Medline ® Abstracts for References 35,39,45,46
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 Lynch syndrome in consecutive patients with colorectal cancer.
Green RC, Parfrey PS, Woods MO, Younghusband HB
J Natl Cancer Inst. 2009;101(5):331.
BACKGROUND: Lynch syndrome is caused by inherited mutations in DNA mismatch repair genes (primarily MSH2, MLH1, MSH6, and PMS2) and is one of the most prevalent inherited cancer syndromes. Several models have been developed to predict the occurrence of Lynch syndrome in high-risk patients and families, but it is not known how these models compare with one another or how they perform for colorectal cancer patients from the general population. We used data from such patients to test the ability of four models--Leiden, MMRpredict, PREMM(1,2), and MMRpro--to distinguish between those who did and did not carry DNA mismatch repair gene mutations.
METHODS: We studied a consecutive series of 725 patients who were younger than 75 years at colorectal cancer diagnosis and whose DNA mismatch repair gene mutation status was available; 18 of the 725 patients carried such a mutation. For each model, we calculated the risk score, compared the observed number of mutations with the expected number, and determined the receiver operating characteristics. All statistical tests were two-sided.
RESULTS: Although all four models overestimated the probability of a mutation (range = 1.2- to 4.3-fold), especially in low-risk patients, they could discriminate between carriers and noncarriers of a mismatch repair mutation. The areas under the receiver operating characteristics curves from the four models ranged from 0.91 to 0.96. Carriers of mutations in the MSH6 or PMS2 genes had lower risk scores than carriers of MSH2 or MLH1 mutations. For example, the MMRpredict model gave median risk scores of 24% and 94% (P<.015) for MSH6-PMS2 and MSH2-MLH1 mutation carriers, respectively. For the Leiden, MMRpredict, and PREMM(1,2) models, correcting the risk scores for bias introduced by family size improved their power to discriminate between carriers and noncarriers. After correcting for family size, the best model was MMRpredict, which achieved a sensitivity of 94% (95% confidence interval [CI]= 73% to 99%) and a specificity of 91% (95% CI = 88% to 93%) and identified a smaller proportion of patients than the revised Bethesda criteria as those who should undergo additional molecular or immunohistochemical testing (11% vs 50%).
CONCLUSION: MMRpredict was the best-performing model for identifying colorectal cancer patients who are at high risk of carrying a DNA mismatch repair gene mutation and thus should be screened for Lynch syndrome.
Department of Genetics, Faculty of Medicine, Memorial University, St John's, Newfoundland, Canada A1B 3V6. email@example.com
Comparison of predictive models, clinical criteria and molecular tumour screening for the identification of patients with Lynch syndrome in a population-based cohort of colorectal cancer patients.
Balmaña J, Balaguer F, Castellví-Bel S, Steyerberg EW, Andreu M, Llor X, Jover R, Castells A, Syngal S, Gastrointestinal Oncology Group of the Spanish Gastroenterological Association
J Med Genet. 2008;45(9):557. Epub 2008 Jun 25.
BACKGROUND: Several models have recently been developed to predict mismatch repair (MMR) gene mutations. Their comparative performance with clinical criteria or universal molecular screening in a population based colorectal cancer (CRC) cohort has not been assessed.
METHODS: All 1222 CRC from the EPICOLON cohort underwent tumour MMR testing with immunohistochemistry and microsatellite instability, and those with MMR deficiency (n = 91) underwent MLH1/MSH2 germline testing. Sensitivity, specificity and positive predictive value (PPV) of the PREMM(1,2) and the Barnetson models for identification of MLH1/MSH2 mutation carriers were evaluated and compared with the revised Bethesda guidelines (RBG), Amsterdam II criteria, and tumour analysis for MMR deficiency. Overall discriminative ability was quantified by the area under the ROC curve (AUC), and calibration was assessed by comparing the average predictions versus the observed prevalence.
RESULTS: Both models had similar AUC (0.93 and 0.92, respectively). Sensitivity of the RBG and a PREMM(1,2) score>or =5% was 100% (95% CI 71% to 100%); a Barnetson score>0.5% missed one mutation carrier (sensitivity 87%, 95% CI 51% to 99%). PPVs of all three strategies were 2-3%. Presence of MMR deficiency increased specificity and PPV of predictive scores (97% and 21% for PREMM(1,2) score>or =5%, and 98% and 21% for Barnetson>or =0.5%, respectively).
CONCLUSIONS: The PREMM(1,2) and the Barnetson models offer a quantitative systematic approach to select CRC patients for identification of MLH1/MSH2 mutation carriers with a similar performance to the RBG.
Department of Medical Oncology, Hospital Vall d'Hebron, Medical Department of Universitat Autónoma de Barcelona, Spain. firstname.lastname@example.org
Evaluation of predictive models in daily practice for the identification of patients with Lynch syndrome.
Tresallet C, Brouquet A, JuliéC, Beauchet A, Vallot C, Ménégaux F, Mitry E, Radvanyi F, Malafosse R, Rougier P, Nordlinger B, Laurent-Puig P, Boileau C, Emile JF, Muti C, Penna C, Hofmann-Radvanyi H
Int J Cancer. 2012 Mar;130(6):1367-77. Epub 2011 Jul 25.
The optimal strategy for identifying patients with Lynch syndrome among patients with newly diagnosed colorectal cancer (CRC) is still debated. Several predictive models (e.g., MMRpredict, PREMM1,2 and MMRpro) combining personal and familial data have recently been developed to quantify the risk that a given patient with CRC carries a Lynch syndrome-causing mutation. Their clinical applicability to patients with CRC from the general population requires evaluation. We studied a consecutive series of 214 patients with newly diagnosed CRC characterized for tumor microsatellite instability (MSI), somatic BRAF mutation, MLH1 promoter methylation and mismatch repair (MMR) gene germline mutation status. The performances of the models for identifying MMR mutation carriers (8/214, 3.7%) were evaluated and compared to the revised Bethesda guidelines and a molecular strategy based on MSI testing in all patients followed by the exclusion of MSI-positive sporadic cases from mutational testing by screening for BRAF mutation and MLH1 promoter methylation. The sensitivities of the three models, at the lowest thresholds proposed, were identical (75%), with similar numbers of probands eligible for further MSI testing (almost half the patients). In our dataset, the prediction models gave no better discrimination than the revised Bethesda guidelines. Both approaches failed to identify two of the eight mutation carriers (the same two patients, aged 67 and 81 years, both with no family history). Thus, like the revised Bethesda guidelines, predictive models did not identify all patients with Lynch syndrome in our series of consecutive CRC. Our results support systematic screening for MMR deficiency in all new CRC cases.
AP-HP, Fédération des Spécialités Digestives, Hôpital Ambroise Paré, UniversitéVersailles-Saint Quentin en Yvelines, Boulogne, France.