Molecular Pathogenesis of Earlystage Colon and Rectal Cancers in India Exploring Population Specific Molecular Signatures and Tumor Microenvironment interactions

Abstract

Colorectal cancer (CRC) is the fifth most common cancer occurring in India. Pathogenesis of Early-stage CRC is categorized into two based on the DNA microsatellite instability (MSI). DNA MSI is caused by a deficiency of one or more DNA-binding proteins that are involved in the DNA Mismatch repair mechanism (MMR). CRC cases that fall under the MSI-high molecular subtype showed better prognosis on surgery and/or chemotherapy. MSI-high is seen in about 15 of CRC cases, while MSI-low pathogenicity is seen in about 85 according to the large studies conducted in the Western population. On the contrary, multiple studies in India, especially in Southern India, have shown that the frequency of MSI-high is 30-70%. Multiple methods of detection such as Immunohistochemistry, Polymerase Chain Reaction (PCR) of certain specific Short Tandem Repeat (STR) regions of DNA followed by Fragment Analysis were employed to identify the DNA mismatch repair deficiency reveal microsatellite instability. The underlying molecular pathogenesis of CRC was previously not studied in the Indian population. Moreover, the major cancer molecular studies done in Western countries have not included very many cases from the Indian population. Primary objective To explore and identify the underlying molecular pathogenesis specific to early-stage CRC in the Indian population that causes a higher prevalence of MSI-high molecular pathogenicity. Secondary objectives 1. To compare the test performance between two methods of detection of MMR in cancer tissues, such as Immunohistochemistry of the DNA MMR proteins and MSI PCR and Fragment analysis. 2. To initiate a large-scale multi-gene expression analysis in DNA MMR-characterized early-stage Indian CRC tissues to explore the molecular pathogenesis to find the extent of molecular ix gene signals that are broadly separated between tumor and normal tissues but showed consistent expression changes in multiple samples. 3. To explore and establish a comparison method(s) to compare and corroborate......