Geographic variation of mutagenic exposures in kidney cancer genomes

Scientists from the International Agency for Research on Cancer (IARC) and partner institutions have identified mutational signatures in kidney tumours that indicate the existence of multiple, geographically variable, and as-yet-undiscovered mutagenic exposures, potentially affecting tens of millions of people. The results have been published in Nature.

The researchers sequenced the genetic code of tissue samples from 962 patients with clear cell renal cell carcinoma, a type of kidney cancer. The samples came from 11 countries with varying incidence of kidney cancer. Upon examination, the team found a mutational signature of unknown cause in more than 70% of cases from Japan but in fewer than 2% of cases from the other countries. They also found a signature of unknown cause that was widely present in all countries but was more common in countries with higher kidney cancer incidence rates.

Most cases in Romania, Serbia, and Thailand exhibited mutational signatures that are likely to be caused by exposure to aristolochic acid compounds, a known nephrotoxin and carcinogen. However, this study suggests that the geographical extent and the proportion of the population affected by these mutations are far greater than previously anticipated, possibly affecting many millions of people.

Tobacco smoking, obesity, and hypertension are also known risk factors for clear cell renal cell carcinoma. Previously identified signatures of tobacco smoking were found during the study, but no specific mutational signature was found to be associated with obesity or hypertension, suggesting that these risk factors cause cancer in ways that do not mutate the genome.

The discovery of new mutational signatures, whether they are geographically widespread or relatively confined, requires action to identify their sources and to determine the extent of exposure, to provide a foundation for public health action. This research is part of the Mutographs project, which is funded by a Cancer Research UK (CRUK) Cancer Grand Challenges grant.

Senkin S, Moody, S, Díaz-Gay M, Abedi-Ardekani B, Cattiaux T, Ferreiro-Iglesias A, et al.
Geographic variation of mutagenic exposures in kidney cancer genomes
Nature, Published online 1 May 2024;
https://doi.org/10.1038/s41586-024-07368-2

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