MLH1 and cancer: Although these clinical and immunological observations have been documented by several independent studies, little attention has been attributed to the influence of the origin of MSI cancers on their immunogenicity: Whereas the majority of MSI CRCs develop sporadically, mostly due to hypermethylation of the MLH1 promoter leading to MLH1 silencing [18,19,20,21,22], about 20–30% of MSI CRCs (Figure 1a) have a hereditary background and are associated with Lynch syndrome (LS), the most common inherited CRC syndrome [23].