Known risk factors, such as smoking, obesity and hypertension, do not explain variations in the incidence of clear cell renal cell carcinoma (ccRCC) between different geographical regions. A new study reports that the somatic mutation profiles of ccRCC differ between countries, which indicates substantial geographical variations in mutagenic exposures.

To investigate mutational signatures in ccRCC, Senkin and coauthors sequenced the ccRCC genomes of 962 patients from 11 countries worldwide. The somatic mutation burdens of the ccRCCs varied between countries, with the highest burden in Romania. In most cases of ccRCC from Romania, Serbia and Thailand, but only rare cases elsewhere, the researchers identified mutational signatures that are characteristic of exposure to aristolochic acids, which are known carcinogens. By contrast, more than 70% of cases of ccRCC from Japan had a mutational signature of unknown cause, which was identified in less than 2% of cases from other countries. Another mutational signature of unknown aetiology was identified in cases of ccRCC from all 11 countries. The average country-specific mutation load attributable to this signature positively correlated with the country-specific age-standardized incidence of kidney cancer. Associations were also identified between mutational signatures and tobacco smoking, but not between mutational signatures and other ccRCC risk factors.

已知的危险因素，如吸烟、肥胖和高血压，并不能解释不同地理区域之间透明细胞肾细胞癌 (ccRCC) 发病率的差异。一项新的研究报告称，ccRCC 的体细胞突变谱在不同国家之间存在差异，这表明致突变暴露存在巨大的地理差异。

为了研究 ccRCC 的突变特征，Senkin 和合著者对来自全球 11 个国家的 962 名患者的 ccRCC 基因组进行了测序。 ccRCC 的体细胞突变负担因国家而异，其中罗马尼亚负担最高。在罗马尼亚、塞尔维亚和泰国的大多数 ccRCC 病例中，但在其他地方只有极少数病例中，研究人员发现了暴露于马兜铃酸（已知的致癌物质）特征的突变特征。相比之下，超过 70% 的日本 ccRCC 病例具有不明原因的突变特征，而在其他国家的病例中只有不到 2% 的突变特征被发现。在所有 11 个国家的 ccRCC 病例中发现了另一个未知病因的突变特征。归因于此特征的平均国家特定突变负荷与国家特定年龄标准化肾癌发病率呈正相关。还发现突变特征与吸烟之间存在关联，但突变特征与其他 ccRCC 危险因素之间没有关联。