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Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer.
Int J Cancer. 2010 Feb 15; 126(4):930-9.IJ

Abstract

Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate-high risk for harboring a Lynch-associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy-two tested cases were included. Twenty-five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model-derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63-0.87), 0.86 (0.7-0.96), 0.89 (0.82-0.97), 0.89 (0.81-0.98) and 0.93 (0.86-0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations.

Authors+Show Affiliations

Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

19653273

Citation

Monzon, Jose G., et al. "Validation of Predictive Models for Germline Mutations in DNA Mismatch Repair Genes in Colorectal Cancer." International Journal of Cancer, vol. 126, no. 4, 2010, pp. 930-9.
Monzon JG, Cremin C, Armstrong L, et al. Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer. Int J Cancer. 2010;126(4):930-9.
Monzon, J. G., Cremin, C., Armstrong, L., Nuk, J., Young, S., Horsman, D. E., Garbutt, K., Bajdik, C. D., & Gill, S. (2010). Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer. International Journal of Cancer, 126(4), 930-9. https://doi.org/10.1002/ijc.24808
Monzon JG, et al. Validation of Predictive Models for Germline Mutations in DNA Mismatch Repair Genes in Colorectal Cancer. Int J Cancer. 2010 Feb 15;126(4):930-9. PubMed PMID: 19653273.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer. AU - Monzon,Jose G, AU - Cremin,Carol, AU - Armstrong,Linlea, AU - Nuk,Jennifer, AU - Young,Sean, AU - Horsman,Doug E, AU - Garbutt,Kristy, AU - Bajdik,Chris D, AU - Gill,Sharlene, PY - 2009/8/5/entrez PY - 2009/8/5/pubmed PY - 2010/2/2/medline SP - 930 EP - 9 JF - International journal of cancer JO - Int J Cancer VL - 126 IS - 4 N2 - Lynch syndrome is defined by the presence of germline mutations in mismatch repair (MMR) genes. Several models have been recently devised that predict mutation carrier status (Myriad Genetics, Wijnen, Barnetson, PREMM and MMRpro models). Families at moderate-high risk for harboring a Lynch-associated mutation, referred to the BC Cancer Agency (BCCA) Hereditary Cancer Program (HCP), underwent mutation analysis, immunohistochemistry and/or microsatellite testing. Seventy-two tested cases were included. Twenty-five patients were mutation positive (34.7%) and 47 were mutation negative (65.3%). Nineteen of 43 patients who were both microsatellite stable and normal on immunohistochemistry for MLH1 and MSH2 were also genotyped for mutations in these genes; all 19 were negative for MMR gene mutations. Model-derived probabilities of harboring a MMR gene mutation in the proband were calculated and compared to observed results. The area under the ROC curves were 0.75 (95%CI; 0.63-0.87), 0.86 (0.7-0.96), 0.89 (0.82-0.97), 0.89 (0.81-0.98) and 0.93 (0.86-0.99) for the Myriad, Barnetson, Wijnen, MMRpro and PREMM models, respectively. The Amsterdam II criteria had a sensitivity and specificity of 0.76 and 0.74, respectively, in this cohort. The PREMM model demonstrated the best performance for predicting carrier status based on the positive likelihood ratios at the >10%, >20% and >30% probability thresholds. In this referred cohort, the PREMM model had the most favorable concordance index and predictive performance for carrier status based on the positive LR. These prediction models (PREMM, MMRPro and Wijnen) may soon replace the Amsterdam II and revised Bethesda criteria as a prescreening tool for Lynch mutations. SN - 1097-0215 UR - https://www.unboundmedicine.com/medline/citation/19653273/Validation_of_predictive_models_for_germline_mutations_in_DNA_mismatch_repair_genes_in_colorectal_cancer_ L2 - https://doi.org/10.1002/ijc.24808 DB - PRIME DP - Unbound Medicine ER -