Barnetson RA et al. (2006) Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med 354: 2751–2763

The early identification of patients carrying germline mutations in the DNA mismatch-repair genes is vital to the successful management of colorectal cancer, as progression from adenoma to carcinoma occurs rapidly in these individuals. Given the expense of genotyping, a clinically driven method for identifying likely carriers could help optimize the use of resources.

Barnetson et al. present a model that identifies likely mutation carriers among patients newly diagnosed with colorectal cancer. The researchers used a prospective population-based approach to recruit 870 patients in Scotland with early-onset colorectal cancer. Data on several clinical variables were recorded for each patient, and family history was established following enrollment. Germline DNA from each participant was examined for DNA mismatch-repair mutations, and tumor samples were analyzed for microsatellite instability and by immunohistochemistry. A two-stage model was developed from these data using multivariate logistic regression. The first stage involves univariate analysis of clinical variables to identify likely carriers of mismatch-repair mutations. Tumor samples from these individuals are then tested to refine the carrier prediction. The model has a sensitivity of 62%, with an 80% positive predictive value, and has been validated in an independent cohort.

Among the original study participants, 38 mutations were identified. Carrier frequencies were two times higher in men than in women. Survival over 2,938 patient-years of follow-up did not differ between carriers and noncarriers. The authors suggest that this model (available at http://www1.hgu.mrc.ac.uk/Softdata/MMRpredict.php) could facilitate genetic testing decisions in patients with early-onset colorectal cancer.