Integrated clinicopathological and mutational profiling accumulates histological characteristics of rare and conventional colorectal cancer in Indian patients

Molecular heterogeneity in histological subtypes of Colorectal Cancer (CRC) patients in India is under-researched. Present study employs whole exome sequencing to distinguish mutational landscapes of rare (mucinous adenocarcinoma , signet-ring cell carcinoma ) and conventional adenocarcinoma of 35 surgically resected tumors in 34 patients using GATK pipeline. Variant annotation was performed using ANNOVAR, VEP tools. Histopathologically, 22 patients had conventional, while 12 patients had rare tumors. Tumor mutational burden, microsatellite instability, pathway based TMB, overall survival and clinicopathology were integrated.Hypermutation and microsatellite instability were recorded in 50% of the samples. MSI tumors were enriched with somatic variants. UBR5 and LRP1B were most frequently mutated genes irrespective of histology. Our findings focused on oncogenes, tumor suppressor genes and driver genes reported earlier in Intogen and OncoKB databases. MTOR and NOTCH involved with immune response were less involved in SRCC projecting poor survival. A novel mutation and two pathogenic mutations rs2067914706, rs779025515were evidenced in driver gene RFX5. Alternate WNT pathway activation by RNF43 and AMER1 mutations rather than APC was noted. Poor survival was predicted for CoAD patients with mutated gene sets of DNAH5 and DYNC2H1 (p-value: 0.0116) as well as DNAH5 and CIT (p-value: 0.0150).Although studies have been conducted globally evidenced with sequencing, this study portrays the mutational landscape of histopathologically differentiated tumors in Indian patients. Hypermutation is associated with better overall survival which may be used as additional prognostic marker. Favourable findings from this study are significant to establish efficient therapeutic strategies for different subtypes of CRC.