Henry T. Lynch

Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.

The question, "Is cancer hereditary?" has been answered beyond any doubt through the discovery of germ-line cancer-causing mutations in a subset of colorectal cancers (CRCs). Clearly, this authentication of the role of genetics was not solely dependent on molecular genetic studies, since hereditary cancer syndromes such as familial adenomatous polyposis (FAP) had been known for at least 100 years, but molecular advances are clarifying and refining clinical impressions. Have clinicians acted on the importance of hereditary factors in cancer so that this knowledge might be translated into patient benefit? Data showing that 59% of patients with FAP still die of metastatic CRC suggest that the answer is no.

The meeting was financially supported by the Foundation for the Detection of Hereditary Tumours, the National Cancer Society, and EUROFAP.