Prediction of MLH1 and MSH2 Mutations in Lynch Syndrome

Balmañà, Judith; Stockwell, David H.; Steyerberg, Ewout W.; Stoffel, Elena M.; Deffenbaugh, Amie M.; Reid, Julia; Ward, Benjamin D.; Scholl, Thomas; Hendrickson, Brant C.; Tazelaar, John; Burbidge, Lynn Anne; Syngal, Sapna

doi:10.1001/jama.296.12.1469

Cited by 164 publications

(122 citation statements)

References 32 publications

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“…Because of missing information, 362 probands were excluded. Data from 1,914 probands were available for analysis (9).…”

Section: Methodsmentioning

confidence: 99%

“…Mutation analysis was done using methods previously described (9). Full gene sequencing of MLH1 and MSH2 was done on 898 unrelated probands that submitted blood samples to Myriad Genetics starting in 2000.…”

Section: Methodsmentioning

confidence: 99%

“…demographic data pertaining to ancestry and country of origin have been previously reported (9). Ninety-eight percent of the samples and data provided were by individuals residing in the United States.…”

Section: Methodsmentioning

confidence: 99%

“…Clinicians are challenged by the heterogeneity that exists when assessing the Lynch syndrome phenotype (8). Multiple predictive models have been recently developed to aid in the recognition of mutation carriers (9)(10)(11). However, whether there is a difference in genotype-phenotype expression between carriers of the two most common mismatch repair gene mutations, MLH1 and MSH2, has not been resolved.…”

Section: Introductionmentioning

confidence: 99%

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Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States

Kastrinos

Stoffel

Balmañà

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background and Aims: Lynch syndrome is caused by germ-line mismatch repair gene mutations. We examined the phenotypic differences between MLH1 and MSH2 gene mutation carriers and whether mutation type (point versus large rearrangement) affected phenotypic expression. Methods: This is a cross-sectional prevalence study of 1,914 unrelated probands undergoing clinical genetic testing for MLH1 and MSH2 mutations at a commercial laboratory. Results: Fifteen percent (285 of 1,914) of subjects had pathogenic mutations (112 MLH1, 173 MSH2). MLH1 carriers had a higher prevalence of colorectal cancer (79% versus 69%, P = 0.08) and younger mean age at diagnosis (42.2 versus 44.8 years, P = 0.03) than MSH2 carriers. Forty-one percent of female carriers had endometrial cancer and prevalence was similar in both

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“…Because of missing information, 362 probands were excluded. Data from 1,914 probands were available for analysis (9).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States

Kastrinos

Stoffel

Balmañà

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…In this issue of JAMA, Balmaña and colleagues 16 and Chen and colleagues 17 present 2 new algorithms for predicting the likelihood of carrying a germline mismatch repair gene mutation. In addition, a third algorithm has recently been proposed by Barnetson et al 18 The 3 rules differ in the type of algorithm used to predict carrier status, in the patient populations used to develop and validate the rule, in the genetic testing methods used to identify carriers and evaluate prediction accuracy, and in the mismatch repair genes assessed by the methods.…”

mentioning

confidence: 99%

Predicting and Preventing Hereditary Colorectal Cancer

Ford¹,

Whittemore²

2006

JAMA

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Identification of Lynch Syndrome Among Patients With Colorectal Cancer

Moreira

Balaguer

Lindor

et al. 2012

JAMA

454

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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Prediction of MLH1 and MSH2 Mutations in Lynch Syndrome

Cited by 164 publications

References 32 publications

Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States

Phenotype Comparison of MLH1 and MSH2 Mutation Carriers in a Cohort of 1,914 Individuals Undergoing Clinical Genetic Testing in the United States

Predicting and Preventing Hereditary Colorectal Cancer

Identification of Lynch Syndrome Among Patients With Colorectal Cancer

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