Change in gene may be underlying molecular defect in some colorectal cancers

Inactivation of a DNA repair gene may be an early step in the development of sporadic colorectal tumors, and detection of the molecular basis for this inactivation may ultimately be useful in risk assessment for colorectal cancer, according to a new study in the current issue of the Journal of the National Cancer Institute.

Cancers can arise from a region of cells with a "field defect", cells that appear normal but that have an underlying molecular defect. The molecular basis for the field defect is easy to understand when tumors develop from cells that all have similar genetic abnormalities, such as those that occur in patients who are genetically predisposed to a cancer or those who undergo an exposure to a carcinogen such as tobacco smoke. However, how the field defect may arise in most sporadic cancers in unclear.

In colorectal cancer, the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) is often methylated--that is, the gene's promoter region has methyl groups added to it, which inactivate the gene. Jean-Pierre J. Issa, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston, and colleagues hypothesized that MGMT promoter methylation could be one of the characteristics of the field defect in colorectal cancer, so they studied MGMT promoter methylation in the tumor, adjacent mucosa, and nonadjacent mucosa of 95 colorectal cancer patients and in the colon mucosa of 33 subjects without cancer.

MGMT promoter methylation was found in 50% to 94% of colorectal tumors, depending on the method of detection, and normal-appearing colon mucosa up to 10 cm away from the tumor had detectable MGMT methylation. In addition, the authors detected MGMT methylation in the normal colon mucosa of several subjects who did not have cancer.

"Because a loss of MGMT protein function is a plausible predisposing factor for cancer through the increased occurrence of mutations…, our data indicate that MGMT promoter methylation may qualify as a marker of the field defect in colorectal cancer," the authors write. In addition, "given the high lifetime risk of colorectal tumor development in the U.S. population, it is reasonable to propose testing to determine whether healthy persons with MGMT promoter methylation in normal colorectal mucosa are at higher risk of developing a colon tumor than those without such methylation."

In an editorial, Edward Giovannucci, M.D., Sc.D., of the Harvard School of Public Health, and Shuji Ogino, of Brigham and Women's Hospital, both in Boston, review the concept of the field defect (also called the field effect or field cancerization). They also raise several questions about how these findings may affect related areas of research, such as approaches to chemoprevention and "whether the reversal of DNA methylation in precancerous cells may prevent the development of new primary cancers in the same organ," they write.