'Across virtually every type of cancer, occurrence rates are higher in males than in females. In some cases, the difference might be very small – just a few percent – but in certain cancers the incidence is two or three times higher in males,' said Dr Andrew Lane of the Dana-Farber Cancer Institute in Boston, Massachusetts, one of the authors of the study. Overall males have a 20 percent higher risk of cancer than females.
While females have two copies of the X chromosome, and males have one X and one Y chromosome, in females one copy of each X chromosome is normally inactivated in cells. 'That's thought to be to balance out the gene expression,' said Dr Lane.
However, the researchers hypothesised that a few genes on the X chromosome that protect against cancer might escape this inactivation. They dubbed these EXITS – Escape from X-Inactivation Tumour Suppressor genes.
'Under this theory, one of the reasons cancer is more common in males is that male cells would need a harmful mutation in only one copy of an EXITS gene to turn cancerous,' said Dr Lane. 'Female cells, by contrast, would need mutations in both copies.'
The researchers examined more than 4000 cancers of 21 tumour types, looking for mutations that might explain the difference. Of the 800 genes found only on the X chromosome, they found six genes that were frequently mutated in males than in females. Five of these genes were known to be ones that escape X-chromosome inactivation. Among more than 18,000 genes they test on other chromosomes, none showed a similar difference according to sex.
'The fact that the very genes which are more often mutated in males are found exclusively on the X chromosome – and that several of them are known to be tumour suppressors and escape X inactivation – is compelling evidence of our theory,' said Dr Lane. 'The protection afforded by the working copies of these genes in female cells may help explain the lower incidence of many cancers in women and girls.'
It had previously been assumed that there were environmental reasons for the differences between rates of male and female cancer rates – perhaps because men were more likely to smoke than women. However, as smoking rates have fallen, the difference remains. Boys and are also more likely to get cancer than girls.
The possibility that there may be genetic reasons why males are more susceptible to cancer should inform research, and to better understand these differences, more data from both female and male patients is required, said Dr Lane. 'The escaped genes accounts for some of the gender gap, but not all.'
The research was published in Nature Genetics.