International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden¹. In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence². Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases and but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics.

许多癌症类型的发病率在国际上存在差异，这表明传统流行病学尚未确定的致癌物暴露的存在对癌症负担做出了重大贡献¹。在透明细胞肾细胞癌中，肥胖、高血压和吸烟是危险因素，但它们并不能解释其发病率的地理差异²。通过对不同发病率人群的癌症基因组进行测序并检测体细胞突变模式的差异，可以推断出根本原因。在这里，我们对来自 11 个国家不同发病率的 962 例透明细胞肾细胞癌进行了测序。不同国家的体细胞突变情况不同。在罗马尼亚、塞尔维亚和泰国，大多数情况下都存在马兜铃酸化合物的突变特征，但在其他地方很少见。在日本，超过 70% 的病例发现了不明原因的突变特征，但在其他地方这一比例不到 2%。未知原因的进一步突变特征普遍存在，但在肾癌发病率较高的国家表现出较高的突变负荷。已知的吸烟特征与烟草消费相关，但没有特征与肥胖或高血压相关，这表明非诱变作用机制是这些危险因素的基础。这项研究的结果表明存在多种、地理上可变的诱变暴露，可能影响数以千万计的人，并说明了通过大规模全球癌症基因组学对癌症因果关系有新见解的机会。