Genes Linked To Early Onset, Location Of Hereditary Colon Cancer

The study involved people with hereditary nonpolyposis colorectal cancer (HNPCC), the most common form of hereditary cancer.

The results help explain why some people with the same HNPCC-related genetic mutation develop colorectal tumors at age 30 while others develop tumors at age 60. They also help explain why tumors in some patients develop in the distal area of the large intestine (that is, regions closer to the rectum) rather than in regions closer to the large intestine’s junction with the small intestine, which is more typical.

The genes identified by the researchers are all involved in the detoxification of cancer-causing chemicals in cells.

“Our findings suggest that even in individuals with a strong genetic predisposition to colorectal cancer, exposure tocarcinogens and an individual’s genetic capacity to detoxify them may play a role in the development of tumors,” said Paivi Peltomaki, associate professor in the Human Cancer Genetics Program at Ohio State’s Comprehensive Cancer Center.

It also implies that measures found to help prevent colon cancer may also help delay onset in people genetically predisposed to the disease. These measures include eating a diet high in fruits, vegetables, and whole grains; avoiding foods that are high in fat and low in fiber; and getting at least 30 minutes of physical activity on most days.

The study, led by Peltomaki and involving a team of researchers, appeared in the December issue of the journal Gastroenterology. It involved 76 individuals in Finland with HNPCC who had colorectal tumors. These individuals all had the HNPCC-related mutation in the MLH1 gene. The MLH1 gene is one of five genes linked to HNPCC.

The average age of cancer diagnosis in the group was about 42 years. When looked at individually, however, the age at diagnosis ranged from 26 years to 55 years. The average age of onset for colorectal cancer generally is 70 to 75 years.

Also in the group, proximal tumors (those located closer to the small intestine) were twice as common as distal tumors (those occurring closer to the rectum). This 2-to-1 ratio of proximal to distal tumors is typical of HNPCC, but why most people develop proximal tumors and some develop distal tumors has been unknown.

To explore why this variation in age of onset and tumor location exists, the researchers looked at three genes that produce enzymes for detoxifying cancer-causing, or carcinogenic, chemicals. These were the gene for N-acetyltransferase 1 (NAT1), and two forms of the glutathione S-transferase (GST) gene known as M1 and T1 (GSTM1 and GSTT1 respectively). Specifically, the researchers looked for the presence or absence of GSTM1 and GSTT1.

NAT1 is responsible for processing highly carcinogenic aromatic amines found frequently in the environment, in the diet and in cigarette smoke. The GST enzymes detoxify a variety of carcinogens and toxic drugs.

The researchers found that patients with one form of the NAT1 gene, known as NAT1-10, and who were missing the GSTM1 and GSTT1 genes, tended to develop colorectal tumors at a younger age.

When the researchers looked at tumor location, they found that nearly half of patients with the NAT1-10 gene had distal tumors, which is significantly higher than the typical population of people with HNPCC.

People who had the GSTT1 gene also tended to have more tumors located in the distal colon than usual. There was no correlation between tumor location and the presence or absence of the GSTM1 gene.

Overall, said Peltomaki, “the presence of the NAT1-10 gene in individuals was associated with earlier tumor development and with distal location of the tumor.”

Peltomaki and her colleagues are working to verify their findings in a larger group of people with HNPCC, and they are looking for other genes that might also be influence age of onset and tumor location.

HNPCC is also associated with an increased risk of cancers of the uterus, stomach, small intestine, pancreas, kidney, and uterus. The researchers also hope to learn why some people develop these “extracolonic” tumors and others don’t.