EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome

1. Clarifying how to define the clinical disorder—Lynch syndrome. In this supplementary review, Lynch syndrome refers to individuals with a predisposition to CRC and certain other malignancies as a result of a germline mis- match repair (MMR) gene mutation—including those with an existing cancer and those who have not yet developed cancer. This definition allows planned analyses of clinical validity and utility to be more straightforward. Several recent editorials and publications recommend that the ambiguous term HNPCC be abandoned and that this clarified definition of Lynch syndrome should be used instead. 2. Removing family history from consideration as a prelim- inary test. A previous evidence review showed that screening performance of both the Amsterdam and the Bethesda criteria to identify individuals with Lynch syn- drome were highly heterogeneous, possibly due to differ- ences among the populations tested. In a general popula- tion, Amsterdam criteria are associated with relatively low sensitivity (28-45%), but high specificity (99%), whereas Bethesda criteria are associated with higher sen- sitivity (73-91%), but at the cost of lower specificity (82-77%). Neither provides the necessary high sensitivi- ty/specificity in a reliable and consistent manner. There are also gaps in knowledge relating to the time required to collect family history, the consistency with which it is collected, and the accuracy of the information. These shortcomings have led us to remove family history from consideration as a preliminary test in individuals newly diagnosed with CRC. However, family history may still be an important component of CRC risk assessment in the general population. 3. Documenting the clinical validity of DNA-based prelimi- nary tests. Because of rapid advances in knowledge and technology regarding molecular testing and Lynch syn- drome, we generally limited this review to publications from 2003 and later. Although not formally studied, this is a likely reason why several of our estimates differ from those provided in an earlier evidence report. There was "Adequate" (a formal EWG term) evidence showing the sensitivity of microsatellite instability (MSI) testing to be about 89% (for mutations in the MMR genes MLH1 and MSH2), with a lower sensitivity of about 77% for MSH6 mutations. Sensitivity was higher when three or more mononucleotide markers were included in the panel. Specificity was estimated to be 90.2%, with an adequate level of evidence. There was also good evidence showing