Genetics and Epigenetics of Sex Bias: Insights from Human Cancer and Autoimmunity

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Genetics and Epigenetics of Sex Bias: Insights from Human Cancer and Autoimmunity

Understanding Sex Bias in Human Disease Is the First Step towards Personalized Medicine

Ever-improving sequencing and genome engineering techniques now enable us to sample and modify the genome and epigenome in thousands of individuals, thus holding the promise to make precision medicine a reality. However, we still do not know why certain diseases are more frequently observed in men versus women, or vice versa. This is due to the overwhelming lack of consideration of sex in basic and translational research. The exclusion of women from clinical trials led to dramatic effects on public health. A study commissioned by the US General Accounting office, for example, found that eight of ten drugs withdrawn from the market posed greater health risks for women than men. The molecular mechanisms underlying sex bias in humans, however, remain unknown. Several human diseases show a bias in their incidence, phenotypic outcome, and/or response to treatment in men versus women. This is particularly evident for immune disorders and cancer. Women are resilient to certain infections but show a higher incidence of autoimmune diseases, including multiple sclerosis (MS) (see Glossary), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE). By contrast, cancer has an overall higher incidence in men, with treatment and survival showing typically worse responses in men than in women. Historically, most of the studies investigating sex differences focused on gonadal sex hormones –estradiol and progesterone produced from the ovaries and testosterone from the testes. Together they showed that sex hormones influence the development and function of several cells and tissues, including immune and cancer cells, suggesting they might contribute to disease pathogenesis. While it is widely accepted that sex hormones play a role in the sex bias of human diseases, genetic and epigenetic foundations did not emerge until recently. Here, we review recent evidence of intrinsic genetic and epigenetic differences that contribute to the sex bias in human diseases. In particular, recent studies in cancer and autoimmunity showcase how sex biases in the activity, repair, and folding of the human genome are associated with differences in disease incidence and outcome between men and women. Overall, a new scenario arises: diseases classified based on their histopathological phenotype might have distinct molecular etiologies in men and women. Understanding the molecular mechanisms underlying sex bias in human diseases will be instrumental in truly moving forwards into the era of personalized medicine by sex-tailored diagnostic and therapeutic approaches that are affordable by the health care expenditure of many countries.

Sex Bias in Genome Mutation and Repair Is Revealed by Cancer Genome Studies

The Cancer Genome Atlas and the Pan-Cancer Analysis of Whole Genomes have greatly facilitated the detection of sex biases that were previously undetectable in low-powered studies, by the sampling of cancer genomes across many human individuals and tissues. One of the first studies taking advantage of these genome-wide analyses investigated the genomic differences underlying male bias in metastatic melanoma. The authors found that male melanomas have significantly more missense mutations than females, showing for the first time a sex difference in the overall tumor mutation burden. A recent study confirmed a male bias in the overall mutation burden of melanoma and revealed that the correlation between mutations induced by UV radiation and the cell cycle is also prevalent in male tumors. This suggests that males are more susceptible to UV damage than females, possibly due to intrinsic cell division differences. The initial finding in melanoma was further supported by pan-cancer analyses of sex biases in the somatic mutation profiles of ~20 different tumor types. These broad studies demonstrated a clear sex bias in the mutation burden that is generally higher in male than in female tumors – both overall cancer and several specific tumor types, such as bladder, kidney, liver, and skin cancers. One study revealed a correlation between the somatic mutation load and the incidence of cancer, meaning that a higher number of mutations in men characterize cancers with a male prevalence and vice versa. Interestingly, somatic mutations accumulate approximately 10 years earlier in men than in women, suggesting that sex differences in aging rates might account at least in part for the observed bias in genome mutation. This is consistent with observations that associate age-related changes, such as accumulation of DNA damage, cellular senescence, and genome instability, with sex biases in genome mutation.

Sex-Specific Mutation Hotspots: Driven by Selection or Genome Architecture?

Pan-cancer analyses also showed that distinct gene loci are more frequently mutated in one sex. For example, somatic mutations in known cancer driver genes such as β-catenin (CTNNB1) and BAP1 de-ubiquitinylase, were found to be strongly enriched in hepatocellular cancers of males and females, respectively. Sex differences in somatic mutations were also confirmed by more recent analyses of the noncoding genome. The latter showed that CTNNB1 mutations are found in a larger proportion of male-derived tumors, in contrast to PTCH1, which is mostly mutated in the majority of female samples. The largest sex disparity was observed in thyroid cancers where TERT promoter mutations were observed in 64% of male tumors versus 11% of females, as also found in other studies. Interestingly, this noncoding TERT mutation is associated with the increased mutation burden observed in male thyroid tumors, suggesting a causal relationship between TERT and genome load. Further sex biases were observed in copy number aberrations and their genomic locations. This is exemplified by the higher percentage of alterations in chromosome 7 in male samples and the male-dominated copy number gains at the MYC and ERBB2 oncogenes and at the driver CTNNB1. Notably, it was shown that copy number variations alter the gene expression level in a sex-specific manner, thus potentially contributing to sex dimorphism in gene expression.

Sex Chromosomes Influence Sex Biases in Immunity and Cancer

The most striking genetic difference between men and women is the presence of a different set of sex chromosomes in females and males (i.e., XX and XY, respectively). Differences in gene content, genetic variants, and gene expression dosage between the X and Y chromosome can account for sex differences. Genes on the X and Y chromosomes are only partially conserved and many of the X and Y homologs are not functionally equivalent. For example, it has been recently shown that a single amino acid difference generates severe deficits in maturation, surface expression, and synaptogenesis in NLGN4Y compared with its homolog NLGN4X. Interestingly, NLGN4X variants associated with autism spectrum disorder surround this critical amino acid and phenocopy NLGN4Y, suggesting that functional differences in this X/Y homolog gene pair might underlie the male bias observed in NLGN4X-associated autism. Moreover, the unbalance in X and Y genetic dosage is only partially compensated by the inactivation of one of the two X chromosomes in females. This process, named X chromosome inactivation (XCI), is incomplete and some genes remain biallelically expressed from both X chromosomes in somatic tissues. These genes are believed to ‘escape’ inactivation and include both pseudo-autosomal genes with a homologous counterpart on the Y chromosome and genes that are nonconserved. The presence/absence of differential expression of genes on the X or Y chromosome can be one of the possible causes of sex bias in gene expression and,
consequently, in traits and disease.

Author: Sara Carmela Credendino, Christoph Neumayer, and Irene Cantone

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