A person’s sex can affect the kinds of cancer-causing mutations they develop, according to a genomic analysis spanning nearly 2,000 tumours and 28 types of cancer.
The results show striking differences in the cancer-causing mutations found in people who are biologically male versus those who are biologically female — not only in the number of mutations lurking in their tumours, but also in the kinds of mutations found there.
Liver tumours from women were more likely to carry mutations caused by a faulty system of DNA mending called mismatch repair, for instance. And men with any type of cancer were more likely to exhibit DNA changes thought to be linked to a process that the body uses to repair DNA with two broken strands.
These biases could point researchers to key biological differences in how tumours develop and evolve across sexes. (The study did not look at the gender of those who donated tissue samples, which could differ from their biological sex.) The work was published last month as a preprint on the bioRxiv server1.
The data add to a growing realization that sex is important in cancer, and not only because of lifestyle differences, says Kenneth Buetow, a geneticist at Arizona State University in Tempe. Lung and liver cancer, for example, are more common in men than in women — even after researchers control for disparities in smoking or alcohol consumption. The source of that bias, however, has remained unclear.
“This is a remarkably understudied component in the cancer-research portfolio,” Buetow says. “There has been a generic assumption, not formally tested until recently, that there wouldn’t be dramatic differences.”
In 2014, the US National Institutes of Health began encouraging researchers to consider sex differences in preclinical research by, for example, including female animals and cell lines from women in their studies. And some studies have since found sex-linked biases in the frequency of mutations in protein-coding genes in certain cancer types, including some brain cancers2 and advanced melanoma3.
But the bioRxiv preprint, which has not yet been peer-reviewed, is the most comprehensive study of sex differences in tumour genomes so far, says Buetow. It looks at mutations not only in genes that code for proteins, but also in the vast expanses of DNA that have other functions, such as controlling when genes are turned on or off. The study also compares male and female genomes across many different cancers, which can allow researchers to pick up on additional patterns of DNA mutations, in part by increasing the sample sizes.
Geneticist Paul Boutros of the University of California, Los Angeles, and his colleagues analysed full genome sequences gathered by the International Cancer Genome Consortium. They looked at differences in the frequency of 174 mutations known to drive cancer, and found that some of these mutations occurred more frequently in men than in women, and vice versa. When they looked more broadly at the loss or duplication of DNA segments in the genome, they found 4,285 sex-biased genes spread across 15 chromosomes.
There were also differences in when some mutations seemed to arise during tumour development, suggesting that some cancers follow different evolutionary paths in men and women.
Boutros and his colleagues also looked at particular patterns of DNA changes. Such patterns can, in some cases, reflect the source of the mutation. Tobacco smoke, for example, leaves behind a particular signature in the DNA.
Altogether, the team found eight patterns of mutations that occurred more frequently in one sex. Across all cancers, 97% of samples from women carried a particular DNA signature characteristic of defects in mismatch repair, for example. But only 89% of male-derived samples had these patterns. In liver cancer, the difference was more extreme, with 88% of women bearing that signature versus 58% of men.
This bias hints at fundamental biological differences in the processes that cause the mutations, Boutros says. Those discrepancies caught his team by surprise: “We were expecting differences in the number of mutations, not the type,” he says. “For example, women might be more affected by tobacco smoke than men. We didn’t expect a new process.”
Taken together, the results highlight the importance of accounting for sex, not only in clinical trials but also in preclinical studies, says Boutros.
Doing so could eventually allow researchers to pin down the sources of many of the differences that Boutros and his colleagues found, says Buetow. His lab has published a preprint on bioRxiv that finds sex-based differences in gene activity within liver tumours4.
Liver cancer is roughly three times as common in men as in women in some populations, and its incidence is increasing in some countries. “A better understanding of its aetiology may turn out to be really important,” Buetowsays. “We want to get ahead of where we are in terms of prevention strategies and treatments.”
Li, C. H. et al. Preprint at bioRxiv https://doi.org/10.1101/528968 (2019).
Sun, T., Plutynski, A., Ward, S. & Rubin, J. B. Cell. Mol. Life Sci. 72, 3323–3342 (2015).
Gupta, S., Artomov, M., Goggins, W, Daly, M. & Tsao, H. J. Natl Cancer Inst. 107, djv221 (2015).
Natri, H. M., Sayres, M. W. & Buetow, K. Preprint at bioRxiv https://doi.org/10.1101/507939 (2018).