Identification of Lynch syndrome among patients with colorectal cancer

Moreira L, Balaguer F, Lindor N, de la Chapelle A, Hampel H, Aaltonen LA, Hopper JL, Le Marchand L, Gallinger S, Newcomb PA, Haile R, Thibodeau SN, Gunawardena S, Jenkins MA, Buchanan DD, Potter JD, Baron JA, Ahnen DJ, Moreno V, Andreu M, Ponz de Leon M, Rustgi AK, Castells A, Consortium E (2012) Identification of Lynch syndrome among patients with colorectal cancer. JAMA : the journal of the American Medical Association 308:1555-1565

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 patients with 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: 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="">