The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important its management.
Dr Rebecca Barnetson and colleagues recruited without preselection, and regardless of family history, 870 patients under the age of 55 years.
The patients were recruited soon after they received a diagnosis of colorectal cancer.
The investigative team studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6.
A 2-stage model was developed by multivariate logistic regression for the prediction of the presence of mutations in these genes.
Stage 1 of the model incorporated only clinical variables.
The team reported that stage 2 comprised analysis of the tumor by immunohistochemical staining, and tests for microsatellite instability.
The model was validated in an independent population of patients.
The investigators analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.
|Adding immunohistochemical analysis in the model had a positive predictive value of 80%|
|New England Journal of Medicine|
The team found 38 mutations in the participants.
Of these mutations, 15 were in MLH1, 16 in MSH2, and 7 in MSH6.
The investigators found that carrier frequencies in men and women differed significantly.
The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62%, and a positive predictive value of 80%.
There were 35 mutations in the validation series of 155 patients.
The team noted that 19 of these mutations were in MLH1, 13 in MSH2, and 3 in MSH6.
The performance of the model was robust among a wide range of cutoff probabilities.
The investigators also found that it was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer.
Survival among carriers was not significantly different from that among noncarriers.
Dr Barnetson's team commented, “We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes.”
“Survival was similar among carriers and noncarriers.”