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.

Keywords: cancer; epigenetics; gender; gene networks; genetics; genomics; sex.

Figure 1

Cancers with sex disparity in incidence and mortality rates. Age-adjusted incidence and mortality rates per 100,000 individuals in the US were retrieved from the Surveillance, Epidemiology, and End Results explorer. Bars show the average rate from 2000 to 2017 and 95% confidence interval. Cancer sites are ordered according to the male-to-female incidence rate ratio; starting from cancer sites with higher incidence rates in males compared to females.

Figure 2

Sex differences in genomics, which can be modulated by host and environmental factors, influence cancer biology and outcomes.

Figure 3

The interplay between sex, gender, and genomics. Biological sex and gender-influenced behavior, such as smoking, influence cancer genomics. In smoking-associated lung cancer, female lung tissue present higher level of DNA adducts, higher TP53 mutation, higher expression level of the carcinogen-metabolizing enzyme CYP1A1, and less efficient DNA repair.

Figure 4

Using systems-based approach to study sex differences. Multi-omic data can be integrated to reconstruct gene networks that combine sex- and gender-biased effects and map how the connectivity and activity of genes differ between males and females. Analyzing the network topology and changes in network structure of males and females can provide insights into molecular mechanisms involved with sex differences in cancer. TF, transcription factor.

Figure 5

Methodological approach to study sex differences in genomics. (A) Perform sex-informed sequence alignment. The framework proposed in the XYalign tool (153), first identifies whether the sequencing reads are derived from an XX or XY genome, considering the balance of reads aligned to X and Y chromosomes. Next, sequencing reads from an XX genome are aligned against a reference genome with the Y chromosome masked, and sequencing reads from an XY genome are aligned against a reference genome masked for regions in the Y that are identical to X, the pseudoautosomal regions (PAR). (B) Use the genomic data to annotate biological sex based on sex chromosome complement. (C) Sex-based analysis may show how the effect of a genomic marker varies between males and females. PCA, Principal component analysis.

Figure 6

Sex differences in colorectal cancer. Males and females present differences in colorectal cancer incidence, mortality, anatomic site location, genetics, epigenetics, and transcriptional regulatory processes characterized by gene regulatory networks. Incidence and mortality rates per 100,000 individuals in the US were retrieved from the Surveillance, Epidemiology, and End Results explorer (2000–2017).