Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome

Chen, Sining; Wang, Wei Lien; Lee, Joe; Nafa, Khédoudja; Lee, Johanna; Romans, Kathy; Watson, Patrice; Gruber, Stephen B.; Euhus, David M.; Kinzler, Kenneth W.; Jass, Jeremy R.; Gallinger, Steven; Lindor, Noralane M.; Casey, Graham; Ellis, Nathan A.; Giardiello, Francis M.; Offit, Kenneth; Parmigiani, Giovanni

doi:10.1001/jama.296.12.1479

Cited by 337 publications

(249 citation statements)

References 68 publications

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“…MMRpro (previously known as CRCAPRO; ref. 69) was developed by Chen and colleagues (70) and it assumes that all familial aggregation is due to dominantly inherited, highly penetrant mutations in MLH1, MSH2, or MSH6. It predicts the probability of being a mutation carrier, by gene, as well as age-specific CRC (and endometrial cancer) risks for unaffected individuals.…”

Section: Genetic Modelsmentioning

confidence: 99%

“…It predicts the probability of being a mutation carrier, by gene, as well as age-specific CRC (and endometrial cancer) risks for unaffected individuals. This model assumes a mutation carrier frequency of 0.0009 (1 in 1,100) for MLH1, 0.0010 (1 in 1,000) for MSH2, and 0.00036 (1 in 2,800) for MSH6 with penetrance functions based on published estimates (70). There are several limitations of this model: (i) it uses family history of CRC only up to second-degree relatives (Table 1); (ii) it does not incorporate the MMR gene PMS2, which accounts for 15% of MMR gene mutations (71), although this probably has little impact given risk estimates are robust to mutation frequencies in this range; (iii) it does not include any environmental risk factors; and (iv) it does not predict second primary cancer risk for affected individuals.…”

Section: Genetic Modelsmentioning

confidence: 99%

“…To our knowledge, the models of Driver and colleagues (80) and Wei and colleagues (65) have not been validated. For MMRpro (70), some studies (e.g., refs. 81, 82) have evaluated the probability of a mismatch repair gene mutation status, but not CRC risk.…”

Section: Evaluation Of Risk Prediction Modelsmentioning

confidence: 99%

See 2 more Smart Citations

Risk Prediction Models for Colorectal Cancer: A Review

Win

MacInnis

Hopper

et al. 2012

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Risk prediction models are important to identify individuals at high risk of developing the disease who can then be offered individually tailored clinical management, targeted screening and interventions to reduce the burden of disease. They are also useful for research purposes when attempting to identify new risk factors for the disease. In this article, we review the risk prediction models that have been developed for colorectal cancer and appraise their applicability, strengths, and weaknesses. We also discuss the factors to be considered for future development and improvement of models for colorectal cancer risk prediction. We conclude that there is no model that sufficiently covers the known risk factors for colorectal cancer that is suitable for assessment of people from across the full range of risk and that a new comprehensive model is needed. Cancer Epidemiol Biomarkers Prev; 21(3); 398-410. Ó2011 AACR.

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Section: Genetic Modelsmentioning

confidence: 99%

Section: Genetic Modelsmentioning

confidence: 99%

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Risk Prediction Models for Colorectal Cancer: A Review

Win

MacInnis

Hopper

et al. 2012

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Lynch syndrome, a subset of Hereditary Non-Polyposis Colorectal Cancer (HNPCC), is an autosomal dominant cancer susceptibility syndrome characterized by inherited defects in the DNA mismatch repair system (DMMR) (1). Family members with this syndrome have an increased risk of colorectal (CRC), endometrial, ovarian, stomach, kidney, ureter, small intestine and hepatobilliary tract malignancies (2).…”

Section: Introductionmentioning

confidence: 99%

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

Case

Zighelboim

Mutch

et al. 2008

Gynecologic Oncology

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Objectives-We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication.Methods-A detailed history and review of medical records was undertaken to construct a fourgeneration pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation.Results-Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer.Conclusions-We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.

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“…In vitro subunit interaction MLH1 MSH2 MSH6 PMS2 193,194,202,220,223,226,231,234,238,240,241,24,73,115,195,[250][251][252][253][254][255][256][257][258][259][260][261][262][263][264] …”

Section: In Vitro Cellular Localizationmentioning

confidence: 99%

Interpreting the clinical significance of mismatch repair gene sequence variants

Thompson¹

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The clinical classification of inherited nucleotide sequence variants identified in disease-related genes has a direct impact on the clinical management of patients and their families. Lynch syndrome is an autosomal dominant cancer predisposition syndrome caused by germline mutations in the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2). However, ~30% of MMR gene variants identified in suspected Lynch cases are of uncertain clinical significance, which constitutes a challenge for genetic counselling and clinical management of families. In the past there has been no uniform system to tackle these variants, and mainly ad hoc methods have been utilized to determine if they are disease causing. The multifactorial likelihood model approach was initially developed for the evaluation of sequence variants in the BRCA1/2 cancer predisposition genes. It was adapted for MMR gene variants to provide a quantitative measure of risk in the form of probability of pathogenicity. Estimates of prior probability of pathogenicity based on evolutionary sequence conservation and physicochemical characteristics of predicted alterations were combined with variant segregation information and tumour features. Microsatellite instability (MSI) and somatic BRAF V600E tumour data for unselected colorectal cancer probands of known pathogenic variant status were used to derive likelihood ratios (LR) for tumour characteristics using the Colon Cancer Family Registry resource.The LR in favour of pathogenicity was estimated to be ~12-fold for a MSI and BRAF V600E mutation-negative colorectal tumour. Our findings provide a working multifactorial likelihood model for classifications that carefully considers mode of ascertainment for gene testing.

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Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome

Cited by 337 publications

References 68 publications

Risk Prediction Models for Colorectal Cancer: A Review

Risk Prediction Models for Colorectal Cancer: A Review

Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair

Interpreting the clinical significance of mismatch repair gene sequence variants

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