Gastroenterology

Gastroenterology

Volume 126, Issue 1, January 2004, Pages 42-48
Gastroenterology

Clinical-alimentary tract
The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC

https://doi.org/10.1053/j.gastro.2003.10.043Get rights and content

Abstract

Background & Aims: The adenoma-carcinoma sequence in hereditary nonpolyposis colorectal cancer (HNPCC) is accelerated. It remains unknown whether the mismatch repair (MMR) defect also promotes the development of adenomas. The aim of this study was to compare the risk of developing colorectal adenoma and carcinoma in HNPCC carriers and noncarriers (controls) and to compare the features of adenomas in both groups. Methods: Eighty-six families with a known MMR gene mutation from the Dutch HNPCC Registry were analyzed. Subjects with known mutation status with colonoscopies performed for the purpose of surveillance were selected for this study. Information on the surveillance examinations was obtained from medical reports. The histology of all adenomas was confirmed. Immunohistochemistry was performed in a subgroup of adenomas. Results: We identified 249 carriers and 247 controls. The proportion of subjects free of an adenoma at the age of 60 years was 29.7% for carriers and 70.8% for controls (P < 0.05). The adenomas in carriers were larger, and a higher proportion had villous components and/or high-grade dysplasia (P < 0.05, all analyses). The adenomas and carcinomas of the carriers were located predominantly in the proximal colon. Most adenomas showed absent staining of the MMR proteins. Conclusions: This study indicates that the MMR defect is involved in the early stages of development of adenomas. We recommend immunohistochemical staining of large adenomas with high-grade dysplasia in young patients (younger than 50 years) to identify patients with suspected HNPCC.

Section snippets

Patients and methods

In 1987, a registry of families with HNPCC was established in The Netherlands at The Netherlands Foundation for the Detection of Hereditary Tumors. The regulations of the registry have been described elsewhere.15 When an HNPCC family was registered, all members of that family were informed about the risk of developing colorectal cancer and were advised to participate in the surveillance program. Nowadays, counseling, mutation diagnostics, and presymptomatic testing occur in clinical genetic

Results

In the 86 families with a known MMR gene mutation, we identified 247 noncarriers and 249 carriers. The noncarriers constituted the control group. The characteristics of both groups are shown in Table 1. There were significantly more men in the control group, and the mean age at first colonoscopy was significant younger in the carriers. Moreover, the follow-up time (since first colonoscopy) and screening intervals were significantly different between both groups.

Discussion

The present study provides clinically important information on the development of adenomas in HNPCC. Carriers of an MMR gene defect developed adenomas more frequently than control subjects of the same age. In addition, carriers developed adenomas at a younger age than controls. The adenomas in the carriers were larger, and significantly higher proportions showed high-grade dysplasia and a tubulovillous architecture. In most of the adenomas in the carriers, immunohistochemical analysis showed

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