Colorectal cancer is one of the leading causes of cancer mortality in the
United States today. Although the underlying etiology is still not fully
understood, it is increasingly apparent that genetic susceptibility plays
a prominent role in a subset of these patients. Hereditary non-polyposis
colon cancer (HNPCC) may account for the majority of the inherited forms
of colon cancer, and it is estimated that as many as 1 out of every 200
individuals in the general population may be a carrier. This frequency
makes HNPCC one of the most common inherited genetic disorders in humans.
For a variety of reasons, including small family size and unavailable
medical information, this diagnosis can be difficult to establish.
Therefore, a reliable method is needed to define individuals who are at
greatest risk for development of colon cancer and who would benefit most
from aggressive management. Until recently, a strong family history of
cancer was the only measure available to the clinician to decide which
patients were at great risk. However, two types of molecular genetic
markers have recently been identified that may enhance our ability to
define colon cancer risk for families and individuals. These include the
demonstration of tumor microsatellite instability ("mutator phenotype"),
which is indicative of defective DNA mismatch repair, and the direct
analysis of the genetic susceptibility loci responsible for this
particular phenotype, hMSH2, hMLH1, hPMS1, and hPMS2. Importantly, as a
result of these discoveries, the opportunity now exists to better define
the natural history of this disease and to develop more useful clinical
and molecular tools for the identification and pre-symptomatic diagnosis
of those individuals at high risk for developing cancer. Because of the
multitude of mutations that can occur within these genes, additional data
on implications for phenotype are urgently needed. This data must be
collected on population-based series of cancer patients to avoid the
potential bias in risk that can arise from the study of HNPCC families
ascertained because of their exceptional family history of cancer. Given
a pressing need to address these issues, we have focused our attention on
methods that would help identify those individuals who are most likely to
benefit from genetic testing for heritable cancer risk, and on the
characterization of both somatic and germline alterations within the
genetic susceptibility loci. Our specific aims, therefore, are to: 1)
assess the association of family history with tumor microsatellite
instability; 2) estimate the frequency of germline mutations and define
the spectrum of mutations in the four genetic susceptibility loci among
patients demonstrating tumor microsatellite instability and/or a positive
family history; 3) develop and evaluate a questionnaire that is effective
in identifying patients who are most likely to have a genetic
predisposition for cancer; and 4) determine the frequency of tumor
microsatellite instability in an Alaska Native population.
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