Our long-term objective is to elucidate the etiologic factors contributing to disparate colon cancer (CRC) outcomes in African Americans (AA), who continue to exhibit the highest CRC incidence and mortality rates in the U.S, even after accounting for socioeconomic and access to care factors. We recently reported the first comprehensive molecular characterization of AA CRCs, identifying a 15 gene-set as preferentially mutated in AA as compared to Caucasian CRCs. On a broader scale, it is likely that these ethnicity-associated differences in CRC mutational landscapes may have potential to impact on broader disparities in cancer behaviors. In particular, our study identified the, accounting for ~6% of AA vs. 0% of Caucasians CRC cases. EPHA6 belongs to a broader family of ephrin receptor tyrosine kinases that function as oncogenes or tumor suppressors depending on the cancer type. Intriguingly, our study was the first to implicate EPHA6 in CRCs, with the finding of recurrent mutations in this gene selectively in AA CRCs, suggesting a provocative ethnicity-associated difference in routes of colon carcinogenesis. Accordingly, the specific goals of the current proposal are:
(AIM 1) To characterize EPHA6 signaling and determine the functional consequences of EPHA6 mutations identified in AA CRCs. We will use in-depth phospho-proteomics and gene expression profiling approaches in AA CRC cell lines engineered to express wild-type (WT) or mutant versions of EPHA6 to characterize EPHA6 signaling and to determine the molecular consequences of EPHA6 mutations. Furthermore, we will compare the phenotypic effects of WT vs. mutant EPHA6 on tumor growth characteristics, using in vitro and xenograft models;
(AIM 2) To determine if loss of EPHA6 enhances susceptibility to colon cancer. We will use EPHA6 null mice to determine if loss of EPHA6 induces colon tumorigenesis in chemical carcinogen and Apc Min models of colon cancer. As a complementary approach to Aim 1, we will further dissect and refine EPHA6 signaling pathway, in vivo, using proteomics and gene profiling in EPHA6 WT vs. null mouse colons;
(AIM 3) To determine the generality of EPHA6 mutations, and their association with clinically-relevant histopathological features. The AA CRC cases used in our initial study were derived exclusively from Northeast Ohio. Given the history of differing patterns of mass internal migration of AAs within U.S, we will re-sequence EPHA6 in AA CRC cases from Southwestern Texas, to test if EPHA6 is common CRC mutational target in geographically distinct AA populations. Furthermore, given that all of the EPHA6-mutant CRCs identified in our initial study arose in proximal colon, we will re-sequence EPHA6 in a fresh set of AA CRCs from Northeast Ohio to determine if EPHA6-mutant CRC cases define a distinct, morphologically recognizable, subset of CRCs. Success in these studies will uncover new mechanisms underlying colon tumorigenesis and may identify new therapeutic targets for CRC, in addition to having broad epidemiological implications in elucidating the etiologic factors potentially contributing to aggressive colon cancer phenotypes in African Americans.
African Americans are more likely to be diagnosed with and to die as a result of colon cancer than any other ethnic group in the United States. Identifying the mechanisms involved in colon tumor progression in African Americans is therefore critical for elucidating the etiologic factors contributing to outcome disparities in African Americans. Our proposed studies are designed to delineate the molecular mechanisms associated with colon cancer progression in African Americans with an overarching goal of guiding clinical management for this deadly disease in this population.
| Evans, Daniel R; Venkitachalam, Srividya; Revoredo, Leslie et al. (2018) Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer. Hum Mutat 39:1092-1101 |
| Venkitachalam, Srividya; Guda, Kishore (2017) Altered glycosyltransferases in colorectal cancer. Expert Rev Gastroenterol Hepatol 11:5-7 |
| Blum, Andrew E; Venkitachalam, Srividya; Guo, Yan et al. (2016) RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas. Cancer Res 76:5628-5633 |
| 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: |
