Finding Lynch Syndrome among Patients with Colorectal Cancer:
Routine Tumor Testing Looks Best

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Oncologists generally agree that screening patients with colorectal cancer for Lynch syndrome is a good thing. Patients who turn out to have the hereditary syndrome can inform their first-degree relatives, who in turn can undergo genetic testing. Those who have the characteristic mutations can take preventive measures—frequent colonoscopies, for instance—that are known to be effective. The question is who to screen and how.

Now, a large study suggests that testing tumor samples of all patients with newly diagnosed colorectal cancer—a strategy known as universal tumor testing—is more sensitive and efficient than other strategies that rely on family history and clinical criteria. The study, a pooled analysis involving more than 10,000 patients, was led by Leticia Moreira, MD, of the University of Barcelona, Spain, and published in the Journal of the American Medical Association.1

People with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer, or HNPCC) have germline mutations in one or more mismatch repair (MMR) genes. The mutations cause microsatellite instability (MSI) and put carriers at high risk of colorectal cancer as well as endometrial and other cancers.

Design and Data

To determine which patients with colorectal cancer should undergo germline genetic testing for Lynch syndrome, the researchers compared universal tumor testing with three other approaches: (1) the Bethesda guidelines, which combine family history with clinical and pathologic criteria; (2) the Jerusalem recommendations, which call for testing of all patients with colorectal cancer under age 70; and (3) a “selective strategy,” which identified patients for testing who were age 70 and younger or fulfilled at least one of the criteria in the revised Bethesda guidelines.

Of the 10,206 patients in the analysis, 3.1% were mismatch repair gene mutation carriers. As expected, universal tumor testing was 100% sensitive at identifying patients with Lynch syndrome. The specificity of this approach was 93%.

Next most efficient was the selective strategy, with 95.1% sensitivity and 95.5% specificity, indicating fewer false-positives. The Bethesda guidelines had 87.8% sensitivity and 97.5% specificity, the Jerusalem recommendations, 85.4% sensitivity and 96.7% specificity.

Study Conclusions

These data indicate that “unless a universal screening approach, consisting of tumor [mismatch repair] testing in all patients with colorectal cancer, is performed, a clinically meaningful proportion of [mismatch repair] gene mutation carriers will remain undiagnosed,” the authors wrote.

They also noted that the selective strategy had almost the same diagnostic yield as universal tumor testing. It missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer patients requiring tumor mismatch repair testing and 28.6% fewer patients undergoing germline mutational analysis.

Where resources are limited, the selective strategy could be an alternative to universal tumor testing, the authors said, though “it remains to be demonstrated whether this strategy can be implemented consistently in a clinical setting.” They added that more cost-effectiveness research is needed on all the strategies evaluated in their study. ■

Disclosure: Dr. Moreira reported no potential conflicts of interest.


1. Moreira L, Balaguer F, Lindor N, et al: Identification of Lynch syndrome among patients with colorectal cancer. JAMA 308:1555-1565, 2012