A recent pan-cancer analysis has uncovered sex differences in oncogenic mutational processes.
Cancer sex disparities
Disparities between sexes have been previously found across different aspects of cancer, including epidemiology, treatment and biology. Overall, cancer risk in males corresponds with a higher incidence in most tumour types. Males also have a higher cancer mortality rate compared to females. Responses in treatment also differ. For example, female colorectal cancer patients respond better to surgery and adjuvant chemotherapy than males.
There is growing evidence of sex differences in cancer genomics, yet the molecular origins and clinical implications of these remain unclear. Most studies have explored sex differences within protein coding regions, while differences within non-coding regions remain largely unexplored. In this study, published in Nature Communications, researchers used data from the ICGC/TCGA Pan-cancer Analysis of Whole Genomes (PCWAG) consortium to identify sex-biased mutations. They had 1,983 samples (1,213 male, 770 female) from 28 tumour subtypes, excluding those of the sex organs. The team focused on sex differences from autosomal chromosomes in cancers affecting both men and women.
Oncogenic sex differences
The team were able to validate previously reported findings in a novel dataset. They observed male-dominated bias in the mutational frequency of oncogenic driver genes. Across all pan-cancer samples, the burden of somatic SNVs for coding, non-coding and overall mutation load was also higher in males.
The team also examined percent genome altered (PGA), a measure for genome instability. Although they did not find associations between sex and autosome-wide PGA, they did observe sex-biases in the copy number burden for specific chromosomes. In individual tumour subtypes, they detected sex-biased PGA in renal cell cancer (chromosomes 7 and 12) and hepatocellular cancer (chromosomes 1 and 16).
When looking at mutational signatures, the team identified three signatures that occurred more frequently in one sex over the other. When they repeated the analysis for each tumour subtype, they identified six sex-biased signatures in hepatocellular cancer. They also identified differences in the proportions of particular signatures within B-cell non-Hodgkin lymphoma.
This analysis of whole-genome sequencing data has uncovered sex differences within non-coding autosomal regions. The team demonstrated sex-biases through a number of measures, including non-coding mutation density and mutation signatures. These biases suggest differences in the origins and trajectories of tumours between males and females. It also indicates how they are influenced by different endogenous and environmental factors. In addition, the team have provided a glimpse into the tumour subtype-specific differences in cancers, e.g. liver and kidney. The team believe that these results strengthen the call for increased consideration of sex within molecular cancer research.
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