A Prospective, Multicenter, Population-Based Study of BRAF Mutational Analysis for Lynch Syndrome Screening

Bessa, Xavier; Ballesté, Belen; Andreu, Montserrat; Castells, Antoni; Bellosillo, Beatríz; Balaguer, Francesc; Castellví–Bel, Sergi; Payá, Artemio; Jover, Rodrigo; Alenda, Cristina; Titó, Llúcia; Martínez-Villacampa, M.; Vilella, Àngels; Xicola, Rosa M.; Pons, Elisenda; Llor, Xavier

doi:10.1016/j.cgh.2007.10.011

Cited by 83 publications

(55 citation statements)

References 31 publications

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“…In agreement with previous reports, the sensitivity of the absence of BRAF mutation is very high in identifying MLH1 mutation carriers 16,18,21,39 (Table 3 and Supplementary Data Table 5). A single false-negative was identified adding to the increasing number of LS tumors harboring a BRAF mutation.…”

Section: Discussionsupporting

confidence: 92%

“…First, the low prevalence of BRAF mutations observed in our selected population (11% of MSI tumors and 20% of those lacking MLH1 protein expression). This is in the lower range of reported series 16,18,21,39 but likely to reflect the experience of referral centers. 21 Second, the significant number of LS cases and MLH1 germline carriers analyzed allows more accurate estimates.…”

Section: Discussionmentioning

confidence: 67%

“…The association of BRAF mutation with MLH1 hypermethylation and the MSI phenotype resulted in its evaluation as a potential prescreening tool in the LS diagnostic algorithm 10,11,13,16,19,20,38 (Table 3 and Supplementary Data Table 5). In agreement with previous reports, the sensitivity of the absence of BRAF mutation is very high in identifying MLH1 mutation carriers 16,18,21,39 (Table 3 and Supplementary Data Table 5).…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12][13][14][15] It has been used to distinguish LS-associated from sporadic MSI-positive tumors. 10,11,[16][17][18][19][20][21] The lack of BRAF mutations identifies with high sensitivity (96-100%) and lower specificity (22-100%) CRC cases associated with LS. 10,11,[16][17][18][19][20][21] Occasionally, BRAF mutations have been detected in LS patients.…”

Section: Introductionmentioning

confidence: 99%

“…10,11,[16][17][18][19][20][21] The lack of BRAF mutations identifies with high sensitivity (96-100%) and lower specificity (22-100%) CRC cases associated with LS. 10,11,[16][17][18][19][20][21] Occasionally, BRAF mutations have been detected in LS patients. 22 Methylation of the MLH1 promoter, leading to a loss of MLH1 expression, is also strongly associated with sporadic MSI-positive CRCs.…”

Section: Introductionmentioning

confidence: 99%

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MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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The analytical algorithm of Lynch syndrome (LS) is increasingly complex. BRAF V600E mutation and MLH1 promoter hypermethylation have been proposed as a screening tool for the identification of LS. The aim of this study was to assess the clinical usefulness and cost-effectiveness of both somatic alterations to improve the yield of the diagnostic algorithm of LS. A total of 122 colorectal tumors from individuals with family history of colorectal cancer that showed microsatellite instability and/or loss of mismatch repair (MMR) protein expression were studied. MMR germline mutations were detected in 57 cases (40 MLH1, 15 MSH2 and 2 MSH6). BRAF V600E mutation was assessed by single-nucleotide primer extension. MLH1 promoter hypermethylation was assessed by methylation-specific multiplex ligation-dependent probe amplification in a subset of 71 cases with loss of MLH1 protein. A decision model was developed to estimate the incremental costs of alternative case-finding methods for detecting MLH1 mutation carriers. One-way sensitivity analysis was performed to assess robustness of estimations. Sensitivity of the absence of BRAF mutations for depiction of LS patients was 96% (23/24) and specificity was 28% (13/47). Specificity of MLH1 promoter hypermethylation for depiction of sporadic tumors was 66% (31/47) and sensitivity of 96% (23/24). The cost per additional mutation detected when using hypermethylation analysis was lower when compared with BRAF study and germinal MLH1 mutation study. Somatic hypermethylation of MLH1 is an accurate and cost-effective pre-screening method in the selection of patients that are candidates for MLH1 germline analysis when LS is suspected and MLH1 protein expression is absent.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MLH1 promoter hypermethylation in the analytical algorithm of Lynch syndrome: a cost-effectiveness study

et al. 2012

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Identification of Lynch Syndrome Among Patients With Colorectal Cancer

Moreira

Balaguer

Lindor

et al. 2012

JAMA

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472

378

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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.

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