Genes Linked to Early Onset, Distal Location of Hereditary Colon Cancer

Researchers have identified a mechanism that may explain where colorectal tumors arise and at what age the tumors develop in people with hereditary nonpolyposis colorectal cancer (HNPCC). The results of the study, conducted at Ohio State’s Comprehensive Cancer Center, help clarify why some people with the same HNPCC-related genetic mutation develop colorectal tumors at 30 years of age 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 rather than in regions closer to the large intestine’s junction with the small intestine, which is more typical.

Genetic Capacity to Detoxify Carcinogens

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 to carcinogens and an individual’s genetic capacity to detoxify them, may play a role in the development of tumors,” said Paivi Peltomaki, MD, PhD, associate professor in the Human Cancer Genetics Program at Ohio State’s Comprehensive Cancer Center and leader of the study.

The findings also imply that measures found to help prevent colon cancer may help delay its 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 appeared in the December 1999 issue of 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, one of five genes linked to HNPCC.

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

Proximal tumors in the group were twice as common as distal tumors. This 2:1 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.

NAT1, GSTM1, and GSTT1

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

The NAT1 gene is responsible for processing highly carcinogenic aromatic amines frequently found 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-l0, who were missing the GSTM1 and GSTT1 genes tended to develop colorectal tumors at a younger age. When they 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 with HNPCC.

People who had the GSTT1 gene also tended to have more tumors located in the distal colon than is usual. There was no correlation between tumor location and the presence or absence of the GSTM1 gene. Overall, said Dr. Peltomaki, “the presence of the NAT1-10 gene in individuals was associated with earlier tumor development and with distal location of the tumor.”

Larger Study Planned

Dr. Peltomaki and her colleagues are working to verify their findings in a larger study, and they are looking for other genes that might also influence age of onset and tumor location. Hereditary nonpolyposis colorectal cancer is also associated with an increased risk of cancer of the uterus, stomach, small intestine, pancreas, and kidney. The researchers also hope to learn why some people develop these “extracolonic” tumors and others do not.