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 States 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 intestines 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
individuals 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
States 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
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
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.