Identification of Lynch Syndrome Among Patients With Colorectal Cancer

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 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.

The current value of determining the mismatch repair status of colorectal cancer: A rationale for routine testing

“…ing had been driven by the use of clinical guidelines based on age and family history, such as the Amsterdam (Vasen et al, 1991;Vasen et al, 1999) and Bethesda criteria (Rodriguez-Bigas et al, 1997;Umar et al, 2004). However, it has been shown that up to 50% of mutation carriers do not fulfill the Amsterdam criteria and 40-45% of families fulfilling Amsterdam criteria do not have MSI on tumor testing (Pino and Chung, 2011;Syngal et al, 2000) The Bethesda guidelines incorporate tumor histopathologic features and while more sensitive, can still miss 12-28% of LS cases (Canard et al, 2012;Hampel et al, 2008;Julie et al, 2008;Moreira et al, 2012b;van Lier et al, 2012). In 2009, the 'Jerusalem criteria' recommended IHC or MSI testing be carried out on all CRC, where the patient is under the age of 70 at diagnosis (Boland and Shike, 2010).…”

“…Despite this, it has long been established the presence of dMMR or MSI in rectal cancer is highly predictive of Lynch syndrome (≤75% cases) (de Rosa et al, 2016;Nilbert et al, 1999). Thus, whenever a dMMR rectal cancer is identified, confirmatory genetic testing should be pursued, either through direct genetic testing of MMR genes (Beamer et al, 2012;Dineen et al, 2015;Moreira et al, 2012a) or as part of a multiplex NGS gene panel (Yurgelun et al, 2015). Even after diagnosis, the optimal management of Lynch patients with rectal cancer remains controversial.…”

Economic evaluation of genetic screening for Lynch syndrome in Germany

“…2 Performance of clinical criteria was taken from a recent international study. 27 The family mutation test in relatives was assumed to have 100% sensitivity and specificity. 14 Disease epidemiology.…”

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…Clinical presentation, histopathologic features, genetic susceptibility, and recommendations for surveillance Registry data from Denmark, Finland, Italy, Australia, and from the Epicolon study suggest that 21-73% of the families that fulfil the AC1 and/or AC2 represent FCCTX 16,[26][27][28] (Figure 1). Age at onset shows considerable interfamily as well as intrafamily variability with colorectal cancer diagnosed at a higher mean age (mean 57.3 years) in FCCTX than in Lynch syndrome (mean 49.7 years; Figure 1).…”