Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
Clonal Relatedness and Mutational Differences between Upper Tract and Bladder Urothelial Carcinoma
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DOI：
10.1158/1078-0432.ccr-18-2039
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发表时间：
2019-02-01
影响因子：
11.5
通讯作者：
Solit, David B.
中科院分区：
文献类型：
--
作者：
Audenet, Francois;Isharwal, Sumit;Solit, David B.
目的：为了研究上尿路上皮癌（UTUC）和膀胱癌（UCB）之间的基因组差异，重点是定义时间上不同的tumors.Experimental designs克隆相关性：我们前瞻性地测序肿瘤和匹配的生殖系DNA使用有针对性的下一代测序方法。该队列包括195名UTUC患者和454名UCB患者。对于一个亚组的29例UTUC和随后的UCB的历史，这两个肿瘤进行了分析，以评估其克隆relatedness.Results：随着发展到更高的UTUC临床状态，有较少的RTK/RAS通路的改变，但更多的TP 53/MDM 2的改变。与UCB相比，UTUC中TP 53、RB 1和ERBB 2的改变频率较低（分别为26% vs. 46%、3% vs. 20%、8% vs. 19%; Q < 0.001），而FGFR 3和HRAS的改变频率较高（分别为40% vs. 26%、12% vs. 4%; Q < 0.001）。基于对肿瘤突变负荷、MSISensor评分和突变特征的综合分析，7.2%的UTUC肿瘤被归类为MSI-H/dMMR缺陷型（MSI-H/dMMR）。UTUC后膀胱复发的风险与FGFR 3、KDM 6A、CCND 1和TP 53的突变显著相关。比较UCB与相应的UTUC肿瘤从同一patient支持他们的克隆relatedness.Conclusions：UTUC和UCB表现出显着差异的常见基因组变异的患病率。在有两种肿瘤病史的个体患者中，UCB和UTUC总是克隆相关的。UTUC的基因组特征提供了有关膀胱复发风险的信息，并可以识别与Lynch综合征相关的肿瘤。
Purpose: To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors.Experimental Design: We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness.Results: With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.Conclusions: UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.