Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer

Loughrey, Maurice B.; Waring, Paul; Tan, Angela; Trivett, Melanie; Коваленко, С. Г.; Beshay, Victoria; Young, Mary; McArthur, Grant A.; Boussioutas, Alex; Dobrovic, Alexander

doi:10.1007/s10689-007-9124-1

Cited by 149 publications

(109 citation statements)

References 43 publications

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“…Therefore, the proposed use of BRAF analysis to exclude LS, which is based on results from MLH1 and MSH2 mutation carriers, 49,50 may not be applicable in the case of PMS2 mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

et al. 2008

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Background and Aims-Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers.

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Section: Discussionmentioning

confidence: 99%

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

et al. 2008

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“…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%

“…The concomitant existence of BRAF mutations or MLH1 promoter hypermethylation in LS patients has been extensively documented. 10,11,13,16,[18][19][20][21][26][27][28] The clinical usefulness of MLH1 hypermethylation analysis relies, in part, on the low prevalence observed. MLH1 hypermethylation analysis does not only outperform BRAF mutation analysis but it is also more cost-effective, in terms of incremental cost per additional MLH1 mutation carrier detected.…”

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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Identification of Lynch Syndrome Among Patients With Colorectal Cancer

Moreira

Balaguer

Lindor

et al. 2012

JAMA

470

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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Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer

Cited by 149 publications

References 43 publications

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

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

Identification of Lynch Syndrome Among Patients With Colorectal Cancer

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