This application addresses the Program Announcement - Exploratory/Developmental Grants Program for Basic Research in Cancer Health Disparities. PA Number: PAR-09-160. The grant proposal is entitled: 'Identification of Significant Race Associated Colon Cancer Driver Gene Mutations'. The goal of this proposal is to test the hypothesis that patterns of driver gene [CAN gene] mutations differ among colon cancers arising in individuals of different race, reflecting at the molecular level differences in disease epidemiology, lifestyle, and environmental exposures among these groups. CRC is one of the common cancers with significant disparities attributed to racial/ethnic etiologic factors. African Americans have a significantly higher incidence of morbidity and mortality caused by CRC than the Caucasian population. Tumor CAN gene mutation profiles are directly related to cancer progression and clinical behavior in virtually all cancer systems. Our recent identification of the 140 CRC CAN genes and our ability to molecularly stratify CRC patients in terms of racial heritage - as well as using patient self-declared status - places us in a unique position to look at the influence of race on this fundamental aspect of cancer biology. Furthermore we have developed the ability to assess the influence of a patient's ancestry on individual tumor CAN gene mutations.
The aim of this proposal will be to sequence the 140 CAN genes in a matched set of CRCs from African Americans and Caucasians. These patients will be initially stratified by self-declared race. Furthermore, these patients will be reclassified based on each individual's African and European Ancestry Informative Markers. These studies are enabled by a number of different efforts by our group. We have constructed a large, well-annotated, biorepository containing colon cancer tissue specimens from patients treated at a large medical center over the last 20 years. The majority of these specimens are formalin-fixed paraffin embedded tissues [FFPE]. Over the last few years we worked to develop sophisticated approaches to enhance the reliability of DNA extraction from FFPE materials. In tandem with these efforts we developed an infrastructure and knowledge base to support high throughput sequencing such as envisioned in this proposal. This includes the acquisition of a 'Next Generation'sequencer and hiring of faculty members to further extend the depth of expertise in this area at our institution. This proposal has the potential to significantly advance the understanding of the effects of racial/ethnic predisposition in cancers overall and in CRC - the second most common human cancer.

Public Health Relevance

African Americans disproportionately suffer excess morbidity and mortality from most forms of cancer compared to the population at large. The largest differences occur in colon cancer. The results from the research proposed in this application may have broad implications for developing more individualized approaches to managing colon cancer in the African American community as well as the population as a whole.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-OBT-A (50))
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Das, Rina
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Case Western Reserve University
Internal Medicine/Medicine
Schools of Medicine
United States
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Wang, Zhenghe; Li, Li; Guda, Kishore et al. (2016) Adverse Clinical Outcome Associated With Mutations That Typify African American Colorectal Cancers. J Natl Cancer Inst 108:
Guda, Kishore; Veigl, Martina L; Varadan, Vinay et al. (2015) Novel recurrently mutated genes in African American colon cancers. Proc Natl Acad Sci U S A 112:1149-54
Varadan, Vinay; Singh, Salendra; Nosrati, Arman et al. (2015) ENVE: a novel computational framework characterizes copy-number mutational landscapes in colorectal cancers from African American patients. Genome Med 7:69
Adams, Mark D; Veigl, Martina L; Wang, Zhenghe et al. (2012) Global mutational profiling of formalin-fixed human colon cancers from a pathology archive. Mod Pathol 25:1599-608