Development of Cancer Immunoprevention in a High-Risk Population of CMMRD: Characterization of Frameshift Neoantigens in Mismatch Repair Deficient Individuals

The Constitutional Mismatch Repair Deficiency syndrome (CMMRD) is an inherited disease passed from both mother and father, which results in an extremely high risk of developing multiple cancers including brain (>50%) and gastrointestinal (>40%) tumors, leukemia or lymphoma (>30%), and other types of cancers during childhood. CMMRD is caused by one faulty DNA mismatch repair gene (MLH1, PMS2, MSH2 or MSH6) needed to fix the errors during the cell division, which can result in accumulation of certain type of gene mutations (e.g., “frameshift mutations”) and abnormal proteins (“frameshift peptide neoantigens”), and ultimately, increased risk of cancers (mismatch repair deficient cancers). We and other groups recently demonstrated the utility of vaccines targeting some of these abnormal proteins in treatment and prevention of mismatch repair deficient cancers in Lynch Syndrome (LS), the adult cancer syndrome related to CMMRD. We also developed a curated panel of frameshift mutations detectable in LS cancer patients’ blood as the potential minimally invasive biomarker for disease monitoring strategy. We hypothesize that these strategies for LS will also be effective for CMMRD.