Abstract 3884: DNA mismatch repair defects, MSI, does not play major role in colon carcinogenesis in young African Americans

Abstract

Back ground: African Americans (AAs) are known to display a higher rate and even earlier age of colorectal cancer (CRC) than in the general population. Genetically, 10-12% microsatellite instability (MSI) cases involved in CRC development. However, if it occurs below the age of 50 it could be suspicious of Lynch syndrome. Aims and methods: We aimed to assess the role of MSI in pathogenesis of sporadic colorectal cancer in young African American. The CRC patients in this study were less than 50 years and referred to Howard University Hospital from 2005 to 2008. The medical records (n=50) as well as the pathology reports were reviewed. The MSI status was assessed in a multiplex PCR targeting 5 markers: BAT25, BAT26, NR21, NR27 and NR24. The PCR products were analysed in an Applied Biosystems Gene Scan 3130 machine. Samples with two or more instable markers were labeled MSI-H, with one instable marker: MSI-L and no stable marker: MSS. The presence or absence of expression of four DNA MMR proteins: MLH1, PMS2, MSH2 and MSH6 were evaluated using immunohistochemistry on a Tissue Microarray (TMA, n=26, duplicate) consisting (stage1: 3; stage 2: 6; stage3: 5; stage4: 4).TMA IHC staining were read by two different pathologists who were not aware of the patient clinical status and were scored thus in an objective manner. Two patients were MSI-L and one MSI-H. The response to 5-FU based therapy was reported. Results: Twenty six patients [age, median: 44.5; age range: 26-49; male, 17 (65.4%)] were enrolled in the study. Seven out of 13 available data had family history of CRC. Fourteen CRC cases were left sided. MSI analysis revealed that out of 24 patients: one was MSI-H and two were MIS-L and the rest were MSS. The MSI high patient and one of the MSI low had family history of CRC. MLH1, PMS2, MSH2 and MSH6 were not expressed in 7 (26.9%), 1 (3.8%), 0 (0%) and 5 (19.2%) of tumors, respectively. IHC confirmed the MSI-H tumor. There was a recurrence with lung and brain metastases at 72 months in one of the MSI-L patients following adjuvant chemotherapy with 5 Fluorouracil and Leucovorin. Discussion: Our results show that MSI is not a major pathway in tumorgenesis of sporadic CRCs in young AAs and we may need to study chromosomal instability or CpG Island methylator phenotype as alternative pathways which occur in African Americans and make them present the disease at younger age and advanced stage. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3884. doi:10.1158/1538-7445.AM2011-3884