Molecular pathogenesis of microsatellite instability-high early-stage colorectal adenocarcinoma in India.

Abstract

The prevalence of microsatellite instability (MSI) subtype among all colon cancers in India is about 30 %, approximately two times more than that of western population suggesting different molecular pathogeneses. A NanoString analysis-based Pan cancer differential expression (DE) profile was determined in a primary cohort of early-stage CRC (tumor=10, normal=7), and correlated against MSI status. Using RT-PCR, tumor-specific DE genes were validated in another cohort of MSI-high CRC (n=15). Among the most differentially expressed genes, AXIN2, ETV4, and RNF43 were tumor cell-specific signals, while a set of genes including COL11A1, COMP, INHBA, SPP1, MMP3, TLR2, and others were immune cell-specific signals, that had a differential expression between MSI and MSS groups. When overlapped with The Cancer Genome Atlas (TCGA) studies using the Tumor immune estimation resource tool (TIMER), and protein-protein interaction analysis by STRING.db, these genes were segregated to representative tumor cells and immune cells. On validation, the tumor-specific gene signals were inversely associated with TLR4 expression. The differential expression distribution of AXIN2, ETV4, and RNF43 among tumor and immune cells, suggests more than one pathological subset in the MSI-H subgroup of early-stage CRC in the Indian population.