Abstract

Colorectal Cancer (CRC) is a lifestyle associated disease and a major health problem in the Caucasian population, where it is primarily an aging related cancer with tumors predominantly arising from the colon rather than the rectum. In addition, aberrant constitutive activation of the Wnt signaling cascade causing chromosomal instability (CIN) andmismatch repair (MMR) inactivation leading to microsatellite instability are major drivers of CRC in the West.India has seen a recent rapid rise in CRC incidence during the past 2-3 decades probably owing to rapid urbanization. In contrast to the West however, CRC in India often occurs in younger individuals with tumors localized to the rectum rather than colon. Thus, early-onset rectal cancer (EORC) is the predominant but poorly understood CRC subtype in India. We performed a comprehensive evaluation of more than one thousand sporadic CRC samples from Indian patients that revealed distinct clinico-pathological and biological features. More importantly, a significant proportion of EORC tumors appeared to be devoid of activated Wnt signaling and MMR inactivation. Genome-wide DNA copy number profiling revealed extensive CIN in both Wnt+ and Wnt- tumors. Transcriptome profiling (using microarrays as well as next generation sequencing) revealed a (non-Wnt) gene signature surprisingly harboring genes related to the Ca2+/NFAT pathway enriched specifically in Wnt- EORC. Separately, we performed mutation profiling (using next generation exome sequencing) of Wnt- EORC samples revealing known (APC, KRAS, P53, PIK3CA) and novel frequently mutated genes. Surprisingly, we identified APC mutations in the absence of Wnt activation indicating possible non-canonical role for APC in CRC. Our study has therefore revealed several unique genetic aberrations distinct from the West that drive CRC in India.