The discovery,in the early 90’s, that most hereditary colorectal cancer resulted from pathogenic variants in the mismatch repair system was a pivotal moment in the emergence of genomic medicine. Subsequently it was found that mismatch repair deficiency is a key factor in around 1 in 6 colorectal cancers. Significant progress has been made in prevention of cancer death in known hereditary cases by the introduction of routine surveillance and prompt response to symptoms. The fact that fewer than 10% of gene carriers are identified, even in the best centres, limits the health gain.
The preferred term is now Lynch syndrome and our European prospective LS database (PLSD) has emphasised the unusually good prognosis for these cancers. This is attributed to the high level of immunogenicity which results from the Frame Shift Peptides (FSPs) released by the malignant cells which have lost MMR capacity. These FSPs can account for the excellent response to the new immunotherapeutic drugs and may offer a biomarker of cancers which are destroyed by the normal immune reaction. This possibility is being examined in the CaPP3 trial launched in the UK, Australia and Finland which is following the discovery in CAPP2 that LS cancers can be prevented by daily aspirin. CaPP3 will compare three different doses prior to efforts to repurpose aspirin as a cancer preventive in this population.
A major challenge is to improve identification of gene carriers. The InSiGHT variant database hosted in Melbourne is a key contribution to this global effort. In addition, we have developed a simple new test for microsatellite instability to speed dissemination of routine somatic testing to all colorectal and endometrial cancers. The possibility of vaccination based on the FSPs is under development and should facilitate, in combination with routine use of aspirin and generalised tumour testing, an even more effective prevention of death due to MMR deficiency in future.