Abstract：
OBJECTIVE: 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).
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
目的：本研究调查了一个现实世界的多中心泌尿系癌症（UTC）患者队列，主要疾病部位包括膀胱，尿道,和上束，他们参加了生殖系和肿瘤的研究分子测试。这项研究的目的是评估可能影响鉴定临床上可行的种系致病变异（PV）的可能性的因素。
方法：从肿瘤学研究信息交换网络联盟的10个癌症研究所确定了UTC患者。数据集包括抽象的临床数据与种系和肿瘤基因组数据，并进行了比较分析。
结果：在354例患者中的16例（4.5%）中发现了癌症易感基因中临床可操作的种系PV。以尿道和上尿路为原发部位的患者肺静脉的比例较高，患病率为11％（5/45），在以膀胱为主要疾病部位的患者中，这一比例仅为3.6%(11/308)(P=.04)。基因组不稳定性的标志物没有显着差异（例如肿瘤突变负荷，微卫星不稳定性[MSI]，和杂合性的丧失，副本编号,和染色体不稳定性)在有PV的人和没有PV的人之间(P>.05)。在确定的PV中，同源重组修复(HRR)基因中有10个(62%),三个（19％）在错配修复（MMR）基因，和三个（19％）与其他途径相关的基因。
结论：基于组织的基因组不稳定性评估，如MSI，不能可靠地指示种系PV。除了MMR基因外，还包括HRR基因的综合临床种系测试方法可能会在大约10位患有非膀胱原发性疾病部位（例如上尿道和尿道）的患者中产生PV。
方法：从肿瘤学研究信息交换网络联盟的10个癌症研究所确定了UTC患者。数据集包括抽象的临床数据与种系和肿瘤基因组数据，并进行了比较分析。
结果：在354例患者中的16例（4.5%）中发现了癌症易感基因中临床可操作的种系PV。以尿道和上尿路为原发部位的患者肺静脉的比例较高，患病率为11％（5/45），在以膀胱为主要疾病部位的患者中，这一比例仅为3.6%(11/308)(P=.04)。基因组不稳定性的标志物没有显着差异（例如肿瘤突变负荷，微卫星不稳定性[MSI]，和杂合性的丧失，副本编号,和染色体不稳定性)在有PV的人和没有PV的人之间(P>.05)。在确定的PV中，同源重组修复(HRR)基因中有10个(62%),三个（19％）在错配修复（MMR）基因，和三个（19％）与其他途径相关的基因。
结论：基于组织的基因组不稳定性评估，如MSI，不能可靠地指示种系PV。除了MMR基因外，还包括HRR基因的综合临床种系测试方法可能会在大约10位患有非膀胱原发性疾病部位（例如上尿道和尿道）的患者中产生PV。
