title: Validation of predictive models for germline mutations in DNA mismatch repair genes in colorectal cancer.
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: Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada.
authors: Jose G
authors: JG
authors: Monzon
authors: Carol
authors: C
authors: Cremin
authors: Linlea
authors: L
authors: Armstrong
authors: Jennifer
authors: J
authors: Nuk
authors: Sean
authors: S
authors: Young
authors: Doug E
authors: DE
authors: Horsman
authors: Kristy
authors: K
authors: Garbutt
authors: Chris D
authors: CD
authors: Bajdik
authors: Sharlene
authors: S
authors: Gill
mesh_terms: D000328:Adult; D017668:Age of Onset; D000951:Antigens, Neoplasm / Q000235:genetics; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics*; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D053843:DNA Mismatch Repair / Q000235:genetics*; D010450:Endopeptidases; D005190:Family; D005260:Female; D018093:Gelatinases / Q000235:genetics; D006580:Genetic Carrier Screening; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D009857:Oncogenes / Q000235:genetics; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012697:Serine Endopeptidases / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000951:Antigens, Neoplasm; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha