Dataset Information

Prediction of germline mutations and cancer risk in the Lynch syndrome.

ABSTRACT: Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing colorectal or endometrial cancer.External validation of the MMRpro model was conducted on 279 individuals from 226 clinic-based families in the United States, Canada, and Australia (referred between 1993-2005) by comparing model predictions with results of highly sensitive germline mutation detection techniques. MMRpro models the autosomal dominant inheritance of mismatch repair mutations, with parameters based on meta-analyses of the penetrance and prevalence of mutations and of the predictive values of tumor characteristics. The model's prediction is tailored to each individual's detailed family history information on colorectal and endometrial cancer and to tumor characteristics including microsatellite instability.Ability of MMRpro to correctly predict mutation carrier status, as measured by operating characteristics, calibration, and overall accuracy.In the independent validation, MMRpro provided a concordance index of 0.83 (95% confidence interval, 0.78-0.88) and a ratio of observed to predicted cases of 0.94 (95% confidence interval, 0.84-1.05). This results in higher accuracy than existing alternatives and current clinical guidelines.MMRpro is a broadly applicable, accurate prediction model that can contribute to current screening and genetic counseling practices in a high-risk population. It is more sensitive and more specific than existing clinical guidelines for identifying individuals who may benefit from MMR germline testing. It is applicable to individuals for whom tumor samples are not available and to individuals in whom germline testing finds no mutation.

SUBMITTER: Chen S

PROVIDER: S-EPMC2538673 | biostudies-literature | 2006 Sep

REPOSITORIES: biostudies-literature

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Prediction of germline mutations and cancer risk in the Lynch syndrome.

Chen Sining S Wang Wenyi W Lee Shing S Nafa Khedoudja K Lee Johanna J Romans Kathy K Watson Patrice P Gruber Stephen B SB Euhus David D Kinzler Kenneth W KW Jass Jeremy J Gallinger Steven S Lindor Noralane M NM Casey Graham G Ellis Nathan N Giardiello Francis M FM Offit Kenneth K Parmigiani Giovanni G

JAMA 20060901 12

<h4>Context</h4>Identifying families at high risk for the Lynch syndrome (ie, hereditary nonpolyposis colorectal cancer) is critical for both genetic counseling and cancer prevention. Current clinical guidelines are effective but limited by applicability and cost.<h4>Objective</h4>To develop and validate a genetic counseling and risk prediction tool that estimates the probability of carrying a deleterious mutation in mismatch repair genes MLH1, MSH2, or MSH6 and the probability of developing col ...[more]

PMID: 17003396

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Project description:ObjectiveWhole-exon sequencing (WES) is a commercially available tool for hereditary disease testing. However, little is known about hereditary upper-tract urothelial carcinoma (UTUC) in the Chinese population. This study aims to investigate the prevalence of Lynch syndrome (LS) in UTUC patients with high-risk features and identify the germline mutations of genetic predisposition gene mutations in those patients.MethodsIn total, 354 consecutive UTUC patients undergoing surgery were universally recruited, of whom 108 patients under 60 years old or with a personal/family history of cancer underwent universal immunohistochemistry staining to detect the expression of mismatch repair (MMR) proteins (MLH1, MSH2, MSH6 and PMS2). Patients with deficient or weak MMR protein staining or meeting the Amsterdam II criterion were defined as suspected LS patients, who further experienced microsatellite instability (MSI) (BAT25, BAT26, BAT40, D2S123, D5S346, D17S250) detection and performed WES analysis to explore germline pathogenic/likely pathogenic (P/LP) alterations.ResultsOf 108 patients, 90 (83.3%) cases were included due to younger than 60 years, and 18 cases due to personal/family history. IHC staining identified 21 patients with deficient MMR protein staining and 15 cases with weak MMR protein staining. Three cases met the Amsterdam II criterion but with proficient MMR protein staining. Finally, WES analysis was performed in 38 suspected LS patients and P/LP germline mutations were identified in 22 individuals. Genetic testing confirmed 5 LS cases, including 3 cases with novel mutations. MSI-harboring tumor was discovered in 4 LS cases, one of whom had weak MMR protein staining. Germline P/LP variants in DNA damage repair genes were found in 11 cases. In addition, we found that 11 patients had high- or moderate- penetrance P/LP mutations other than MMR genes. The common P/LP variants in high- or moderate-penetrance genes were 4 in ATM, 3 in MSH6 and KIT, and 2 in APC, NF1 and DICER.ConclusionsWe identified approximately 11% of UTUC cases as suspected LS and at least 1.4% patients with confirmed LS-associated UTUC. In addition, broader germline genetic testing could be considered to screen for cancer severity in hereditary UTUC patients.

Project description:Lynch syndrome is an inherited cause of colorectal cancer caused by mutations of DNA mismatch repair (MMR) genes. A number of extracolonic tumors have been associated with the disorder, including pancreatic cancer; however, the risk of pancreatic cancer in Lynch syndrome is uncertain and not quantified.To estimate pancreatic cancer risk in families with germline MMR gene mutations.Cancer histories of probands and their relatives were evaluated in MMR gene mutation carriers in the familial cancer registries of the Dana-Farber Cancer Institute (n = 80), Boston, Massachusetts, and University of Michigan Comprehensive Cancer Center (n = 67), Ann Arbor, Michigan. Families enrolled before the study start date (June 2008) were eligible. Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk were calculated and compared with the general population using modified segregation analysis, with correction for ascertainment.Age-specific cumulative risks and hazard ratio estimates of pancreatic cancer risk.Data on 6342 individuals from 147 families with MMR gene mutations were analyzed. Thirty-one families (21.1%) reported at least 1 case of pancreatic cancer. Forty-seven pancreatic cancers were reported (21 men and 26 women), with no sex-related difference in age of diagnosis (51.5 vs 56.5 years for men and women, respectively). The cumulative risk of pancreatic cancer in these families with gene mutations was 1.31% (95% confidence interval [CI], 0.31%-2.32%) up to age 50 years and 3.68% (95% CI, 1.45%-5.88%) up to age 70 years, which represents an 8.6-fold increase (95% CI, 4.7-15.7) compared with the general population.Among 147 families with germline MMR gene mutations, the risk of pancreatic cancer was increased compared with the US population. Individuals with MMR gene mutations and a family history of pancreatic cancer are appropriate to include in studies to further define the risk of premalignant and malignant pancreatic neoplasms and potential benefits and limitations of surveillance.

Dataset Information

Prediction of germline mutations and cancer risk in the Lynch syndrome.

Publications

Prediction of germline mutations and cancer risk in the Lynch syndrome.

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