(ChemotherapyAdvisor) – Universal testing of tumors for germline mutations in DNA mismatch repair (MMR) genes among colorectal cancer (CRC) probands had a greater sensitivity for identification of Lynch syndrome when compared with alternative strategies, “although the increase in the diagnostic yield was modest,” investigators reported in the October 17 issue of JAMA.
“Identification of patients with Lynch syndrome needs to be improved because, unless there is strong clinical suspicion, the majority of cases remain undetected, leading to the lack of implementation of highly effective preventive measures,” noted Leticia Moreira, MD, of the University of Barcelona, Spain, and colleagues. “Indeed, intensive CRC screening by colonoscopy and prophylactic gynecological surgery have been demonstrated to reduce both the incidence and mortality of these tumors.”
Although tumor MMR testing is the cornerstone for identification of Lynch syndrome, which patients with CRC should undergo analyses “is still under debate,” they added.
To determine if a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers could be identified, the investigators analyzed personal and family characteristics and other tumor and genetic factors using pooled data from four large groups of newly diagnosed CRC probands recruited between 1994 and 2010 from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki.
Of 10,206 unrelated CRC probands, 312 (3.1%) were found to be carriers of the MMR gene mutation. The researchers found that universal tumor testing (sensitivity, 100%; specificity, 93.0%; diagnostic yield, 2.2%) was superior to the selective strategy (sensitivity, 95.1%; specificity, 95.5%; diagnostic yield, 2.1%), Bethesda guidelines (sensitivity, 87.8%; specificity, 97.5%; diagnostic yield, 2.0%), and Jerusalem recommendations (sensitivity, 85.4%; specificity, 96.7%; diagnostic yield, 1.9%).
These results show “ that unless a universal screening approach consisting of tumor MMR testing in all CRC patients is performed, a clinically meaningful proportion of MMR gene mutation carriers will remain undiagnosed,” the authors wrote. “Specifically, use of the revised Bethesda guidelines will miss approximately 12%, use of the Jerusalem recommendations will miss approximately 15%, and use of a selective criteria will miss approximately 5%.
“…the more patients who are diagnosed, the more at-risk relatives can undergo genetic evaluation and receive appropriate cancer surveillance and other preventive interventions,” they concluded.
An accompanying editorial noted “the potential for individualized preventive medicine provides the rationale for screening for Lynch syndrome,” given “the same considerations that govern screening for CRC in the general population” can be applied. These include that the condition should be common enough to justify screening and allow for effective intervention, with benefits outweighing risks, and that costs of screening “and its consequences are acceptable.”