Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum

Jass JR, Iino H, Ruszkiewicz A, Painter D, Solomon MJ, Koorey DJ, Cohn D, Furlong KL, Walsh MD, Palazzo J, Edmonston TB, Fishel R, Young J, Leggett BA (2000) Neoplastic progression occurs through mutator pathways in hyperplastic polyposis of the colorectum. Gut 47:43-49

AIM: Colorectal cancer has been described in association with hyperplastic polyposis but the mechanism underlying this observation is unknown. The aim of this study was to characterise foci of dysplasia developing in the polyps of subjects with hyperplastic polyposis on the basis of DNA microsatellite status and expression of the DNA mismatch repair proteins hMLH1, hMSH2, and hMSH6. MATERIALS AND METHODS: The material was derived from four patients with hyperplastic polyposis and between one and six synchronous colorectal cancers. Normal (four), hyperplastic (13), dysplastic (13), and malignant (11) samples were microdissected and a PCR based approach was used to identify mutations at 10 microsatellite loci, TGFbetaIIR, IGF2R, BAX, MSH3, and MSH6. Microsatellite instability-high (MSI-H) was diagnosed when 40% or more of the microsatellite loci showed mutational bandshifts. Serial sections were stained for hMLH1, hMSH2, and hMSH6. RESULTS: DNA microsatellite instability was found in 1/13 (8%) hyperplastic samples, in 7/13 (54%) dysplastic foci, and in 8/11 (73%) cancers. None of the MSI-low (MSI-L) samples (one hyperplastic, three dysplastic, two cancers) showed loss of hMLH1 expression. All four MSI-H dysplastic foci and six MSI-H cancers showed loss of hMLH1 expression. Loss of hMLH1 in MSI-H but not in MSI-L lesions showing dysplasia or cancer was significant (p<0.001, fisher's="" exact="" test).="" loss="" of="" hmsh6="" occurred="" in="" one="" msi-h="" cancer="" and="" one="" mss="" focus="" of="" dysplasia="" which="" also="" showed="" loss="" of="" hmlh1="" staining.="" conclusion:="" neoplastic="" changes="" in="" hyperplastic="" polyposis="" may="" occur="" within="" a="" hyperplastic="" polyp.="" neoplasia="" may="" be="" driven="" by="" dna="" instability="" that="" is="" present="" to="" a="" low="" (msi-l)="" or="" high="" (msi-h)="" degree.="" msi-h="" but="" not="" msi-l="" dysplastic="" foci="" are="" associated="" with="" loss="" of="" hmlh1="" expression.="" at="" least="" two="" mutator="" pathways="" drive="" neoplasia="" in="" hyperplastic="" polyposis.="" the="" role="" of="" the="" hyperplastic="" polyp="" in="" the="" histogenesis="" of="" sporadic="" dna="" microsatellite="" unstable="" colorectal="" cancer="" should="" be="">