Colorectal cancer (CRC) is the second leading cause of cancer death among U.S. men and women. Racial
disparities in CRC survival exist, where the CRC mortality rate for African Americans is 40% higher than the
mortality rate for non-Hispanic white Americans. Evidence suggests there may be racial differences in intrinsic
CRC tumor biology. We hypothesize that the molecular profile of CRC tumors is more aggressive on average
for African Americans than white Americans, and that these tumor differences contribute to the racial disparity
in survival. The overarching goal of the project is to define how the CRC survival disparity experienced
by African Americans may be influenced by complex biologic differences in tumor characteristics,
measured by molecular subtypes, driver gene status, and clinicopathologic markers. The research plan
uses molecular epidemiologic and cancer biology approaches to achieve our study aims by leveraging
resources from three established research studies, including CRC tumor tissue data from approximately 420
African American CRC patients and 404 non-Hispanic white CRC patients from the Southern Community
Cohort Study, the Black Women’s Health Study, and The Cancer Genome Atlas (TCGA). To fulfill Aim 1, we
will characterize CRC tumors from white and African American CRC patients for clinicopathologic markers
(anatomic site, stage), microsatellite instability, driver gene status (BRAF, and RAS mutation status), and the
recently-defined CRC consensus molecular subtypes. The proposed project will be the first study to define
CRC consensus molecular subtypes in African Americans. Bioinformatics approaches will identify novel gene-
expression molecular subtypes, measured using RNA-seq, to explore the possibility of detecting molecular
subtypes that are more prevalent among African American tumors and that may be linked to CRC prognosis.
(Aim 2). Lastly, to fulfill Aim 3, associations will be determined between the abovementioned tumor
characteristics and CRC survival, and assessed for differences by race. The scientific impact of the proposed
study will be to determine the biological mechanisms contributing to CRC survival disparities experienced by
African Americans by uncovering the molecular attributes of the tumors themselves. The results of the study
will establish the essential foundation for future interventional studies. Currently, CRC treatment is determined
by a combination of molecular factors including stage and the presence of somatic mutations. Emerging CRC
therapies may be guided by additional tumor factors such as tumor gene-expression or the presence of other
targetable features. The existing limited knowledge of the biologic properties of African American CRCs
reduces the prospect that precision medicine will be effective. The proposed study aims to provide data on
African American CRC tumor molecular profiles to support subtype-specific treatments and precision health
strategies to decrease mortality and reduce racial disparities.
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