January 26, 2012

Colorectal cancer risk related to gene’s expression

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Scott Williams, Ph.D., graduate student Marquitta White and colleagues are studying the APC gene’s role in colorectal cancer risk. (photo by John Russell)

Colorectal cancer risk related to gene’s expression

Individuals who are outside the “normal” range of expression for the APC gene have an increased risk of colorectal cancer, according to a study published in the January issue of Gastroenterology.

Mutations in the APC (adenomatous polyposis coli) gene – and variations in the expression of the gene’s two copies (allele-specific expression) — are associated with inherited forms of colorectal cancer.

Scott Williams, Ph.D., and graduate student Marquitta White, both in the Center for Human Genetics Research at Vanderbilt University, teamed with investigators in Italy to examine whether variations in APC allele-specific expression also contribute to common, sporadic forms of colorectal cancer.

The investigators examined APC expression in patients with colorectal cancer and in controls. They found no difference in the average APC allele-specific expression between cases and controls. But looking more carefully at the data, they noticed that the overall distribution of values was broader and more variable in the cases.

“One of the things I like to say is: before you analyze the data, look at the data, and after you analyze the data, look at the data,” said Williams, professor of Molecular Physiology and Biophysics.

In general, scientists test for a difference between two groups by asking, “Is the mean (average) different? That’s what everybody does,” Williams explained.

“But in this case, the mean’s not different, but people who are at increased risk of disease are more likely to be farther away from that mean value.”

There appears to be a normal, acceptable range for allele-specific expression of APC, Williams said, and “the farther you get away from that range, the worse off you are.”

Individuals who were farthest away had an increased risk for colorectal cancer that approached the risk of individuals with inherited colorectal cancer.

The findings suggest that “there’s a continuum of APC allele-specific expression, with familial cases of colorectal cancer at the extremes and sporadic cases somewhere between extreme and normal,” Williams said.

In cases where expression differed most from the typical value, the investigators determined the sequence of the APC gene. In one patient, they found a mutation known to be associated with inherited colorectal cancer, and a re-examination of the pathology confirmed that the patient had numerous polyps.

The findings suggest that allele-specific expression of APC may serve as a marker for colorectal cancer risk.

Williams noted that differences in the distribution of gene expression – rather than in an average value – between cases and controls could play a role in other disease processes.

“No one’s ever looked at this in a rigorous way,” he said. “I think our approach has the potential to change how we view disease risk, not only in colon cancer but perhaps other diseases.”

Next up for the investigators is a search for genetic associations that cause the change in allele-specific expression of APC.

“If we know what’s causing this difference in expression, we may be able to therapeutically intervene,” Williams said.

The research was supported by the Italian Ministry of Instruction, University, and Research and the National Institute of General Medical Sciences-funded Training Program on Genetic Variation and Human Phenotypes at Vanderbilt.