Informal Seminar - Murali Dharan Bashyam

Abstract: Colorectal cancer, perhaps the best understood of all cancer types, is primarily driven by mutational inactivation of the tumor suppressor adenomatous polyposis coli triggering nuclear translocation and oncogenic activation of b-catenin causing colorectal tumors exhibiting ‘chromosomal instability'. Secondly, promoter hypermethylation induced silencing of MLH1 causes defective mismatch repair leading to tumors exhibiting ‘microsatellite instability'. However, these cardinal findings are based on analysis of late-onset colon cancer, the predominant CRC subtype in the West. CRC in developing nations like India however occurs more frequently in the young and manifests predominately in the rectum. Of interest, early-onset rectal cancer (EORC), unlike overall CRC, is exhibiting a rise in incidence worldwide!

I shall present a gist of our findings from two decades of research on patient derived EORC tumor samples. Firstly, we show reduced occurrence of b-catenin activation and MMR inactivation in addition to the enrichment of Ca2+-NFAT signaling in EORC. Secondly, we reveal frequent mutational inactivation of SWI/SNF subunits, especially ARID2, besides describing how tumor cells hijack cytoplasmic mis-localization of ARID2. Finally, via discovery of gene fusions from transcriptome data sets generated for EORC (and pan cancer), we describe a novel mode of gene activation across cancer types emanating from fusions arising from genes located in orthogonal chromatin compartments.