Background & Aims We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1 , MSH2 , and MSH6 based on personal and family history of cancer. ...Methods Data were analyzed from 4539 probands tested for mutations in MLH1 , MSH2 , and MSH6 . A multivariable polytomous logistic regression model (PREMM1,2,6 ) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. Results Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1 , 250 in MSH2 , and 71 in MSH6 ). The PREMM1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals CIs): male sex (1.9; 1.5–2.4), a CRC (4.3; 3.3–5.6), multiple CRCs (13.7; 8.5–22), endometrial cancer (6.1; 4.6–8.2), and extracolonic cancers (3.3; 2.4–4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82–0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83–0.92) for MSH2 , and 0.81 (95% CI, 0.69–0.93) for MSH6 ; in validation, they were 0.88 for the overall cohort (95% CI, 0.86–0.90) and the population-based cases (95% CI, 0.83–0.92). Conclusions We developed the PREMM1,2,6 model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1 , MSH2 , and MSH6 . This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.
CONTEXT Patients with multiple colorectal adenomas may carry germline mutations in the APC or MUTYH genes. OBJECTIVES To determine the prevalence of pathogenic APC and MUTYH mutations in patients ...with multiple colorectal adenomas who had undergone genetic testing and to compare the prevalence and clinical characteristics of APC and MUTYH mutation carriers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study conducted among 8676 individuals who had undergone full gene sequencing and large rearrangement analysis of the APC gene and targeted sequence analysis for the 2 most common MUTYH mutations (Y179C and G396D) between 2004 and 2011. Individuals with either mutation underwent full MUTYH gene sequencing. APC and MUTYH mutation prevalence was evaluated by polyp burden; the clinical characteristics associated with a pathogenic mutation were evaluated using logistic regression analyses. MAIN OUTCOME MEASURE Prevalence of pathogenic mutations in APC and MUTYH genes. RESULTS Colorectal adenomas were reported in 7225 individuals; 1457 with classic polyposis (≥100 adenomas) and 3253 with attenuated polyposis (20-99 adenomas). The prevalence of pathogenic APC and biallelic MUTYH mutations was 95 of 119 (80% 95% CI, 71%-87%) and 2 of 119 (2% 95% CI, 0.2%-6%), respectively, among individuals with 1000 or more adenomas, 756 of 1338 (56% 95% CI, 54%-59%) and 94 of 1338 (7% 95% CI, 6%-8%) among those with 100 to 999 adenomas, 326 of 3253 (10% 95% CI, 9%-11%) and 233 of 3253 (7% 95% CI, 6%-8%) among those with 20 to 99 adenomas, and 50 of 970 (5% 95% CI, 4%-7%) and 37 of 970 (4% 95% CI, 3%-5%) among those with 10 to 19 adenomas. Adenoma count was strongly associated with a pathogenic mutation in multivariable analyses. CONCLUSIONS Among patients with multiple colorectal adenomas, pathogenic APC and MUTYH mutation prevalence varied considerably by adenoma count, including within those with a classic polyposis phenotype. APC mutations predominated in patients with classic polyposis, whereas prevalence of APC and MUTYH mutations was similar in attenuated polyposis. These findings require external validation.
Prediction of MLH1 and MSH2 Mutations in Lynch Syndrome Balmaña, Judith; Stockwell, David H; Steyerberg, Ewout W ...
JAMA : the journal of the American Medical Association,
09/2006, Letnik:
296, Številka:
12
Journal Article
Recenzirano
CONTEXT Lynch syndrome is caused primarily by mutations in the mismatch repair genes MLH1 and MSH2. OBJECTIVES To analyze MLH1/MSH2 mutation prevalence in a large cohort of patients undergoing ...genetic testing and to develop a clinical model to predict the likelihood of finding a mutation in at-risk patients. DESIGN, SETTING, AND PARTICIPANTS Personal and family history were obtained for 1914 unrelated probands who submitted blood samples starting in the year 2000 for full gene sequencing of MLH1/MSH2. Genetic analysis was performed using a combination of sequence analysis and Southern blotting. A multivariable model was developed using logistic regression in an initial cohort of 898 individuals and subsequently prospectively validated in 1016 patients. The complex model that we have named PREMM1,2 (Prediction of Mutations in MLH1 and MSH2) was developed into a Web-based tool that incorporates personal and family history of cancer and adenomas. MAIN OUTCOME MEASURE Deleterious mutations in MLH1/MSH2 genes. RESULTS Overall, 14.5% of the probands (130/898) carried a pathogenic mutation (MLH1, 6.5%; MSH2, 8.0%) in the development cohort and 15.3% (155/1016) in the validation cohort, with 42 (27%) of the latter being large rearrangements. Strong predictors of mutations included proband characteristics (presence of colorectal cancer, especially ≥2 separate diagnoses, or endometrial cancer) and family history (especially the number of first-degree relatives with colorectal or endometrial cancer). Age at diagnosis was particularly important for colorectal cancer. The multivariable model discriminated well at external validation, with an area under the receiver operating characteristic curve of 0.80 (95% confidence interval, 0.76-0.84). CONCLUSIONS Personal and family history characteristics can accurately predict the outcome of genetic testing in a large population at risk of Lynch syndrome. The PREMM1,2 model provides clinicians with an objective, easy-to-use tool to estimate the likelihood of finding mutations in the MLH1/MSH2 genes and may guide the strategy for molecular evaluation.
Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of ...unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that approximately 80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants.
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Background: MYH-associated polyposis is an autosomal recessive syndrome caused by biallelic mutations in the base excision repair gene MYH. Initial reports indicated that a majority ...of European biallelic individuals carried two founder mutations, Y165C and G382D. A common MYH analysis strategy involves evaluation of the two founder mutations (FMs) with subsequent full sequencing only if one of the FMs is identified. This study aimed to determine the sensitivity of full MYH sequencing over the strategy described above in a cohort of individuals that has undergone genetic testing by a commercial laboratory. Methods: A retrospective analysis was performed on 1,522 individuals who had clinical MYH testing ordered either independently or in conjunction with APC gene analysis. All patients underwent MYH analysis for Y165C and G382D. Subsequent full gene sequencing was performed for all patients, except for those biallellic for the two FMs. Demographic, personal, and family cancer histories were collected on the test request form. Results: 86 biallelic individuals were identified, with 47 carrying two FMs, 18 carrying one FM and one mutation identified on sequencing, and 21 carrying biallelic mutations identified only on full sequencing. 21/86 (24.4%) biallelic MYH mutation carriers would have been missed by FM analysis only. The mutation spectrum is distributed among different ethnicities (Table). The majority of individuals met clinical criteria for a polyposis syndrome, with 21 individuals reporting more than 99 adenomas (24.4%) and 50 individuals reporting 20-99 adenomas (58.1%). Conclusions: Analysis of only the two MYH FMs would miss 24% of biallelic individuals in our cohort. Due to the ethnicity distribution of mutations, it is difficult to predict who would be missed by this strategy. Consideration of MYH full sequencing is warranted to achieve highest clinical sensitivity. Table: see text
We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes
MLH1,
MSH2, and
MSH6 based on personal and family history of cancer.
Data were analyzed from ...4539 probands tested for mutations in
MLH1,
MSH2, and
MSH6. A multivariable polytomous logistic regression model (PREMM
1,2,6) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases.
Twelve percent of the original cohort carried pathogenic mutations (204 in
MLH1, 250 in
MSH2, and 71 in
MSH6). The PREMM
1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals CIs): male sex (1.9; 1.5–2.4), a CRC (4.3; 3.3–5.6), multiple CRCs (13.7; 8.5–22), endometrial cancer (6.1; 4.6–8.2), and extracolonic cancers (3.3; 2.4–4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82–0.91) for
MLH1 mutation carriers, 0.87 (95% CI, 0.83–0.92) for
MSH2, and 0.81 (95% CI, 0.69–0.93) for
MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86–0.90) and the population-based cases (95% CI, 0.83–0.92).
We developed the PREMM
1,2,6 model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes
MLH1,
MSH2, and
MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.
We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1, MSH2, and MSH6 based on personal and family history of cancer.
Data were analyzed from ...4539 probands tested for mutations in MLH1, MSH2, and MSH6. A multivariable polytomous logistic regression model (PREMM(1,2,6)) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases.
Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1, 250 in MSH2, and 71 in MSH6). The PREMM(1,2,6) model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals CIs): male sex (1.9; 1.5-2.4), a CRC (4.3; 3.3-5.6), multiple CRCs (13.7; 8.5-22), endometrial cancer (6.1; 4.6-8.2), and extracolonic cancers (3.3; 2.4-4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82-0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83-0.92) for MSH2, and 0.81 (95% CI, 0.69-0.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.86-0.90) and the population-based cases (95% CI, 0.83-0.92).
We developed the PREMM(1,2,6) model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1, MSH2, and MSH6. This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.
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