NEW YORK (Reuters Health) - Not all families with what appears to be hereditary nonpolyposis colorectal cancer (HNPCC) have the more dangerous type (Lynch syndrome), characterized by microsatellite instability and mismatch repair deficiency (MMR), investigators report in the Journal of the American Medical Association for April 27th. Individuals with what the authors term “familial colorectal cancer type X” require different follow-up than those with HNPCC-Lynch syndrome.
Furthermore, tumors of patients at risk for HNPCC-Lynch syndrome can be screened using immunohistochemical staining for MSH2 or MLH1 protein expression or microsatellite instability, “a phenotypic indicator of defective DNA mismatch repair,” thus identifying those for whom further DNA analysis is warranted, a second group of authors reports.
For the first report, Dr. Noralane M. Lindor, at the Mayo Foundation in Rochester, Minnesota, and colleagues identified 3422 members of 161 families with hereditary colorectal cancer. Families were grouped into those with a high degree of MMR deficiency (group A) and those with low or absent MMR deficiency (group B).
Group A, but not group B families, had a greatly increased risk of cancers of the uterus, stomach, urinary tract, ovary and small intestine, which are associated with HNPCC.
Group B was associated with only an increased risk of colorectal cancer, and even for this cancer, the standardized incidence ratio was lower than that for group A (2.3 versus 6.1, p < 0.001). Age at which colorectal cancer developed was younger in group A than group B (mean age, 48.7 years versus 60.7 years).
Families like those in group B, whose condition Dr. Lindor’s group calls familial colorectal cancer type X, should not automatically be triaged to HNPCC screening algorithms. Instead, the researchers recommend that colorectal cancer screening should be initiated 5 to 10 years prior to the age of earliest colorectal cancer diagnosis in these families. Aggressive endometrial cancer screening is probably not necessary.
According to the second paper by Dr. Antoni Castells at Hospital Clinic in Barcelona and his team, optimal selection of individuals for HNPCC genetic testing is controversial.
For their prospective study, they selected 1222 patients in Spain diagnosed with colorectal cancer between 2000 and 2001. Tumor tissue was analyzed using microsatellite instability testing and immunostaining for MSH2 and MLH1 proteins. Tumors with microsatellite instability and/or negative results for MSH2/MLH1 staining underwent germline mutation analysis by multiple ligation probe amplification analysis and sequencing.
A total of 287 patients (23.5%) fulfilled at least one criterion of the revised Bethesda guidelines for HPNCC. Ninety-one patients (7.4%) had MMR deficiency, including 83 with microsatellite instability and 81 with loss of expression of either MSH2 or MLH1.
Germline testing revealed seven MSH2 mutations and four MLH1 mutations.
“Strategies based on either microsatellite instability testing or immunostaining previous selection of patients according to the revised Bethesda guidelines were the most effective (sensitivity, 81.8% and 81.8%; specificity, 98.0% and 98.2%; positive predictive value, 27.3% and 29.0%, respectively) to identify MSH2/MLH1 gene carriers,” the authors write.
Dr. Castells’ team points out that, since both strategies are apparently equivalent and highly cost-effective, protein immunostaining may be preferred since it is more available than microsatellite instability DNA analysis in patients meeting the Bethesda guidelines for HNPCC.
In a related editorial, Dr. Hans F. A. Vasen, at Leiden University Medical Center in the Netherlands, and Dr. C. Richard Boland, at Baylor University Medical Center in Dallas, Texas, note that microsatellite instability testing and immunohistochemical analyses are “being applied on a relatively small scale at this time.”
They therefore advise that these molecular diagnostic tools be made available to all clinicians, and that they become familiar with the Bethesda guidelines so they can select patients for whom the tests should be performed.
Source: JAMA 2005;293:1979-1994,2028-2030. [ Google search on this article ]
MeSH Headings:Colonic Diseases: Colorectal Neoplasms, Hereditary Nonpolyposis: Digestive System Neoplasms: DNA Mutational Analysis: Gastrointestinal Neoplasms: Genetic Techniques: Health Occupations: Intestinal Neoplasms: Medicine: Investigative Techniques: Neoplasms: Neoplasms by Site: Neoplastic Syndromes, Hereditary: Colorectal Neoplasms: Clinical Medicine: Sequence Analysis: Sequence Analysis, DNA: Microsatellite Repeats: Tandem Repeat Sequences: Base Pair Mismatch: Analytical, Diagnostic and Therapeutic Techniques and Equipment: Biological Sciences: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
