Individuals who are outside the normal range of expression for the adenomatous polyposis coli (APC) gene have an increased risk of colorectal cancer, according to a study published in the January issue of .
Mutations in the APC gene 鈥� and variations in the expression of the gene鈥檚 two copies (allele-specific expression) 鈥� are associated with inherited forms of colorectal cancer.
, professor of molecular physiology and biophysics, 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.
鈥淥ne 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,鈥� said Williams.
In general, scientists test for a difference between two groups by asking, 鈥淚s the mean (average) different? That鈥檚 what everybody does,鈥� Williams explained.
鈥淏ut in this case, the mean鈥檚 not different, but people who are at increased risk of disease are more likely to be farther away from that mean value.鈥�
There appears to be a normal, acceptable range for allele-specific expression of APC, Williams said, and 鈥渢he farther you get away from that range, the worse off you are.鈥�
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 鈥渢here鈥檚 a continuum of APC allele-specific expression, with familial cases of colorectal cancer at the extremes and sporadic cases somewhere between extreme and normal,鈥� 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 鈥� rather than in an average value 鈥� between cases and controls could play a role in other disease processes.
鈥淣o one鈥檚 ever looked at this in a rigorous way,鈥� he said. 鈥淸rquote]I think our approach has the potential to change how we view disease risk, not only in colon cancer but perhaps other diseases.鈥漑/rquote]
Next up for the investigators is a search for genetic associations that cause the change in allele-specific expression of APC.
鈥淚f we know what鈥檚 causing this difference in expression, we may be able to therapeutically intervene,鈥� Williams said.