Hyperplastic Polyposis (
HPPS) is a poorly characterized syndrome that increases
colorectal cancer (CRC) risk. We aimed to provide a molecular classification of
HPPS. We obtained 282 tumours from 32 putative
HPPS patients with >or= 10 hyperplastic
polyps (HPs); some patients also had
adenomas and
CRCs. We found no good evidence of
microsatellite instability (MSI) in our samples. The epithelium of HPs was monoclonal. Somatic BRAF mutations occurred in two-thirds of our patients' HPs, and KRAS2 mutations in 10%; both mutations were more common in younger cases. The respective mutation frequencies in a set of 'sporadic' HPs were 18% and 10%. Importantly, the putative
HPPS patients generally fell into two readily defined groups, one set whose
polyps had BRAF mutations, and another set whose
polyps had KRAS2 mutations. The most plausible explanation for this observation is that there exist different forms of inherited predisposition to
HPPS, and that these determine whether
polyps follow a BRAF or KRAS2 pathway. Most
adenomas and
CRCs from our putative
HPPS patients had 'classical' morphology and few of these lesions had BRAF or KRAS2 mutations. These findings suggest that tumourigenesis in
HPPS does not necessarily follow the 'serrated' pathway. Although current definitions of
HPPS are sub-optimal, we suggest that diagnosis could benefit from molecular analysis. Specifically, testing BRAF and KRAS2 mutations, and perhaps MSI, in multiple
polyps could help to distinguish
HPPS from sporadic HPs. We propose a specific model which would have diagnosed five more of our cases as
HPPS compared with the WHO clinical criteria.