Colorectal cancer is the third leading cause of new cancer cases and cancer deaths in the United States. A pronounced disparity exists between African American and Caucasian American patients, with African Americans displaying both increased incidence and mortality rates. Although many factors play a role in this health disparity, several findings also suggest a role for tumor biology and genetics. MLH1, MSH2, MSH6 and PMS2 are proteins expressed by mismatch repair genes that are responsible for repairing nucleotide mispairs and small insertions or deletions caused by the DNA replication machinery. Prior studies have revealed that African Americans display a younger age at presentation, a higher incidence of proximal- located tumors and a higher prevalence of the microsatellite instability-high (MSI-H) tumors, a phenotype commonly observed in Lynch Syndrome patients (hereditary nonpolyposis colorectal cancer) and associated with loss of function of the mismatch repair (MMR) proteins. Based upon these findings, I hypothesize that increased alteration of mismatch repair genes in African American patients may account for the higher incidence of MSI-H tumors and, further, that both the frequency and spectrum of mismatch repair gene alterations may be distinct in African American patients. To evaluate this hypothesis, Brooke Sylvester proposes the following aims: aim 1) to analyze a cohort of colorectal cancer patients to determine if demographic factors correlate with tumor pathology, microsatellite instability status and survival, using immunohistochemistry analysis of tissue microarrays and microsatellite instability testing;aim 2) to compare the mutation spectrum and mutation or promoter hypermethylation frequency of mismatch repair genes in our patient population with those previously reported in other populations, using publicly available datasets;aim 3) to determine whether mismatch repair proteins play a role in the DNA damage-induced apoptotic response, utilizing RNA interference techniques to silence the expression of mismatch repair genes. The overall goal of this proposal is to identify the molecular mechanisms leading to the distinct phenotype observed in African American colorectal cancer patients and how this may affect colorectal cancer progression. If this phenomenon plays a role in the increased incidence and mortality rates of colorectal cancer in African American patients, then this study will be relevant in identifying therapies that will reduce or eliminate the unequal burden of cancer in our society.