未经证实:尽管尿路上皮癌(UC)患者的基因组景观,尤其是膀胱UC(UCB),已被全面描述,并与发病机制和治疗偏好相关,上尿路UC(UTUC)的基因组特征尚未完全阐明。
UnASSIGNED:本研究共纳入131例中国UTUC(74例肾盂和57例输尿管)和118例UCB患者,并对618个癌症相关基因进行靶向下一代测序(NGS),以显示体细胞和种系改变的谱.COSMIC数据库,包括30个突变签名,用于评估突变光谱。此外,TCGA-UCB,MSKCC-UCB,和MSKCC-UTUC数据集被检索用于西方和中国UC患者之间的预形成基因组改变(GAs)比较分析。
未经评估:在我们的队列中,93.98%和56.63%的UC患者被确定为致癌和可操作的躯体改变,分别。同时,11.24%的中国UC患者(14.50%和7.63%的UTUC和UCB病例,分别)在22个基因中鉴定出共有32个致病性/可能致病性种系变异,与DNA损伤修复(DDR)相关的BRCA1(1.20%)和CHEK2(1.20%)最为普遍。中国UTUC和UCB患者具有明显的体细胞基因组特征,特别是在KMT2D/C/A的患病率明显不同,GNAQ,ERCC2、RB1和PPM1D。此外,我们还发现,在肾盂癌和输尿管癌之间,ELF3,TP53,PMS2和FAT4的患病率存在显著差异.此外,22.90%和33.90%的UTUC和UCB患者,分别,在DDR相关基因/途径中具有至少一个有害/可能有害的改变。随后,突变特征分析显示,无论UTUC或UCB,具有突变特征22的UC患者,始终具有明显更高水平的肿瘤突变负担(TMB),这被证明是正相关的客观完全/部分缓解率在IMvocor210队列。相比之下,中国和西方UTUC患者在致癌相关基因/途径方面也存在差异,特别是在TP53,RTK/RAS中,和PI3K途径;此外,WNT通路改变较多,但TP53、RTK/RAS较少,HIPPO,在中国UCB中鉴定出PI3K途径。
UNASSIGNED:对基因组突变景观的深入分析揭示了中国UTUC和UCB之间不同的致病机制,和特定的基因组特征可以识别UTUC/UCB的高危人群,并提供有关选择替代治疗方案的信息.
Despite the genomic landscape of urothelial carcinomas (UC) patients, especially those with UC of bladder (UCB), has been comprehensively delineated and associated with pathogenetic mechanisms and treatment preferences, the genomic characterization of upper tract UC (UTUC) has yet to be fully elucidated.
A total of 131 Chinese UTUC (74 renal pelvis & 57 ureter) and 118 UCB patients were enrolled in the present study, and targeted next-generation sequencing (NGS) of 618 cancer-associated genes were conducted to exhibit the profile of somatic and germline alterations. The COSMIC database, including 30 mutational signatures, were utilized to evaluate the mutational spectrums. Moreover, TCGA-UCB, MSKCC-UCB, and MSKCC-UTUC datasets were retrieved for preforming genomic alterations (GAs) comparison analysis between Western and Chinese UC patients.
In our cohort, 93.98% and 56.63% of UC patients were identified with oncogenic and actionable somatic alterations, respectively. Meanwhile, 11.24% of Chinese UC patients (of 14.50% and 7.63% of UTUC and UCB cases, respectively) were identified to harbor a total of 32 pathogenic/likely-pathogenic germline variants in 22 genes, with DNA damage repair (DDR)-associated BRCA1 (1.20%) and CHEK2 (1.20%) being the most prevalent. Chinese UTUC and UCB patients possessed distinct somatic genomic characteristics, especially with significantly different prevalence in KMT2D/C/A, GNAQ, ERCC2, RB1, and PPM1D. In addition, we also found notable differences in the prevalence of ELF3, TP53, PMS2, and FAT4 between renal pelvis and ureter carcinomas. Moreover, 22.90% and 33.90% of UTUC and UCB patients, respectively, had at least one deleterious/likely deleterious alteration in DDR related genes/pathways. Subsequently, mutational signature analysis revealed that UC patients with mutational signature 22, irrespective of UTUC or UCB, consistently had the markedly higher level of tumor mutational burden (TMB), which was proved to be positively correlated with the objective complete/partial response rate in the IMvigor210 cohort. By comparison, Chinese and Western UTUC patients also differed regrading GAs in oncogenic-related genes/pathways, especially in TP53, RTK/RAS, and PI3K pathways; besides, more alterations in WNT pathway but less TP53, RTK/RAS, HIPPO, and PI3K pathways were identified in Chinese UCB.
The in-depth analysis of genomic mutational landscapes revealed distinct pathogenetic mechanisms between Chinese UTUC and UCB, and specific genomic characterizations could identify high risk population of UTUC/UCB and provided information regarding the selection of alternative therapeutic regimens.