title: Cascade genetic testing for mismatch repair gene mutations.
abstract: Mismatch repair gene mutation carriers have a high risk of developing colorectal cancer, and can benefit from appropriate surveillance. A combined population based ascertainment cascade genetic testing approach provides a systematic and potentially effective strategy for identifying such carriers. We have developed a Markov Chain computer model system which simulates various factors influencing cascade genetic testing; including demographics, uptake, genetic epidemiology and family size. This was used to evaluate cascade genetic testing for mismatch repair gene mutations in theory and practice. Simulations focussed on the population of Scotland by way of illustration, and were based on a 20-year programme in which index cases were ascertained from colorectal cancer cases aged<55 years at onset. Results indicated that without practical barriers to cascade genetic testing, 545 (95% CI=522, 568) carriers could be identified; 42% of the population total. This comprised approximately 140 index cases, 302 asymptomatic relatives and 104 previously affected relatives. However, when realistic ascertainment and acceptance rates were used to inform simulations, only 257 (95% CI=246, 268) carriers, about 20% of the carrier population, were identifiable. Of these approximately 112 were index cases, 108 were asymptomatic relatives, and 37 were previously affected relatives. This contrast emphasises the importance of ascertainment and acceptance rates. Likewise the low number of index cases shows that case identification is a limiting factor. In the absence of robust data from epidemiological studies, these findings can inform decisions about the use of cascade genetic testing for mismatch repair gene mutations.
authors.affiliation: Public Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, EH89AG, UK. R.J.Mitchell@ed.ac.uk
authors.forename: R J
authors.initials: RJ
authors.lastname: Mitchell
authors.forename: R K
authors.initials: RK
authors.lastname: Ferguson
authors.forename: A
authors.initials: A
authors.lastname: Macdonald
authors.forename: M G
authors.initials: MG
authors.lastname: Dunlop
authors.forename: H
authors.initials: H
authors.lastname: Campbell
authors.forename: M E
authors.initials: ME
authors.lastname: Porteous
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics; D053843:DNA Mismatch Repair; D001330:Electronic Data Processing; D006580:Genetic Carrier Screening / Q000379:methods; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008390:Markov Chains; D008875:Middle Aged; D008957:Models, Genetic; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins