The hereditary nonpolyposis colorectal cancer syndrome: genetics and clinical implications

Ann Intern Med. 2003 Apr 1;138(7):560-70. doi: 10.7326/0003-4819-138-7-200304010-00012.


Basic studies of DNA replication and repair have provided surprising and pivotal insights into a novel pathway of tumorigenesis. Defects in the DNA mismatch repair process dramatically increase the risk for specific types of cancer because of instability in microsatellite DNA sequences. A germline mutation in either the hMSH2 or hMLH1 mismatch repair gene results in the hereditary nonpolyposis colorectal cancer (HNPCC), or Lynch, syndrome. The lifetime risk for colon cancer is 80% in affected persons, and an aggressive cancer surveillance program is essential not only for these individuals but also for at-risk family members. The diagnosis of HNPCC can be made by fulfillment of the Amsterdam clinical criteria or through genetic testing for germline mutations in hMSH2 or hMLH1. Genetic testing is particularly useful in families with atypical clinical features and also for cancer risk assessment within an established HNPCC kindred. Microsatellite instability (MSI) of DNA is a hallmark feature of HNPCC-associated tumors, and as many as 15% of cases of sporadic colorectal cancer also display MSI. The biological behavior of colorectal tumors with MSI is distinctive; the most intriguing feature is their favorable natural history. The study of HNPCC has provided an example of the powerful interplay between molecular genetics and clinical care.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Base Pair Mismatch*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Repair / genetics*
  • DNA Replication
  • Humans
  • Mutation
  • Risk Factors