<i>MED12</i> is recurrently mutated in Middle Eastern colorectal cancer.

Abstract

Colorectal cancer (CRC) is a common cancer and a leading cause of cancer deaths. Previous studies have identified a number of key steps in the evolution of CRC but our knowledge of driver mutations in CRC remains incomplete. Recognising the potential of studying different human populations to reveal novel insights in disease pathogenesis, we conducted genomic analysis of CRC in Saudi patients. In the discovery phase of the study, we conducted whole genome sequencing of tumour and corresponding germline DNA in 27 patients with CRC. In addition to known driver mutations, we identified three <i>MED12</i> somatic mutations. In the replication phase, we employed a next-generation sequencing approach to capture and sequence <i>MED12</i> and other candidate genes in a larger sample of 400 patients with CRC and confirmed the enrichment for recurrent <i>MED12</i> mutations. In order to gain insight into a plausible biological mechanism for the potential role of <i>MED12</i> mutations in CRC, we studied CRC cell lines that differ substantially in the expression level of <i>MED12</i>, and found the latter to be correlated inversely with transforming growth factor (TGF)-β signalling and directly with apoptosis in response to chemotherapeutic agents. Importantly, these correlations were replicated when <i>MED12</i> expression was experimentally manipulated. Our data expand the recently described role of <i>MED12</i> as a tumour suppressor in other cancers to include CRC, and suggest TGF-β signalling as a potential mediator of this effect.