Analysis of SWI/SNF Remodelling Complex Catalytic Subunits mutations and Drug Sensitivity in Colorectal Carcinoma
Session type: Proffered paper sessions
Theme: Diagnosis and therapy
SWI/SNF (SWitch/Sucrose Non-fermentable) chromatin remodelling complexes are ATP-dependent complexes that alter chromatin structure regulating genetic expression and various biological processes within cells. SWI/SNF complex subunits are frequently mutated in a wide range of human cancers (Shain and Pollack, 2013).
The mutational frequencies and relative drug sensitivity of each of the SWI/SNF and non-SWI/SNF mutant colorectal carcinoma cell lines was derived from detailed database search from COSMIC (Catalogue of Somatic Mutations In Cancer) (Forbes et al., 2015).
Detailed database search has revealed that approximately 44% of the colorectal cancer cell lines are associated with SWI/SNF mutations with high co-mutation rates in both catalytic subunits (SMARCA2 & SMARCA4). SWI/SNF (26%) mutant colorectal cancer cell lines are more sensitive to anticancer therapy compared to non-SWI/SNF (16.7%) mutant cell lines. SNF2-N and bromodomain are the 2 most highly mutated domains in both catalytic subunits.
The effect of high co-mutation rates in both catalytic subunits on survival of tumour cells is dependent the functional specificity of SWI/SNF complex and the subsequent impact of its loss in different cell types. Moreover, the increased drug sensitivity of SWI/SNF compared to non-SWI/SNF mutant cell lines, is deduced to be related to the association of SWI/SNF complexes with DNA repair proteins. Inactivating mutations in the remodelling complex would result in the loss of the repair proteins, affecting the efficiency of DNA repair mechanisms making it more sensitive to anticancer therapy. Recent research revealed that SNF2-N and Bromodomain inhibitors are considered as potential therapeutic targets in the treatment SMARCA4-mutant cancer cells due to their critical role maintaining SWI/SNF function (Vangamudi et al., 2015).