In the first study, a team from Frankfurt, Germany, assessed the Bethesda guidelines for detection of microsatellite instability in colorectal cancer patients. They also determined the role of MLH1 promoter methylation in the disease.
Microsatellite instability is a hallmark of mismatch repair deficiency in HNPCC and results from mutations in the mismatch repair genes MLH1 or MSH2, or from gene inactivation associated with DNA methylation.
A total of 125 consecutive colorectal cancer patients were assessed according to the Bethesda guidelines. Tumor specimens were analyzed for microsatellite instability.
Subsequently, patients with microsatellite instability were tested for MLH1 promoter methylation and MLH1 and MSH2 germline mutations.
Microsatellite instability was detected in 17 of 58 patients who fulfilled - and in 5 of 67 patients who did not fulfill - the criteria of the Bethesda guidelines.
In 11 of 17 patients with microsatellite instability who fulfilled the guidelines, an MLH1 (n = 3), MSH2 (n = 7), or combined MLH1 and MSH2 (n = 1) mutation was found.
Among the patients with microsatellite instability who did not fulfill the guidelines, no mutations were observed.
| Bethseda guidelines useful for selecting patients for microsatellite instability testing.
|Annals of Internal Medicine|
MLH1 promoter methylation was observed in 6 of 11 patients with an MLH1 or MSH2 mutation, and 5 of 11 patients without these mutations.
Dr Jochen Raedle, from the Johann Wolfgang Goethe-University, concluded on behalf of the group, "The Bethesda guidelines are useful for selecting patients for microsatellite instability testing.
"MLH1 and MSH2 testing should be recommended in all patients with colorectal cancer and microsatellite instability who fulfill at least one Bethesda criterion.
"MLH1 promoter methylation may accompany, rather than initiate, carcinogenesis in patients with colorectal cancer who have mismatch repair gene defects."
In the second study, researchers from Seattle, Washington, USA, determined the cost-effectiveness of screening for HNPCC in eligible patients with newly diagnosed colorectal cancer, and their siblings and children. They compared this with standard care.
Eligibile subjects underwent tumor testing for microsatellite instability. Those with microsatellite instability were offered genetic testing for HNPCC.
Siblings and children of patients with cancer and the HNPCC mutation were offered genetic testing. Those who were found to carry the mutation received lifelong colorectal cancer screening.
When only the patients with cancer were considered, cost-effectiveness of screening was found to be $42,210 per life-year gained.
When patients with cancer, and their siblings and children were considered together, cost-effectiveness increased to $7556 per life-year gained.
The model was found to be most sensitive to the estimated survival gain from screening siblings and children, the prevalence of HNPCC mutations among patients with newly diagnosed cancer, and to the discount rate.
Dr Scott D. Ramsey concluded on behalf of his colleagues, "Screening patients with newly diagnosed colorectal cancer for HNPCC is cost-effective, especially if the benefits to their immediate relatives are considered."