Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis

Abstract

AimTo determine a cost-efficient strategy for HNPCC molecular diagnostic testing.Methods138 families referred to a Regional Genetics Service had hMLH1 and hMSH2 mutation analysis. The sensitivity and specificity of clinical selection criteria with or without immunohistochemistry (IHC) and microsatellite instability (MSI) analysis to further refine case selection and the effect of these approaches on the cost of mutation analysis were examined.ResultsClearly deleterious mutations were identified in 49/138 (35.5%) of all families tested. The most sensitive criteria for identifying families with MMR mutations were the full Bethesda guidelines but these have poor specificity. IHC and MSI were useful pre-screening tools.ConclusionA cost-efficient approach in laboratories where IHC and/or MSI analysis are available, is to use inclusive (non-specific) criteria to select cases, followed by IHC and then MSI. Where one or both results are abnormal, proceed to further mutation analysis. Where MSI or IHC or tumour blocks are not available, more restrictive clinical criteria may be more appropriate for cost-efficient case selection.

A systematic review and economic evaluation of diagnostic strategies for Lynch syndrome

“…70,72 Most studies were not specific about the 'current practice' in their respective countries, but their strategies were generally compared against a no testing strategy, implying that there was no standard 'current practice' in each of the countries or that no testing for LS was the 'current practice'. Relevant to our assessment, one of the European studies was based in the UK, 60 but this was 9 years old at the time of writing and was not consistent with our input population; Pigatto and colleagues 60 investigated families referred for genetic testing, rather than newly diagnosed CRC patients aged < 50 years, who were the focus of our investigation.…”

“…34,[59][60][61][62][63][64][65][66][67][68][69][70][71][72] All studies were published between 2000 and 2012 and summary details of each study can be found in Tables 31 and 32.…”

“…There were six studies from the USA, 59,65,[67][68][69]71 six from European countries, 34,[60][61][62][63]66 one from China 64 and two where the setting was not clear. 70,72 Most studies were not specific about the 'current practice' in their respective countries, but their strategies were generally compared against a no testing strategy, implying that there was no standard 'current practice' in each of the countries or that no testing for LS was the 'current practice'.…”

“…With regards to the other studies' input populations, one looked at EC patients 67 and three (including the UK study) examined families who were referred to genetic testing centres, 60,62,66 neither of which were the target population of our TA. The other 11 studies followed newly diagnosed CRC patients, and three of these 59,65,72 included the impact on relatives of the CRC patients.…”

“…As well as having different study populations, the different studies also assessed different tests, which included the following subsets: clinical criteria/FH, 34,[59][60][61]63,64,67,68,70 prediction models, 66 tumour testing 65,34,[59][60][61][62][63][64][66][67][68][69][70][71][72] and genetic testing. 65,34,[59][60][61][62][63][64][66][67][68][69][70][71][72] Genetic testing was split into gene sequencing for probands and targeted genetic testing for relatives.…”