这项研究调查了现实世界的多中心尿路癌 (UTC) 患者队列，原发病灶包括膀胱、尿道和上尿路，这些患者报名参加了生殖系和肿瘤的研究分子检测。本研究的目的是评估可能影响识别临床上可操作的种系致病性变异 (PV) 的可能性的因素。UTC 患者是从肿瘤学研究信息交换网络联盟的 10 个癌症研究所中确定的。该数据集包括抽象的临床数据以及种系和肿瘤基因组数据，并进行了比较分析。在 354 名患者中，有 16 名（4.5%）在癌症易感基因中鉴定出了临床上可操作的种系 PV。以尿道和上尿路为主要发病部位的患者中 PV 的患病率较高，为 11% (5/45)，而以膀胱为主要发病部位的患者中这一比例仅为 3.6% (11/308)疾病部位 (P = .04)。患有PV的人和不患有PV的人之间，基因组不稳定性标志物（例如肿瘤突变负荷、微卫星不稳定性[MSI]以及杂合性丢失、拷贝数和染色体不稳定性）没有显着差异（P > .05）。在确定的 PV 中，10 个 (62%) 属于同源重组修复 (HRR) 基因，3 个 (19%) 属于错配修复 (MMR) 基因，3 个 (19%) 属于与其他途径相关的基因。 基于组织的评估基因组不稳定性（例如 MSI）并不能可靠地指示种系 PV。除了 MMR 基因之外还包括 HRR 基因的综合临床种系检测方法可能会在大约 10 名患有非膀胱原发性疾病部位（例如上尿路和尿道）的患者中产生 PV。

This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV).Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted.Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways.Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.