Serrated Colorectal Cancer: The Road Less Travelled?

Studies of colorectal cancer (CRC) originating through the conventional adenoma-carcinoma sequence have provided insight into the molecular mechanisms controlling its initiation and progression. Less is known about the alternative 'serrated' pathway, which has been associated with BRAF mutation and microsatellite instability. Recent transcriptomics approaches to classify human CRC revealed that mesenchymal and/or desmoplastic features combined with an immunosuppressive microenvironment are key determinants of CRC with the poorest prognosis. Importantly, these aggressive CRCs harbor the characteristics of serrated tumors, suggesting that initiation through this alternative pathway determines how aggressive the CRC becomes. Here, we review recent evidence on how serrated carcinogenesis contributes to the subtype of CRC with the poorest prognosis.