Msi Status Frequency, Msi-Target Genes Mutation Profile And Ancestry Proportions In Brazilian Colorectal Carcinoma Patients

Introduction: Colorectal cancer (CRC) is the fourth in incidence and in mortality worldwide for both sexes. There are three pathways in the pathogenesis of CRC: chromosome instability (CIN), microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). These pathways are closely related and some tumors may harbor alterations in multiple pathways. The MSI is the less common and is more frequently related with HNPCC Syndrome. In Brazil, CRC incidence is increasing and the frequency of MSI and its biological and clinical impact are largely unexplored. Furthermore, the literature has reported the influence of ancestry factors on the incidence and prognosis in this tumor type. Goals: to assess the frequency of MSI status in Brazil CRC tumors; to analyze the mutation profile of MSI target genes in MSI-positive tumors and to determine the patients ancestry by molecular markers. Materials and Methods: 1013 CRC patients were enrolled in the study. The MSI evaluation was performed using a multiplex PCR comprising 5 markers (NR27, NR21, NR24, BAT25, and BAT26). The MSI-H tumors were also assessed for mutations in a panel of 25 MSI-target genes, and their genetic ancestry will be evaluated using a panel of 46 AIMs (Ancestry-Informative Markers). Results: MSS status was observed in 86.0%, MSI-L in 4.0% and MSI-H in 10.0% of cases. The analysis of 25 MSI-target genes in 101 MSI-H cases showed distinct mutations frequencies, with the highest mutated genes been ATM (83.0%), EGFR (80.0%) and MRE11 (78.0%) and the lowest mutated genes been BLM (3.0%), WISP3 (2.0%) and TRBP2 (1.0%). No alterations were observed in BRCA1, BRCA2, XRCC2, PTEN and XPO5. We showed that the average ancestry proportions for MSS+MSI-L group were 74.1% of European, 12.3% of African, 6.6% of Native Americans, and 7.0% of East Asian, while for MSI-H group were 73.7% of European, 14.3% of African, 6.8% of Native Americans, and 5.2% of East Asian. So, no statistical difference was observed between distinct MSI status groups. Conclusion: The MSI frequencies identified in Brazilian CRC patients are in agreement with the international literature. We identify altered MSI-target genes in MSI-H tumors samples with potential clinical impact. For while, the ancestry proportions not showed an important factor for MSI status in Brazilian CRC patients. Citation Format: Gustavo N. Berardinelli, Cristovam Scapulatempo-Neto, Ronilson Duraes, Denise Peixoto-Guimaraes, Armando Melani, Rui Pereira, Rui Reis. MSI status frequency, MSI-target genes mutation profile and ancestry proportions in Brazilian colorectal carcinoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3847. doi:10.1158/1538-7445.AM2015-3847