Skip to main content

Colon Cancer Research

Colorectal (CRC) cancer is the second leading cause of cancer mortality among adult Americans, accounting for 150,000 new cases and 70,000 deaths annually in the United States. The lifetime risk for each American to develop colon cancer is approximately 7%. While the majority of colon and other cancers are sporadic, a significant proportion of cancer is due to inherited susceptibility. It is well established that germline mutations of some of the already known colon cancer susceptibility genes confer a marked risk of early onset colon cancer. We are interested in identifying additional genetic variants that contribute to the risk for developing colon cancer.

Genetics and Colon Cancer: Our Studies

Targeted Exome Profiling for Colorectal Cancer Susceptibility

The genetic underpinning of colorectal cancer susceptibility is used on a clinical basis to identify patients at risk for the disease. For example, genetic testing for highly penetrant colorectal cancer (CRC) syndromes, such as Familial Adenomatous Polyposis (FAP) and Lynch syndrome (LS), are currently based on a combination of family and individual phenotypes that include age of onset, tumor characteristics and family history, prior to initiating genetic testing or other management strategies. While current clinical guidelines for genetic testing can detect rare individuals and kindreds in the population with FAP or LS, this approach does not identify most patients who are at risk for developing CRC. There are several reasons underlying this lack of specificity in genetic testing for CRC, ranging from incomplete testing methods for the gene or genes of interest, inappropriate gene test selection, or the presence of a causative mutation in a gene that is yet to be discovered. In short, the genetic contribution to the patient or family’s cancer could remain undiagnosed after testing, which then severely limits the management options for the patient and family members because the future risks for developing cancer can not be precisely estimated.

Given these impediments, an alternative approach to standard risk assessment and genetic testing for CRC is needed. We envision a new model for cancer risk assessment for CRC based on the individual’s personal genetics pattern of cancer susceptibility alleles. We further hypothesize that a collective genomic risk profile for CRC can be developed from a combination of risk factors, including simultaneous testing of cancer susceptibility alleles plus medical and family history information. Instead of genetic testing after a patient is diagnosed with CRC, genomic profiling would be offered to patients as part of their standard medical care to detect those patients at highest risk of disease and to offer appropriate risk reducing management options. Further, this innovation for cancer risk assessment would cause a shift in the standard genetic testing paradigm, moving “personalized” assessment from the specialist to the primary care clinic.

The project has three specific aims:

  • Specific Aim 1 - Establish the baseline rate of functional exome variants in 22 gastrointestinal cancer susceptibility genes in discovery set of histologically confirmed BioVU CRC cases compared to BioVU controls.
  • Specific Aim 2 - Investigate the correlation between functional exome variants in 22 gastrointestinal cancer susceptibility genes discovery set of histologically confirmed BioVU CRC cases compared to BioVU controls with known CRC risk factors, such as family history, early age at onset, multiple primary tumors, and tumor microsatellite instability.
  • Specific Aim 3 - Replicate significant exome variants identified in SA1 and SA2 in a second set of BioVU cases and controls.

Hereditary Factors in the Development of Colon Cancer

The ultimate goal of this project is to test the prediction that susceptibility to colon polyp formation, and hence the development of colon cancer, is determined by a major susceptibility allele. To do this, we will enroll patients with colon cancer or colon polyps that are likely to have a significant genetic basis. We will obtain medical and family history information, results of past colonoscopies or flexible sigmoidoscopies, blood and tissue for DNA analysis, and the results of flexible sigmoidoscopy for at risk family members.

We will accomplish the overall goals of the study with the following specific aims:

  • To develop a cohort of patients with either colon polyps and or colon cancer and their unaffected and affected family members.
  • To collect whole blood from all subjects for DNA extraction, white blood cell storage, and serum storage.
  • To develop polymorphic markers for candidate gene loci for colon polyp susceptibility.