Abstract 28: Molecular analysis of colorectal cancer progression in an ethnically diverse cohort reveals a higher prevalence of KRAS mutations in African Americans

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Purpose: African American (AA) colorectal cancer (CRC) patients are more likely to present at a younger age, with proximally located tumors, at advanced stages, and with higher incidence and mortality rates when compared to other ethnicities. To determine if differences exist in the molecular pathogenesis of CRC progression between AAs and Caucasians (CAs), we characterized the tumors of CRC patients within an ethnically diverse cohort at a single institution. Patients and Methods: We examined a retrospective cohort of 428 patients diagnosed with CRC at The University of Chicago Medical Center between 1992 and 2002. Tissue sections from 952 lesions were constructed into tissue microarrays and immunostained with antibodies against MLH1, MSH2, MSH6, PMS2, EGFR, IGFR, MGMT, p53, Bcl-2, and Bcl-X. DNA was extracted from matched normal and tumor tissue sections. Microsatellite instability (MSI) analysis was conducted using the following microsatellite markers: BAT25, BAT26, BAT40, D5S346, and BAX. MSI status was categorized as microsatellite stable (MSS) if all markers were stable, microsatellite instability-low (MSI-L) if <30% of markers were unstable, and microsatellite instability-high (MSI-H) if ≥30% of markers were unstable. For BRAF and KRAS recurring mutation analysis, primers were designed targeting the regions surrounding KRAS codons 12 and 13 and BRAF codon 600. The presence of a mutation was assessed by direct sequencing. The molecular findings from the tumors were then correlated with clinical and pathological characteristics of the patients. Results: The study cohort was 50% AAs, 45% CAs, and 53% females. Overall, there were no significant differences in the clinical characteristics between AAs and CAs, except AAs were diagnosed at an older mean age (69 v. 66 years; p=0.03). After adjusting for age, grade, and stage, AAs had a 45% increased risk of death compared to CAs (p=0.01), and this increased risk was isolated to patients with MSS tumors (p=0.005). There were no significant differences in mismatch repair protein expression pattern, MSI frequency, and BRAF V600E mutation frequency between AAs and CAs. However, within the subset of MSS cases, AAs had a higher prevalence of proximally located tumors (59% v. 47%; p=0.04), a higher frequency of KRAS codons 12 and 13 mutations (33% v. 20%; p=0.03), and a different spectrum of these mutations (p=0.02) in comparison to CAs. Conclusions: This study demonstrates that dysregulation of the mismatch repair pathway is not responsible for the increased prevalence of proximally located tumors observed in this cohort of AAs. These findings, together with the observed frequency of KRAS mutations may, in part, underlie the poor outcomes observed in AAs. Our data underscores the need for the development of better therapeutics that target the genetic abnormalities driving CRC progression in diverse populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 28.