They said that there's a fundamental difference in the way males and females respond to chronic liver disease at the genetic level, and this makes men more prone to liver cancer.
The study was led by Arlin Rogers, an MIT experimental pathologist, and a principal research scientist in MIT's Division of Comparative Medicine.
"This is the first genome-wide study that helps explain why there is such a gender effect in a cancer of a nonreproductive organ, where you wouldn't expect to see one," he said
Men develop liver cancer at twice the rate of women in the United States and in Asia, the rate for men can be eight or 10 times that for women. Liver cancer is the fifth most common cancer in the world and the third-biggest killer.
"It's an epidemic waiting to happen," said Rogers.
According to the researchers, Male and female livers are inherently different mainly due to the differences arising during puberty when male livers are exposed to periodic bursts of growth hormone, thereby prompting male livers to express different genes than female livers. This explains why men and women react differently to certain antibiotics and other medications.
Mice also have higher liver cancer rates among males and thus the researchers infected the mice with Helicobacter hepaticus, which produces the same hepatitis symptoms characteristic of human hepatitis B and C.
Healthy males and females both in humans and mice, can respond to acute toxins and other stresses. However, the male liver is not very well equipped to cope with the chronic inflammation triggered by certain infectious agents.
Thus on developing chronic hepatitis some masculine liver genes were upregulated and others were turned off in male mice. Some feminine genes were also reactivated at the same time. This resulted in an unpredictable gene profile termed "liver-gender disruption."
"There's no rhyme or reason to it. There's just a complete scrambling of masculine and feminine genes," said Rogers.
On mapping the sex-specific genes, intimate associations with inflammatory pathways were found. In males with chronic hepatitis, some gender-specific genes were overexpressed and others underexpressed, the liver was unable to maintain normal metabolic function and cancer emerged in a significant number of the animals.
It was suggested that adult females are less susceptible to liver-gender disruption as there is no requirement for the active signaling needed to maintain a masculine gene profile.
Rogers said that due to the female liver following the "default" developmental pathway, a greater disturbance is needed to initiate the cancer process.
The scientists hoped that castrating male mice at one year of age when they had chronic hepatitis, but not cancer, would have a protective effect. Some mice were also given a powerful androgen to examine whether it would promote tumors.
None of the treatments had any effect, indicating that male sex hormones like testosterone do not promote liver cancer in adults directly.
These results may have implications in cancers of other organs, such as the stomach and colon, also associated with chronic inflammation and are more common in men.
The study appeared last month in the journal Cancer Research.