Genetic differences point to ethnic and racial disparities in colorectal cancer risk

Nov 29 2007

Risk of developing colorectal cancer is known to differ across ethnic and racial groups, and now an analysis of 26 studies, involving over 25,000 participants shows that some of these disparities might be explained by distinct patterns of genetic inheritance.

A team of researchers, led by investigators at the University of Pittsburgh, present their findings today in Atlanta at the American Association for Cancer Research conference on The Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved, being held November 27-30.

The researchers found that people who have two “T” copies of the gene that metabolizes folate, a chemical needed to produce and maintain new cells, are 19 percent less likely to develop colorectal cancer than are individuals with two “C” copies of the gene.

By using individual data collected through the Genetic Susceptibility to Environmental Carcinogens study, a collaborative pooled analysis based at the University of Pittsburgh Medical Center and begun in 1997, they were able to look at genetic inheritance in different racial and ethnic groups. The investigators found that the odds of individuals developing colorectal cancer with two “T” genes versus two “C” genes was 31 percent less in Asians, 8 percent less in Caucasians, and 4 percent more in African-Americans, although results were only statistically significant in the Asian population. Conversely, Latinos who inherited one copy of each gene instead of two “C” genes had a 20 percent higher risk of developing the cancer. However, this result was not statistically significant.

“This analysis shows that homozygosity for the T copy of this gene may be protective in different degrees against colorectal cancer in some populations but not in others,” said lead investigator, Mary A. Garza, Ph.D., M.P.H., deputy director of the Center for Minority Health in the University of Pittsburgh's Graduate School of Public Health.

Garza says this is the first pooled analysis to explore the association between specific genes and the risk of developing colorectal cancer across racial/ethnic populations. “We are trying to unlock the role genetics, through gene-environment interactions, may play in understanding the underlying causes of health disparities,” Garza said.

Even though deaths rates from colorectal cancer have been declining in the United States, African-Americans and other minority populations experience a disproportionate share of this cancer burden, Garza says. “This disparity exists even after accounting for various environmental and social factors, so it makes sense that genetics could play a contributing role in this cancer disparity,” she said.

The researchers focused on the metabolic enzyme 5 10-methelenetetrahydrofolate reductase (MTHFR), whose role is to maintain folate in the blood in order to prevent the buildup of homocysteine,a chemical byproduct that is toxic to cells. The CC version of MTHFR is considered the wild type – the version most common in the population as a whole – and the CT or TT alleles carry a variant “T,” a point mutation in which a thymine nucleic acid is substituted for a cytosine in the gene's DNA. Compared to CC, enzymatic activity of the CT mutation is reduced to 65 percent; TT has 30 percent the enzymatic activity of CC.

One common variation of the gene, called C677T, has been associated with a lower risk of colorectal cancer in individuals with high levels of folate and low levels of alcohol use, Garza says.

Their finding that the TT version of the gene seems to offer protection against colorectal cancer in Asian, and possibly in other groups except Latinos warrants further examination, Garza says. “Normally, if one carries the recessive TT which means reduced enzyme activity, you would expect a higher risk of developing colorectal cancer; however, the opposite is true,” she said.

“One could speculate that C677T may contribute in combination with environmental exposures to the differences in colorectal cancer prevalence in racial or ethnic populations,” Garza said. “These findings warrant larger studies to evaluate gene-environment interactions for the MTHFR polymorphism and colorectal cancer risk in different racial or ethnic populations.”