among the least studied factors affecting cancer susceptibility, progression, survival, and therapeutic response. In particular, the molecular mechanisms driving sex differences are poorly understood and so most approaches to precision medicine use mutational or other genomic data to assign therapy without considering how the sex of the individual might influence therapeutic efficacy. The mandate by the National Institutes of Health that research studies include sex as a biological variable has begun to expand our understanding on its importance. Sex differences in cancer may arise due to a combination of environmental, genetic, and epigenetic factors, as well as differences in gene regulation, and expression. Extensive sex differences occur genome-wide, and ultimately influence cancer biology and outcomes. In this review, we summarize the current state of knowledge about sex-specific genetic and genome-wide influences in cancer, describe how differences in response to environmental exposures and genetic and epigenetic alterations alter the trajectory of the disease, and provide insights into the importance of integrative analyses in understanding the interplay of sex and genomics in cancer. In particular, we will explore some of the emerging analytical approaches, such as the use of network methods, that are providing a deeper understanding of the drivers of differences based on sex and gender. Better understanding these complex factors and their interactions will improve cancer prevention, treatment, and outcomes for all individuals.

De novo serine biosynthesis from glucose predicts sex-specific response to antifolates in non-small cell lung cancer cell lines

“…The fact that cell lines such as these have been used for years in laboratory research and still retain sex differences in fundamental metabolic pathways suggest that the selective advantage of retaining these characteristics in cell culture are significant and outweigh the selective pressures of conventional laboratory cell culture. As the majority of genes encoding enzymes involved in central carbon metabolism are not present on sex chromosomes, these findings suggest the presence of epigenetic influences on sex differences, as has been previously identified in cancers including lung (Lopes-Ramos et al, 2018, 2020; Vaissière et al, 2009; Wu et al, 2008).…”

Epigenetic Drift Association with Cancer Risk and Survival, and Modification by Sex

“…Advanced age is typically associated with increased cancer risk and reduced cancer survival [ 2 , 3 , 4 ]. Males and females exhibit different risk profiles in terms of incidence and survival [ 5 , 6 , 7 , 8 , 9 , 10 ], and most cancers for which there is a clear sex difference affect men more frequently than women, with incidence rates ranging from 1.3:1 for Hodgkin lymphoma to 4.9:1 for oropharynx and tonsil cancer [ 10 ]. Several studies [ 11 , 12 , 13 , 14 , 15 ] have investigated age- and sex-specific incidence and mortality rates using population-based data.…”

Fully Automated MR Based Virtual Biopsy of Cerebral Gliomas

“…During the feature selection, gender and laboratory parameters dropped out because of their poor predictive power, so only imaging parameters were used to train the final model. While gender is certainly a risk factor for cerebral gliomas [ 32 ], this feature does not appear to be relevant for differentiating genetic parameters and grading in our study collective. No data on association with grading and genetic parameters are available for the laboratory parameters used.…”