Medline ® Abstracts for References 35-38
of 'Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis'
Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer.
Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, Campbell H, Dunlop MG
N Engl J Med. 2006;354(26):2751.
BACKGROUND: The identification of mutations in germ-line DNA mismatch-repair genes at the time of diagnosis of colorectal cancer is important in the management of the disease.
METHODS: Without preselection and regardless of family history, we recruited 870 patients under the age of 55 years soon after they received a diagnosis of colorectal cancer. We studied these patients for germ-line mutations in the DNA mismatch-repair genes MLH1, MSH2, and MSH6 and developed a two-stage model by multivariate logistic regression for the prediction of the presence of mutations in these genes. Stage 1 of the model incorporated only clinical variables; stage 2 comprised analysis of the tumor by immunohistochemical staining and tests for microsatellite instability. The model was validated in an independent population of patients. We analyzed 2938 patient-years of follow-up to determine whether genotype influenced survival.
RESULTS: There were 38 mutations among the 870 participants (4 percent): 15 mutations in MLH1, 16 in MSH2, and 7 in MSH6. Carrier frequenciesin men (6 percent) and women (3 percent) differed significantly (P<0.04). The addition of immunohistochemical analysis in stage 2 of the model had a sensitivity of 62 percent and a positive predictive value of 80 percent. There were 35 mutations in the validation series of 155 patients (23 percent): 19 mutations in MLH1, 13 in MSH2, and 3 in MSH6. The performance of the model was robust among a wide range of cutoff probabilities and was superior to that of the Bethesda and Amsterdam criteria for hereditary nonpolyposis colorectal cancer. Survival among carriers was not significantly different from that among noncarriers.
CONCLUSIONS: We devised and validated a method of identifying patients with colorectal cancer who are carriers of mutations in DNA repair genes. Survival was similar among carriers and noncarriers.
Colon Cancer Genetics Group, School of Molecular and Clinical Medicine, University of Edinburgh, Edinburgh, United Kingdom.
Prediction of MLH1 and MSH2 mutations in Lynch syndrome.
Balmaña J, Stockwell DH, Steyerberg EW, Stoffel EM, Deffenbaugh AM, Reid JE, Ward B, Scholl T, Hendrickson B, Tazelaar J, Burbidge LA, Syngal S
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 PREMM(1,2) (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>or =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 PREMM(1,2) 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.
Population Sciences Division, Dana-Farber Cancer Institute, and Division of Gastroenterology, Boston, Mass 02115, USA.
Clinical findings with implications for genetic testing in families with clustering of colorectal cancer.
Wijnen JT, Vasen HF, Khan PM, Zwinderman AH, van der Klift H, Mulder A, Tops C, Møller P, Fodde R
N Engl J Med. 1998;339(8):511.
BACKGROUND: Germ-line mutations in DNA mismatch-repair genes (MSH2, MLH1, PMS1, PMS2, and MSH6) cause susceptibility to hereditary nonpolyposis colorectal cancer. We assessed the prevalence of MSH2 and MLH1 mutations in families suspected of having hereditary nonpolyposis colorectal cancer and evaluated whether clinical findings can predict the outcome of genetic testing.
METHODS: We used denaturing gradient gel electrophoresis to identify MSH2 and MLH1 mutations in 184 kindreds with familial clustering of colorectal cancer or other cancers associated with hereditary nonpolyposis colorectal cancer. Information on the site of cancer, the age at diagnosis, and the number of affected family members was obtained from all families.
