Genetics of serrated neoplasia in the colorectum
Colorectal cancer (CRC) has provided a paradigm for the study of molecular pathology in solid tumors. The original molecular model of CRC progression was based on the accumulation of specific mutations in APC and TP53, the central importance of the adenoma as precursor lesion, and chromosomal instability (CIN) as the mechanism of tumorigenesis. However, since the model was introduced, it has been altered by a critical mass of evidence resulting from subset analysis. In 1993, the identification of microsatellite instability (MSI) as a mechanism of tumorigenesis, highlighted an alternative pathway of tumour progression. In 1999 came the recognition of both concordant CpG island methylation (CIMP) and serrated neoplasia. Subsequently, CIMP, MSI and serration were found to be the central elements of an alternative parallel pathway of CRC development. Importantly, serrated lesions showed a largely non-overlapping mutation profile to that found in adenomas. Approximately 10-15% of CRC is likely to have as its basis a genetic predisposition. The two most well-characterised syndromes FAP and HNPCC both develop via the adenoma-carcinoma pathway and account for one-third of familial CRC. We have recently described 11 families with advanced serrated polyps and frequent somatic BRAF mutations suggesting serrated pathway involvement. We have called this disorder, which presents in an autosomal dominant pattern of inheritance, Serrated Pathway Syndrome (SPS). Two related conditions display high levels of both BRAF mutation and CIMP and show features associated with a genetic predisposition. Hyperplastic polyposis (HPP) exhibits multiple serrated precursor lesions with a familial pattern suggesting autosomal recessive inheritance. Sporadic CRC with high levels of MSI also develops through the serrated pathway, and its tendency to multiple lesions and association with smoking suggest a gene-environment interaction. A model of serrated neoplasia predisposition will be presented.