Genetic explanation for cancer’s higher incidence in men than women

Emobileclinic Researchers Corner

The Journal of Nature Genetics has published the findings of researchers who provided explanation on the age long mystery surrounding the reason cancer is more common men than women. The study was conducted by some Boston Scientists and researchers at Dana-Farber Cancer Institute.

The females have an extra copy of certain protective genes in their cells which provide an additional line of defense against the cells growing out of proportion. According to Andrew Lane, “across virtually every type of cancer, occurrence rates are higher in males than in females. In some cases, the difference might be very small but in certain cancers, incidence is two or three times higher in males”. He added further that “data from the National Cancer Institute show that males carry about a 20 percent higher risk than females of developing cancer that translates into 150,000 additional new cases of cancer in men every year.”

Over the years, it has remained a mystery to uncover the reason there exist this huge gap. The historical explanation that men were more likely to smoke cigarettes and be exposed to hazardous chemicals in the work environment is inadequate, because even as smoking rates have dropped and occupational patterns changed, men still have high risk than women in developing many cancers, including some associated with tobacco use such as kidney, renal, bladder, and oral cancers according to lane explanation.

It is interesting to know that early research discovered that in one type of leukemia, the cancer cells often have a mutation in a gene called KDM6A, located on the X chromosome – one of the sex chromosomes that determine whether an individual is male or female. If KDM6A is a tumor-suppressor gene, the mutation could result in cancer by crippling that restraint system.

It is usually expected that female cells should just be as vulnerable to the mutation because during embryo formation, one of the X chromosomes in female cells shuts down and remains off-line for life. A mutation in KDM6A on the active X chromosome, therefore, should lead to the same cell-division havoc as it does in males. Unexpectedly, KDM6A mutations were found most often in male cancers.

The new study sought to uncover this phenomenon- fully functional tumor-suppressor genes on an otherwise idle X chromosome – underlies the broader phenomenon of cancer’s partiality toward male cells. The researchers dubbed such genes “EXITS,” for Escape from X-Inactivation Tumor Suppressors.

According to the team, “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,” Lane said. “Female cells, by contrast, would need mutations in both copies.” The researchers at the Broad Institute scanned the genomes of more than 4,000 tumor samples, representing 21 different types of cancer, with the aim of looking for various types of abnormalities including mutations. After which they examined whether any of the irregularities they discovered were more common in male cells or female cells.

The results revealed that nearly 800 genes found mainly on the X chromosome, six were more frequently mutated and incapacitated in males than females. Of more than 18,000 other genes, none showed a gender imbalance in mutation rates. Of the six genes more likely to be mutated in males, five were known to escape X chromosome inactivation, making them strong candidates to be EXITS genes. Lame said further that “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 tumor-suppressors and escape X-inactivation – is compelling evidence of our theory,” and “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.”
One major implication of the finding is that several cancers may develop through different molecular pathways in men and women. To circumvent the added genetic safeguards against cancer in female cells, tumors in women may employ alternate genetic circuits than in men.

Source

Andrew A. Lane et.al (2016): Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias. Nature Genetics, doi:10.1038/ng.3726