Incidence Rates of Melanoma and Lung Cancer Are Generally Low in the Lynch Syndromes and Vary Across path_MMR Variants: A Prospective Lynch Syndrome Database Report

Abstract

Background/Objectives It is not established whether melanoma and lung cancer are part of the tumor spectrum of the Lynch syndromes (LS). Our first hypothesis was that, if melanoma is associated with LS, most prospectively observed cases would be carriers of pathogenic MSH2 variants (path_MSH2), as for other LS non-endodermal tumors. Our second hypothesis, which was derived from findings of the first study, was that the pattern of differences in the incidence of lung cancer in path_MMR carriers would mirror that for melanoma. Methods We used the Prospective Lynch Syndrome Database (PLSD) data and methods. Results Firstly, consistent with hypothesis, ten of 3154 path_MSH2 carriers followed for 26,309 years developed melanoma, compared with 6 of 5288 path_MLH1/MSH6/PMS2 carriers followed for 45,081 years (p = 0.04). Secondly, although the incidence of melanoma in carriers of path_MSH2 was 0.00041—similar to the populations in which the carriers resided—the average incidence rates for path_MLH1/MSH6/PMS2 carriers was 0.00012, lower than the corresponding population rates. Thirdly, the average lung cancer incidence rates in PLSD were 0.00112 in path_MSH2 carriers and 0.00032 in path_MLH1/MSH6/PMS2 carriers (p = 0.02), both lower than the population rates. Conclusions Melanomas and lung cancers—both of which are immunogenic through mechanisms independent of mismatch repair deficiency—may become even more immunogenic when they also exhibit microsatellite instability. This may lead to an increased likelihood that both tumors are eliminated by the immune system and, thus, show variable and lower incidence. These insights may help inform strategies for cancer prevention or treatment that are aimed at simultaneously interrupting multiple carcinogenic pathways.