Ludwig Center for Cancer Genetics and Therapeutics and the Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Sci Transl Med. 2013 Aug 7;5(197):197ra102. doi: 10.1126/scitranslmed.3006200.
In humans, exposure to aristolochic acid (AA) is associated with urothelial carcinoma of the upper urinary tract (UTUC). Exome sequencing of UTUCs from 19 individuals with documented exposure to AA revealed a remarkably large number of somatic mutations and an unusual mutational signature attributable to AA. Most of the mutations (72%) in these tumors were A:T-to-T:A transversions, located predominantly on the nontranscribed strand, with a strong preference for deoxyadenosine in a consensus sequence (T/CAG). This trinucleotide motif overlaps the canonical splice acceptor site, possibly accounting for the excess of splice site mutations observed in these tumors. The AA mutational fingerprint was found frequently in oncogenes and tumor suppressor genes in AA-associated UTUC. The AA mutational signature was observed in one patient's tumor from a UTUC cohort without previous indication of AA exposure. Together, these results directly link an established environmental mutagen to cancer through genome-wide sequencing and highlight its power to reveal individual exposure to carcinogens.
在人类中，接触马兜铃酸（AA）与上尿路上皮癌（UTUC）有关。对 19 名有明确 AA 接触史的 UTUC 个体进行外显子组测序，发现了大量体细胞突变和一种归因于 AA 的不寻常突变特征。这些肿瘤中的大多数突变（72%）为 A:T 到 T:A 颠换，主要位于非转录链上，在一致序列（T/CAG）中强烈偏向脱氧腺苷。这个三核苷酸基序与规范的剪接受体位点重叠，可能解释了在这些肿瘤中观察到的剪接位点突变过多。AA 突变指纹在 AA 相关 UTUC 的癌基因和肿瘤抑制基因中经常出现。在一个没有先前 AA 暴露迹象的 UTUC 队列中，一位患者的肿瘤中也观察到了 AA 突变特征。这些结果通过全基因组测序直接将已建立的环境诱变剂与癌症联系起来，并突出了其揭示个体接触致癌物的能力。
