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Medical Meeting Reports

American College of Surgery Clinical Congress

October 10-15, 1999


WHEN TO CONSIDER GENETIC TESTING FOR HEREDITARY COLON CANCER
font=>By Karen Sandrick

Jonathan Terdiman, MD, from the University of California, San Francisco, acknowledged that most colorectal surgeons encounter patients they suspect of having hereditary colon cancer at one time or another. The questions are: which ones have a high likelihood of hereditary non-polyposis colorectal cancer (HNPCC), and how can the surgeon pin down the diagnosis?

Profile of HNPCC

Between 20% and 25% of colorectal cancer occurs in patients with a family history of the disease or with an early age of onset, which suggests a genetic propensity. The most important first step for a surgeon to take with any patient who has a classic HNPCC pedigree is to take a family history. These are patients who developed colorectal cancer at an early age and who have family members with extra-colonic cancers, such as uterine and endometrial cancer. Surgeons do not have a clear path, however, for dealing with patients who have other pedigrees.

Criteria and Guidelines

Oncology researchers and clinicians have been striving to create useful guidelines. The Amsterdam criteria were formulated for research, not for clinical care, in 1991. Surgeons nevertheless apply them in clinical situations. The criteria tell physicians to consider HNPCC when three family members have colon cancer, two generations of the family have colon cancer, and at least one individual was diagnosed with the disease before the age of 50.

These criteria do not, however, work well in a population-based examination for colon cancer because up to 2% of non-hereditary colon cancer patients meet them. The criteria also fail to take into consideration extra-colonic cancers.

A National Cancer Institute workgroup established a set of empirical guidelines for deciding which patients with colorectal cancer tumors should have preliminary tumor testing before undergoing germline testing. These are known as the Bethesda guidelines, and they are based on the observation that HNPCC is particularly vulnerable to nucleotide repeat sequences, or so-called microsatellites, that are scattered throughout the genome. Up to 95% of HNPCC- related tumors have multiple mutations in these microsatellites, which play a role in controlling cell growth and apoptosis. A commercially available assay evaluates tumors for microsatellite instability.

According to the Bethesda criteria, a patient qualifies for microsatellite instability testing if he or she: (1) meets the Amsterdam criteria; (2) has two or more HNPCC-related tumors; (3) has a first-degree relative with HNPCC-related cancer; (4) one of the HNPCC-related cancers in family members was diagnosed before the age of 45; and (5) was diagnosed with colon or endometrial cancer before the age of 45.

Testing Criteria in a High-Risk Population

Dr. Terdiman selected individuals from the UCSF colon cancer registry, assessed tumor microsatellite instability status, and conducted full germline testing in those who had a high number of unstable tumors. He tested a total of 113 unrelated patients. Only 20% of these individuals met the Amsterdam criteria, and 66% met Bethesda guidelines. Out of 47 patients with microsatellite unstable tumors, Dr. Terdiman was able to conduct germline testing in 33. Fifteen of these patients had clear mutations in the genes associated with HNPCC.

This approach produced a high yield and targeted only those individuals at high risk for the disease, saving other patients the expense of undergoing germline testing at the outset. Dr. Terdiman therefore recommended the following testing algorithm. A patient should be tested if:

  1. Three or four members have colon cancer or some other HNPCC-related cancer, especially endometrial cancer, at any age.
  2. Two or more family members have colon cancer or some other HNPCC-related cancer and one was diagnosed with cancer before the age of 50.
  3. The patient was diagnosed with colon cancer or some other HNPCC-related cancer before the age of 45.
  4. One member of the family has multiple colon or endometrial cancers regardless of age.

Dr. Terdiman advised surgeons to conduct microsatellite instability testing as the first step in screening such a patient. If this testing does not find an unstable tumor, further investigation should stop. He advocated germline testing if a tumor is not available for the microsatellite instability assay or if the family pedigree is overwhelming.

For professional correspondence, contact Dr. Terdiman at jterd@itsa.ucsf.edu.

Ortho Biotech

Funded through an unrestricted educational grant by Ortho Biotech.



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