The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC

Gastroenterology. 2004 Jan;126(1):42-8. doi: 10.1053/j.gastro.2003.10.043.


Background and 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.

MeSH terms

  • Adenoma / genetics*
  • Adolescent
  • Adult
  • Aged
  • Base Pair Mismatch*
  • Case-Control Studies
  • Colonic Neoplasms / genetics*
  • Colonoscopy
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / pathology
  • DNA Repair*
  • Female
  • Follow-Up Studies
  • Heterozygote
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Mutation*