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Kastrinos F.,Herbert Irving Comprehensive Cancer Center | Kastrinos F.,Columbia University | Steyerberg E.W.,Erasmus Medical Center | Mercado R.,Dana-Farber Cancer Institute | And 14 more authors.
Gastroenterology | Year: 2011

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; 1.52.4), a CRC (4.3; 3.35.6), multiple CRCs (13.7; 8.522), endometrial cancer (6.1; 4.68.2), and extracolonic cancers (3.3; 2.44.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.820.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.830.92) for MSH2, and 0.81 (95% CI, 0.690.93) for MSH6; in validation, they were 0.88 for the overall cohort (95% CI, 0.860.90) and the population-based cases (95% CI, 0.830.92). 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. © 2011 AGA Institute. Source


Perera S.,University of Toronto | Perera S.,Samuel Lunenfeld Research Institute | Li B.,University of Toronto | Li B.,Samuel Lunenfeld Research Institute | And 4 more authors.
Journal of Molecular Diagnostics | Year: 2010

Germline mutations in mismatch repair genes predispose patients to Lynch Syndrome and the majority of these mutations have been detected in two key genes, MLH1 and MSH2. In particular, about a third of the missense variants identified in MLH1 are of unknown clinical significance. Using the PeakPicker software program, we have conducted a proof-of-principle study to investigate whether missense variants in MLH1 lead to allelic imbalances. Lymphocyte RNA extracted from patients harboring known MLH1 variants was used to quantify the ratio of variant to wild-type transcript, while patient lymphocyte DNA was used to establish baseline allelic expression levels. Our analysis indicated that the missense variants c.350C>T, c.793C>T, and c.1852-1853AA>GC, as well as the truncating variant c.1528C>T were all associated with significantly unbalanced allelic expression. However, the variants c.55A>T and c.2246T>C did not demonstrate an allelic imbalance. These results illustrate a novel and efficient method to investigate the pathogenicity of unclassified genetic variants discovered in mismatch repair genes, as well as genes implicated in other inherited diseases. In addition, the PeakPicker methodology has the potential to be applied in the diagnostic setting , which, in conjunction with results from other assays, will help increase both the accuracy and efficiency of genetic testing of colorectal cancer, as well as other inherited diseases. Copyright © American Society for Investigative Pathology and the Association for Molecular Pathology. Source


Perera S.,University of Toronto | Perera S.,Samuel Lunenfeld Research Institute | Pollett A.,University of Toronto | Gallinger S.,University of Toronto | And 4 more authors.
Journal of Human Genetics | Year: 2010

Mutations in mismatch repair genes lead to Lynch Syndrome, the most common form of inherited colorectal cancer. In this report, we describe a novel complex germline mutation c.[1601-1661+92dup; 1591-1611del] of the mismatch repair gene, MSH2. This mutation, which segregates with the disease phenotype, was discovered in a Lynch syndrome kindred that also shows a history of the Muir-Torre syndrome. Interestingly, several tumors from this family displayed microsatellite instability, a hallmark of Lynch syndrome tumors but no consistent, concomitant loss of MSH2 protein expression. In addition, a subset of tumors showed neither prototypical feature of microsatellite instability nor immunohistochemistry deficiency, highlighting the importance of a detailed molecular analysis of rare genetic alterations. This mutation and the atypical clinical manifestations observed underscore the genetic complexity underlying Lynch syndrome, and the importance of comprehensive molecular screening in the diagnosis and early detection of colorectal and other associated cancers. © 2010 The Japan Society of Human Genetics. All rights reserved. Source


Jang J.-H.,University of Toronto | Cotterchio M.,University of Toronto | Borgida A.,Dr Zane Cohen Digestive Diseases Clinical Research Center | Gallinger S.,Dr Zane Cohen Digestive Diseases Clinical Research Center | Cleary S.P.,Dr Zane Cohen Digestive Diseases Clinical Research Center
Carcinogenesis | Year: 2012

