While an association between the MMRd mutation signature and MSI tumorigenesis makes sense, the fact that tobacco may accelerate MSI tumor progression is consistent with previous studies showing a stronger association with gastrointestinal MSI tumors in heavy smokers (82–84) and with the fact that Lynch syndrome patients carrying germline MMR mutations are particularly susceptible to tobacco carcinogens (85). Here, MRC1 is linked to neoplasm.