Lynch Syndrome Improving Diagnostics and Surveillance

Lynch syndrome is the most common hereditary predisposition for colorectal cancer and accounts for 2-3% of all colorectal cancer cases. In addition, these patients are also at increased risk of developing extracolonic cancers, especially endometrial cancer in women.

Since surveillance programs can significantly reduce morbidity and mortality in individuals with Lynch syndrome, identification of these individuals is of great importance. In chapter 3, two prediction models for Lynch syndrome were evaluated and one of those models, the PREMM5 model, was improved by adding the location of colorectal cancer as a new variable. In chapter 4 and 5 we showed that routine molecular screening for Lynch syndrome in colorectal cancer patients and endometrial cancer patients up to 70 years of age is cost-effective. In chapter 6, no Lynch syndrome patients were identified by screening for Lynch syndrome among all advanced adenomas in the population based CRC screening program. Therefore, routine screening of all adenomas is probably not effective.

In chapter 7 and 8 a functional assay to classify variants of unknown significance in the mismatch repair genes was evaluated and 26 variants in MLH1, MSH2 and MSH6 were analyzed. In most cases the classification was in line with clinical data, prediction programs and results of other functional assays.

Although the cancer risk in Lynch syndrome patients is highly dependent on the gene involved, all patients are currently offered the same surveillance. Therefore, chapter 9 evaluates the yield of colonoscopy surveillance in MLH1, MSH2, MSH6 and PMS2 mutation carriers.

Finally, chapter 10 discusses the results of this thesis in perspective of the current guidelines and clinical practice.