Publication
Geographic variation of mutagenic exposures in kidney cancer genomes
Publisher:
Cold Spring Harbor Laboratory
Date:
29-06-2023
DOI:
10.1101/2023.06.20.23291538
Abstract: International differences in the incidence of many cancer types indicate the existence of carcinogen exposures which make a substantial contribution to cancer burden, vary geographically, and have underlying agents thus far unidentified by conventional epidemiology 1 . This pertains to clear cell renal cell carcinomas (ccRCC), for which obesity, hypertension, and tobacco smoking are risk factors but do not explain its geographical variation in incidence 2 . Some carcinogens generate somatic mutations and past exposures can be inferred from the patterns of mutations found in cancer genomes. Therefore, we sequenced the whole genomes of 962 ccRCC from 11 countries of varying incidence. Somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures likely caused by extracts of Aristolochia plants were present in most cases and rare elsewhere. In Japan, a mutational signature of unknown cause was found in % cases and % elsewhere. Another mutational signature of unknown cause was ubiquitous and associated with kidney cancer incidence rates (p-value × 10 −18 ), with higher numbers of mutations in countries with higher risk. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension suggesting non-mutagenic mechanisms of action underlying these risk factors. The results indicate the existence of multiple, widespread, geographically variable mutagenic exposures to known and unknown agents, which may contribute to the incidence of kidney cancer.