Identification of Lynch syndrome among patients with colorectal cancer

Leticia Moreira, Francesc Balaguer, Noralane Lindor, Albert De La Chapelle, Heather Hampel, Lauri A. Aaltonen, John L. Hopper, Loic Le Marchand, Steven Gallinger, Polly A. Newcomb, Robert Haile, Stephen N. Thibodeau, Shanaka Gunawardena, Mark A. Jenkins, Daniel D. Buchanan, John D. Potter, John A. Baron, Dennis J. Ahnen, Victor Moreno, Montserrat AndreuMaurizio Ponz De Leon, Anil K. Rustgi, Antoni Castells

Research output: Contribution to journalArticlepeer-review

301 Scopus citations

Abstract

Context: Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patientswith MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear. Objective: To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands. Design, Setting, and Patients: Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n=10 206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data. Main Outcome Measures: Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening). Results: Of 10 206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n=3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach. Conclusion: Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

Original languageEnglish (US)
Pages (from-to)1555-1565
Number of pages11
JournalJAMA - Journal of the American Medical Association
Volume308
Issue number15
DOIs
StatePublished - Oct 17 2012

ASJC Scopus subject areas

  • Medicine(all)

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