Abstract

Colorectal Cancer (CRC) in the West is mainly driven by deregulated Wnt signaling caused by mutational inactivation of the cytoplasmic -catenin degradation complex leading to chromosomal instability (CIN) or Mismatch repair (MMR) inactivation leading to microsatellite instability. India has witnessed a significant rise in CRC incidence during the past 2-3 decades owing probably to rapid urbanization. In contrast to the West however, a significant proportion of CRC patients in India belong to a younger age group (<50 years) with a preponderance of rectal (rather than the colonic) tumors. We earlier performed comprehensive characterization of early onset sporadic rectal cancer (EOSRC) and detected absence of Wnt or MSI in a sizeable proportion of samples and identified Ca 2+ /NFAT signaling as a major driver. We have now executed whole exome sequencing of 27 EOSRC tumor/normal pairs and identified known and novel mutational events, including inactivating mutations in the AT-Rich Interaction Domain 2 (ARID2) not previously characterized in CRC. Functional analysis of shRNA mediated knockdown in CRC cells as well as in nude mice validated the tumor suppressor function of ARID2. We observed ARID2 loss at mRNA (Q-PCR) and protein (IHC on a tissue microarray) levels in rectal cancer samples. Survival analysis from the TCGA CRC dataset revealed poorer survival in patients with ARID2 alterations. Surprisingly, we also identified APC mutations in the absence of Wnt activation indicating a possible non-canonical role. Our study has therefore revealed several unique genetic aberrations that drive EOSRC, a CRC subtype unique to the Indian population.