Individual susceptibility to the toxic effects of cigarette smoke may be modified by inherited variability in carcinogen metabolism. The purpose of the present study was to investigate pancreatic cancer risk associated with cigarette smoking and 33 variants within carcinogen metabolism genes and examine whether these variants modify the association between smoking and pancreatic cancer. A population-based study was conducted with 455 pancreatic cancer cases and 893 controls. Epidemiological and smoking data were collected from questionnaires and variants were genotyped by mass spectrometry. Age- and sex-adjusted odds ratio (ASOR) and multivariate-adjusted odds ratio (MVOR) estimates were obtained using multivariate logistic regression, and interactions between each variant and smoking were investigated. Current smoker status [MVOR = 2.29, 95% confidence interval (95% CI): 1.62, 3.22], 10-27 pack-years (MVOR = 1.57, 95% CI: 1.13, 2.18), >27 pack-years (MVOR = 1.77, 95% CI: 1.27, 2.46) and longer durations of smoking (19-32 years: MVOR = 1.46, 95% CI: 1.05, 2.05; >32 years: MVOR = 1.78, 95% CI: 1.30, 2.45) were associated with increased pancreatic cancer risk. CYP1B1-4390-GG (ASOR = 0.36, 95% CI: 0.15, 0.86) and Uridine 5'-diphospho glucuronosyltransferase 1 family, polypeptide A7-622-CT (ASOR = 0.77, 95% CI: 0.60, 0.99) were associated with reduced risk. N-acetyltransferase 1-640-GT/GG (ASOR = 1.75, 95% CI: 1.00, 3.05), GSTM1 (rs737497)-GG (ASOR = 1.41, 95% CI: 1.02, 1.95), GSTM1 gene deletion (ASOR = 4.89, 95% CI: 3.52, 6.79) and glutathione S-transferase theta-1 gene deletion (ASOR = 4.41, 95% CI: 2.67, 7.29) were associated with increased risk. Significant interactions were observed between pack-years and EPHX1-415 (P = 0.04) and smoking status and N-acetyltransferase 2-857 (P = 0.03). Variants of carcinogen metabolism genes are independently associated with pancreatic cancer risk and may modify the risk posed by smoking. © The Author 2012. Published by Oxford University Press. All rights reserved. Source


Jang J.-H.,University of Toronto | Cotterchio M.,Prevention and Cancer Control | Borgida A.,Dr Zane Cohen Digestive Diseases Clinical Research Center | Liu G.,University of Toronto | And 4 more authors.
Molecular Carcinogenesis | Year: 2013

Mitotic regulator genes have been associated with several cancers, however little is known about their possible association with pancreatic cancer. Smoking and family history are the strongest risk factors for this highly fatal disease. The main purpose of this study was to determine if polymorphisms of mitotic regulator genes are associated with pancreatic cancer and whether they modify the association between cigarette smoking and pancreatic cancer risk. A population-based case-control study was conducted in Ontario with 455 pathology-confirmed pancreatic cancer cases and 893 controls. Cigarette smoking history was collected using questionnaires and DNA obtained from blood samples. Genotypes were determined by mass-spectrometry. Odds ratio estimates were obtained using multivariate logistic regression. Interactions between genetic variant and smoking were assessed using stratified analyses and the likelihood ratio statistic (significance P<0.05). Variants of MCPH1, FYN, APC, PRKCA, NIN, TopBP1, RIPK1, and SNW1 were not independently associated with pancreatic cancer risk. A significant interaction was observed between pack-years and MCPH1-2550-C>T (P=0.02). Compared to never smokers, individuals with 10-27 pack-years and MCPH1-2550-CC genotype were at increased risk for pancreatic cancer (MVOR=2.49, 95% confidence interval [95% CI]: 1.55, 4.00) as were those with >27 pack-years and MCPH1-2550-TC genotype (MVOR=2.42, 95% CI: 1.45, 4.05). A significant interaction was observed between smoking status and TopBP1-3257-A>G (P=0.04) using a dominant model. Current smokers with the TopBP1-3257 A allele were at increased risk for pancreatic cancer (MVOR=2.55, 95% CI: 1.77, 3.67). MCPH1-2550-C>T and TopBP1-3257-A>G modify the association between smoking and pancreatic cancer. These findings provide insights into the potential molecular mechanisms behind smoking-associated pancreatic cancer. © 2013 Wiley Periodicals, Inc. Source

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