Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2019 Feb 1;25(3):967-976. doi: 10.1158/1078-0432.CCR-18-2039. Epub 2018 Oct 23.
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.
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.
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, and were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; < 0.001), whereas and were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; < 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 and . Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness.
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.
研究上尿路尿路上皮癌（UTUC）和膀胱尿路上皮癌（UCB）之间的基因组差异，重点定义时间上不同的肿瘤的克隆相关性。
我们使用靶向下一代测序方法前瞻性地对肿瘤和匹配的种系 DNA 进行测序。该队列包括 195 例 UTUC 患者和 454 例 UCB 患者。对于 29 例有 UTUC 病史且随后发生 UCB 的患者亚组，分析了这两种肿瘤以评估它们的克隆相关性。
随着 UTUC 临床状态的进展，RTK/RAS 通路的改变减少，但 TP53/MDM2 的改变增多。与 UCB 相比，UTUC 中 和 的改变频率较低（分别为 26%比 46%，3%比 20%，8%比 19%；<0.001），而 和 的改变频率较高（分别为 40%比 26%，12%比 4%；<0.001）。基于肿瘤突变负担、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（MSI-high/错配修复缺陷）。UTUC 后膀胱癌复发的风险与 和 的突变显著相关。对同一患者的 UCB 与相应的 UTUC 肿瘤进行比较，支持它们的克隆相关性。
UTUC 和 UCB 在常见基因组改变的流行率方面存在显著差异。在同时患有这两种肿瘤的患者中，UCB 和 UTUC 总是具有克隆相关性。UTUC 的基因组特征提供了关于膀胱癌复发风险的信息，并可以识别与 Lynch 综合征相关的肿瘤。
