Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma
Aristolochic acid mutational signature defines the low-risk subtype in upper tract urothelial carcinoma
复制标题
马兜铃酸突变特征定义了上尿路尿路上皮癌的低风险亚型
DOI：
10.7150/thno.43251
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Ci, Weimin
中科院分区：
文献类型：
--
作者：
Lu, Huan;Liang, Yuan;Ci, Weimin
理论基础：饮食中暴露于马兜铃酸和类似化合物(统称为AA)是肾病和随后的上尿路癌(UTUC)的重要危险因素。东亚人群中UTUC的患病率很高，他们有一种不寻常的全基因组AA诱导突变模式(宇宙标志22)。将突变特征分析与临床病理信息相结合，可能显示出对UTUC亚型进行风险分级的巨大潜力。方法：对90例UTUC患者进行全基因组测序，提取突变特征。来自26名UTUC患者的尿液无细胞DNA的基因组测序数据被用来非侵入性地鉴定突变特征。26例患者中有8例进行了原发肿瘤的基因组测序。采用Kaplan-Meier方法计算无转移生存率(MFS)和肿瘤特异性生存率(CS)。结果：数据分析显示，相当大比例的患者具有AA突变特征，并与服用含有AA的草药、女性、肾功能低下和多灶性有关。野性癌变被发现对多灶性有部分作用。然而，与非AA Sig亚型相比，AA Sig亚型UTUC患者表现出更好的CSS和MFS结果。此外，AA Sig亚型患者表现出更高的肿瘤突变负荷，预测的新抗原数量更多，以及浸润性淋巴细胞，这表明免疫治疗的潜力。我们还在AA处理的人肾小管HK-2细胞中证实了AA的签名。值得注意的是，可以使用临床适用的测序策略(低覆盖率)在原发肿瘤和尿液无细胞DNA中确定AA亚型，作为治疗选择的基础。结论：AA突变特征作为筛查工具定义了具有治疗相关性的低风险UTUC。AA突变特征作为输尿管镜检查和/或尿液无细胞DNA的分子预后标志物，在考虑保肾治疗和/或免疫检查点抑制治疗时，对于诊断的不确定性特别有用。
Rationale: Dietary exposure to aristolochic acids and similar compounds (collectively, AA) is a significant risk factor for nephropathy and subsequent upper tract urothelial carcinoma (UTUC). East Asian populations, who have a high prevalence of UTUC, have an unusual genome-wide AA-induced mutational pattern (COSMIC signature 22). Integrating mutational signature analysis with clinicopathological information may demonstrate great potential for risk ranking this UTUC subtype. Methods: We performed whole-genome sequencing (WGS) on 90 UTUC Chinese patients to extract mutational signatures. Genome sequencing data for urinary cell-free DNA from 26 UTUC patients were utilized to noninvasively identify the mutational signatures. Genome sequencing for primary tumors on 8 out of 26 patients was also performed. Metastasis-free survival (MFS) and cancer-specific survival (CSS) were measured using Kaplan-Meier methods. Results: Data analysis showed that a substantial proportion of patients harbored the AA mutational signature and were associated with AA-containing herbal drug intake, female gender, poor renal function, and multifocality. Field cancerization was found to partially contribute to multifocality. Nevertheless, AA Sig subtype UTUC patients exhibited favorable outcomes of CSS and MFS compared to the No-AA Sig subtype. Additionally, AA Sig subtype patients showed a higher tumor mutation burden, higher numbers of predicted neoantigens, and infiltrating lymphocytes, suggesting the potential for immunotherapy. We also confirmed the AA signature in AA-treated human renal tubular HK-2 cells. Notably, the AA subtype could be ascertained using a clinically applicable sequencing strategy (low coverage) in both primary tumors and urinary cell-free DNA as a basis for therapy selection. Conclusion: The AA mutational signature as a screening tool defines low-risk UTUC with therapeutic relevance. The AA mutational signature, as a molecular prognostic marker using either ureteroscopy and/or urinary cell-free DNA, is especially useful for diagnostic uncertainty when kidney-sparing treatment and/or immune checkpoint inhibitor therapy were considered.