Identification of Lynch Syndrome Among Patients With Colorectal Cancer
Year: 2012
Type: article
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 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 modest.
Source: JAMA
Authors: 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 Andreu, Maurizio Ponz de Leon, Anil K. Rustgi, Antoni Castells
Institutions: Hospital Clínic de Barcelona, Universitat de Barcelona, Mayo Clinic, University of Hawaii System, University of Helsinki, The University of Melbourne, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Fundació de Recerca Clínic Barcelona-Institut d’Investigacions Biomèdiques August Pi i Sunyer, The Ohio State University, University of Hawaiʻi at Mānoa, Fred Hutch Cancer Center, University of Southern California, QIMR Berghofer Medical Research Institute, University of Colorado Denver, Universitat Pompeu Fabra, University of Modena and Reggio Emilia, University of Pennsylvania
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: University of Southern California, University of Pennsylvania, Ohio State University, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, National Institutes of Health, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1229672300, USC Consortium:Colorectal Cancer Family Registry, G1584786142, G2201668368, G2714647962, G3062694220, Seattle Colorectal Cancer Family Registry (CFR), Hawaii Colorectal Cancer Family Registry, Ontario Registry for Studies of Familial Colon Cancer, NATURAL HISTORY AND INCIDENCE OF HEREDITARY COLON CANCER, Familial Colorectal Neoplasia Collaborative Group, G5269726731, G5629724085, G5786682175, G6034862151, INCIDENCE AND MOLECULAR SCREENING FOR HEREDITARY CANCER, G7555119139, G796664094, The LIN28b-Let7-IMP1 axis in colonic epithelial biology, AUSTRALASIAN COLORECTAL CANCER FAMILY REGISTRY, G9000000019, G9000093618, Cancer Center Support Grant, G980164052
OpenAlex ID: W1993051520