中国女性患者上尿路上皮癌复发的多基因机制研究

Upper urinary tract urothelial carcinoma (UTUC) is a rare and heterogonous disease. The multifocality and incidence of bladder recurrence is much higher in UTUC, which is associated with surgery complications, higher costs of treatment, and potential further radical cystectomy. However, none of the molecular markers has fulfilled the clinical and statistical criteria necessary to support their introduction in daily clinical decision making. Our previous studies had shown that a higher incidence of UTUC has also been described in Chinese patients compared to the western patients. Preliminary data indicates that arsenic exposure promotes UTUC tumorigenesis. It has been shown that AA will form DNA adduct (AL-DNA) which leads to unique genetic mutations, A to T. Due to the broadly consumption of Chinese herbs which contain aristolochic acid (AA) in Chinese patients. We hypothesize that arsenic exposure may contribute the unique clinical features in Chinese patients. To prove it, we will detect genomic variants by whole genome sequencing. By comparing the AA-associated UTUC (AA-UTUC) with non-AA-associated UTUC (NAA-UTUC), we will systematically elucidate the molecular subtypes and mechanisms of Chinese UTUC tumorigenesis and recurrence. Then, we will integrate functional analysis and network analysis to identify the critical genetic variations which promote the tumor initiation and recurrence. Taken together, our study will facilitate the establishment of clinical prediction models which might help to guide decision-making with regard to timing of surveillance and type of treatment strategies.

上尿路尿路上皮癌(upper urinary tract urothelial carcinoma，UTUC)的生物学特性和预后存在异质性，术后容易出现复发。课题组前期通过大样本的临床研究发现：中国人群UTUC患者的临床病理特征与西方人群明显不同：女性患者比例高、病理级别低、复发率高等。这可能与中国人群广泛服用含有马兜铃酸（Aristolochic acid，AA）的中草药有关。因此，本课题将主要研究女性UTUC患者的分子病理分型、复发的分子机制以及致癌的关键基因和驱动基因；并比较分析AA相关性UTUC和非AA相关性UTUC的异同，建立临床预后模型，以指导临床诊断治疗、估评预后危险因素、提高患者生存率。

上尿路尿路上皮癌（UTUC）是一种罕见但是具有异质性的肿瘤。UTUC具有多病灶性和较高的膀胱复发发生率，这与手术并发症、较高的治疗费用和根治性膀胱切除术有关。然而，目前并没有一种达到临床和统计标准的UTUC分子标记物能够应用于临床决策。课题组前期的研究发现与西方患者相比，中国患者的UTUC发病率更高。由于中国患者广泛食用含有马兜铃酸（AA）的中草药，我们推测AA暴露可能导致中国患者的独特临床特征。本项目以全基因组及全基因组甲基化测序数据作为研究对象，在整合公共数据的基础上，对泌尿生殖系统肿瘤，包括UTUC进行了诊断、分级以及其潜在的生物学特征进行了研究。本课题在95例无肿瘤个体和168例泌尿生殖系统癌症患者中，利用低覆盖度全基因组测序技术评估了每一例患者的拷贝数变异（CNAs），并使用支持向量机等方法开发了一种基于拷贝数变异的尿液cfDNA检测算法（UCdetector）。在此基础上，利用225例泌尿生殖癌症患者和88例健康人的尿沉渣低深度全基因组重亚硫酸氢盐测序，同时整合CNA和DNA甲基化突变数据，建立了一个集成分类算法（GUseek），用于对泌尿生殖肿瘤进行诊断和溯源。我们的结果表明UCdetector和GUseek在泌尿生殖肿瘤，包括UTUC中进行经济有效、无创地检测和诊断方面有巨大的潜力，能够应用于临床有助于风险分级和预后预测。同时，本课题对90例中国UTUC患者进行全基因组测序，单核苷酸和拷贝数变异检测并对相应突变特征进行临床关联研究。研究发现AA亚类实际上是一个低风险的亚组，并且利用低覆盖的全基因组测序数据能够在UTUC患者的尿液中检测到与原发肿瘤一致的AA突变特征，暗示AA突变特征作为预后分子标物的潜力。本课题从UTUC队列中识别了6个拷贝数突变特征，而且发现拷贝数突变特征可作为独立的预后因子，暗示了拷贝数突变特征作为UTUC风险评估的可行性，为UTUC的精准诊治提供了理论基础。