RESULTS: Mutations of MSH2 or MLH1 were found in 47 of the 184 kindreds (26 percent). Clinical factors associated with these mutations were early age at diagnosis of colorectal cancer, the occurrence in the kindred of endometrial cancer or tumors of the small intestine, a higher number of family members with colorectal or endometrial cancer, the presence of multiple colorectal cancers or both colorectal and endometrial cancers in a single family member, and fulfillment of the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer (at least three family members in two or more successive generations must have colorectal cancer, one of whom is a first-degree relative of the other two; cancer must be diagnosed before the age of 50 in at least one family member; and familial adenomatous polyposis must be ruled out). Multivariate analysis showed that a younger age at diagnosis of colorectal cancer, fulfillment of the Amsterdam criteria, and the presence of endometrial cancer in the kindred were independent predictors of germ-line mutations of MSH2 or MLH1. These results were used to devise a logistic model for estimating the likelihood of a mutation in MSH2 and MLH1.
CONCLUSIONS: Assessment of clinical findings can improve the rate of detection of mutations of DNA mismatch-repair genes in families suspected of having hereditary nonpolyposis colorectal cancer.
Department of Human Genetics, Leiden University Medical Center, The Netherlands.
Comparison of Prediction Models for Lynch Syndrome Among Individuals With Colorectal Cancer.
Kastrinos F, Ojha RP, Leenen C, Alvero C, Mercado RC, Balmaña J, Valenzuela I, Balaguer F, Green R, Lindor NM, Thibodeau SN, Newcomb P, Win AK, Jenkins M, Buchanan DD, Bertario L, Sala P, Hampel H, Syngal S, Steyerberg EW, Lynch Syndrome prediction model validation study group
J Natl Cancer Inst. 2016;108(2) Epub 2015 Nov 18.
BACKGROUND: Recent guidelines recommend the Lynch Syndrome prediction models MMRPredict, MMRPro, and PREMM1,2,6 for the identification of MMR gene mutation carriers. We compared the predictive performance and clinical usefulness of these prediction models to identify mutation carriers.
METHODS: Pedigree data from CRC patients in 11 North American, European, and Australian cohorts (6 clinic- and 5 population-based sites) were used to calculate predicted probabilities of pathogenic MLH1, MSH2, or MSH6 gene mutations by each model and gene-specific predictions by MMRPro and PREMM1,2,6. We examined discrimination with area under the receiver operating characteristic curve (AUC), calibration with observed to expected (O/E) ratio, and clinical usefulness using decision curve analysis to select patients for further evaluation. All statistical tests were two-sided.
RESULTS: Mutations were detected in 539 of 2304 (23%) individuals from the clinic-based cohorts (237 MLH1, 251 MSH2, 51 MSH6) and 150 of 3451 (4.4%) individuals from the population-based cohorts (47 MLH1, 71 MSH2, 32 MSH6). Discrimination was similar for clinic- and population-based cohorts: AUCs of 0.76 vs 0.77 for MMRPredict, 0.82 vs 0.85 for MMRPro, and 0.85 vs 0.88 for PREMM1,2,6. For clinic- and population-based cohorts, O/E deviated from 1 for MMRPredict (0.38 and 0.31, respectively) and MMRPro (0.62 and 0.36) but were more satisfactory for PREMM1,2,6 (1.0 and 0.70). MMRPro or PREMM1,2,6 predictions were clinically useful at thresholds of 5% or greater and in particular at greater than 15%.
CONCLUSIONS: MMRPro and PREMM1,2,6 can well be used to select CRC patients from genetics clinics or population-based settings for tumor and/or germline testing at a 5% or higher risk. If no MMR deficiency is detected and risk exceeds 15%, we suggest considering additional genetic etiologies for the cause of cancer in thefamily.
Herbert Irving C omprehensive Cancer Center and Division of Digestive and Liver Diseases, Columbia University, Medical Center, New York, NY (FK); Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN (RPO); Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands (CL); Statistical and Data Analysis Center, Harvard School Public Health, Boston, MA (CA); Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA (RCM); Department of Oncology (JB) and Genetics Department (IV), University Hospital Vall d'Hebrón, Barcelona, Spain; Department of Gastroenterology, Hospital Clinic of Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain (FB); Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St John's, NL, Canada (RG); Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ (NML); Division of Molecular Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic,