98 A new study has revealed significant geographic differences in the mutational signatures of kidney cancer, shedding light on the environmental and lifestyle factors that may contribute to the disease. Researchers analysed the genomes of 962 clear cell renal cell carcinomas (ccRCCs) from patients in 11 countries, identifying striking variations in the patterns of DNA mutations across different regions. The findings were published in the journal Nature. The study, conducted by an international team of scientists, focused on mutational signatures – distinct patterns of genetic changes caused by specific biological processes or exposures. One of the key findings was the prevalence of a mutational signature associated with aristolochic acid exposure in Romania, Serbia, and Thailand. Aristolochic acid, a compound found in certain herbal remedies, has long been recognised as a potent carcinogen. In these countries, the majority of cases exhibited this signature, often with high mutation loads, underscoring a significant environmental exposure to this substance. But this pattern was rare or absent in the other regions studied, highlighting the localised nature of this risk factor. In Japan, researchers discovered another unique mutational signature, present in over 70% of ccRCC cases but nearly non-existent elsewhere. The cause of this signature remains unknown, but its prevalence suggests exposure to a regional carcinogen. This finding calls for further investigation to identify the agent responsible and to determine its impact on public health. The stark geographic differences in mutational patterns suggest that environmental and lifestyle factors play a more complex role in cancer development than previously understood. Tobacco smoking, a well-documented risk factor for various cancers, was confirmed as a contributor to kidney cancer in this study. Regions with higher tobacco consumption displayed mutational signatures associated with smoking-related carcinogens. But other recognised risk factors, such as obesity and hypertension, did not show corresponding mutational signatures. This suggests that these factors might promote cancer through non-mutagenic pathways, challenging traditional views of cancer risk. The study highlights the limitations of conventional epidemiology in identifying cancer-causing agents and demonstrates the potential of genomic analysis to uncover hidden risks. By examining somatic mutations in tumour genomes, researchers can trace the footprints of environmental exposures that might otherwise go undetected. This approach provides a powerful complement to traditional methods, enabling a deeper understanding of cancer’s aetiology. The findings also raise pressing public health concerns. In Southeast Europe and parts of Asia, the widespread presence of aristolochic acid-linked mutations indicates that tens of millions of people may have been exposed to this carcinogen. While the source of exposure remains unclear, addressing this risk is critical. Similarly, identifying the agent behind the mutational signature found in Japan could pave the way for preventive measures in the affected population. Further research is needed to explore the newly identified mutational patterns and their implications for cancer prevention. Larger genomic studies and detailed investigations into environmental exposures could help pinpoint the unknown agents and clarify their global impact. These efforts will be essential for developing strategies to reduce the burden of kidney cancer and other related diseases.