Analyses Of MSI Status Frequency, MSI-Target Genes Mutation Profile, And Association With Genetic Ancestry In A Large Series Of Brazilian Colorectal Cancer Patients

Rui REIS, Barretos Cancer Hospital, Brazil

1 Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, Brazil
2 Pathology Department, Barretos Cancer Hospital, Barretos, Brazil
3 Medical Oncology Department, Barretos Cancer Hospital, Barretos, Brazil
4 IPATIMUP –Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
5 Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal

Colorectal cancer (CRC) is the fourth in incidence and in mortality worldwide. Chromosome instability, microsatellite instability (MSI) and CIMP are important in its pathogenesis. MSI is less common and is frequently related with HNPCC Syndrome. In Brazil, the MSI frequency and clinical impact is unexplored. Furthermore, it has been reported that ancestry can influence cancer behavior. In this study we aimed to assess the MSI status frequency in series of 1018 CRC, to analyze the a panel of 25 MSI target-genes, and to determine the molecular ancestry. The MSI evaluation was performed using 5 mononucleotide markers. The MSI-positive tumors were assessed for 25 MSI target-genes by fragment analyses, which were further analyzed for MLH1 promoter methylation and BRAF V600 mutation status. The molecular ancestry was evaluated using 46 ancestry-informative markers (AIMs). We observed that 10.5% (107/1018) of cases exhibited a MSI-H phenotype. The study of MSI target-genes in these 107 cases showed distinct mutations frequencies, with the highest mutated genes been ATM, EGFR, and HSP110 and the lowest ones BLM, WISP3 and TRBP2. In the MSI-H with loss MLH1 expression cases, the frequency of MLH1 promoter methylation was 72% and the frequency of BRAF V600 mutation was 43%. We showed that the ancestry average for all cases was 74% for European component, 12% for African, 7% for Native Americans and 7% for East Asian, and no statistical difference was observed between MSS, MSI-L and MSI-H groups. Concluding, we showed that MSI frequencies in Brazilian CRC are in agreement with literature. We identify altered MSI target-genes with potential clinical impact. Methylation was main cause of MLH1 alteration and almost half of MSI-H with MLH1 negative cases were BRAF V600 mutated. Finally, the MSI status in Brazilian CRC is not associated with the distinct ancestry background of patients