Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain.
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.
To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.
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.
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).
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
Notes
Cites: Ann Intern Med. 2011 Jul 19;155(2):69-7921768580
Cites: J Mol Diagn. 2011 May;13(3):271-8121497289
Cites: J Med Genet. 2012 Mar;49(3):151-722368298
Cites: N Engl J Med. 2003 Mar 6;348(10):919-3212621137
Cites: Ann Intern Med. 2001 Oct 16;135(8 Pt 1):577-8811601929
Cites: Cancer J. 2011 Nov-Dec;17(6):405-1522157284
Cites: Ann Intern Med. 2003 Apr 1;138(7):560-7012667026
Cites: J Natl Cancer Inst. 2004 Feb 18;96(4):261-814970275