Routine testing for microsatellite instability of colorectal tumors that develop before age 50 years was implemented in 2008 in the Netherlands which was based on our previous research (Gut 2005; guideline). The introduction of this screening enhanced the recognition of families with Lynch syndrome (Eur J Cancer 2011). However, in a subset of patients with these tumor characteristics, no germ line mutations could be identified, thus hampering adequate advises to prevent CRC. These patients were the basis of our research on other genetic causes.
In 2009 we identified a novel genetic mechanism leading to inactivation of the MSH2 gene in some of the unexplained Lynch patients: inactivation of the 3’ end of EPCAM, the gene 5’ of MSH2, leads to epigenetic inactivation of MSH2 in cells that express EPCAM. Transcriptional read through from the EPCAM gene into the MSH2 gene leads to hypermethylation of the downstream MSH2 promoter, predisposing the patient to CRC (Nat Genet 2009). EPCAM deletions of different sizes, all leading to MSH2 promoter hypermethylation, were subsequently identified worldwide (Hum Mutat 2011). This has led to the global adaptation of diagnostic Lynch protocols. The risk for developing CRC in patients with an EPCAM deletion is similar to that of patients with an inactivating mutation within the MSH2 gene. In contrast, the risk for endometrial cancer in women with such deletion is lower than that of women with an MSH2 mutation (Lancet Oncol 2011). Hypermethylation of the MLH1 promoter can also be genetically defined. In an international collaboration we unraveled a specific haplotype surrounding the MLH1 locus (Eur J Hum Genet 2014).
In a subset of patients with tumors characteristics of Lynch syndrome, we are currently able to exclude Lynch syndrome based on the presence of biallelic somatic mutations in the mismatch repair genes, which warrants less stringent surveillance in this patient group (Gastroenterology 2014). A novel cost-effectiveness study on the Lynch predicting tumor test (Ann Oncol 2014) led to the implementation of a new guideline for Lynch syndrome screening for all patients with CRC under the age of 70. The specific tumor characteristics of Lynch syndrome patients are also used to provide alternative prevention measures. Specific antigens that Lynch syndrome patients develop are used as a target for dendritic cell vaccination to prevent subsequent cancer development (Cancer Immunol Immunother 2016; Cancer Lett 2017). Other studies are aimed at improving awareness on lifestyle recommendations for cancer prevention (Clin Genet, 2018). Recently, we obtained a Dutch Cancer Society grant to study the role of microbiome in patients with Lynch syndrome.