Dataset Information

Genomic Sequencing for Bladder Urothelial Carcinoma and Its Clinical Implications for Immunotherapy.

ABSTRACT:

Purpose

This study aimed to explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI).

Materials and methods

We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, programmed death-ligand 1 (PD-L1) expression was evaluated in a subset of patients (n=57) including those treated with ICI (n=8).

Results

We identified frequent molecular dysregulations in chromatin regulatory genes (KDM6A, ARID1A, MLL2, and STAG2) and recurrent copy number alterations. Thirty-five samples (54.7%) were PD-L1-positive (PD-L1 combined positive score ≥ 1) with a significantly higher exonic tumor mutational burden (TMB) compared to PD-L1-negative BC samples (p=0.010). We observed that various immune-responsive pathways, including the PD-L1 signaling pathway, were enriched significantly in PD-L1-positive BCs. Interestingly, genes in the CTLA4 pathway were enriched significantly in PD-L1-positive BC as well. Among eight patients who received ICI, progressive disease was confirmed in one patient, whose tumor had low exonic TMB, negative PD-L1 status, and a relatively colder microenvironment.

Conclusion

Gaining new insights into the molecular landscape of BC will improve treatment strategies. Our analysis suggests a rationale for studying dual checkpoint inhibition against BC.

SUBMITTER: Kim R

PROVIDER: S-EPMC9296940 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Publications

Genomic Sequencing for Bladder Urothelial Carcinoma and Its Clinical Implications for Immunotherapy.

Kim Ryul R Hong Jung Yong JY Lee Jeeyun J Kwon Ghee Young GY Jeong Byong Chang BC Park Se Hoon SH

Cancer research and treatment 20211117 3

<h4>Purpose</h4>This study aimed to explore the genomic and transcriptomic landscape of bladder cancer (BC) and its implication for treatment with an immune checkpoint inhibitor (ICI).<h4>Materials and methods</h4>We analyzed whole-exome and -transcriptome sequences of tumor samples from 64 BC patients who underwent surgical resection with either transurethral resection or radical cystectomy. For exploratory purposes, programmed death-ligand 1 (PD-L1) expression was evaluated in a subset of pati ...[more]

PMID: 34793662

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Project description:BackgroundsDespite 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.Materials and methodsA 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.ResultsIn 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.DiscussionsThe 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.

Project description:BackgroundDifferent genomic characterization in urothelial carcinoma (UC) by site of origin may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity.Materials and methodsWe prospectively sequenced 118 tumors and matched blood DNA from Chinese patients with UC using next-generation sequencing techniques, including 45 UTUC and 73 UCB. Two hundred twenty-six patients with UTUC and 350 patients with UCB for The Cancer Genome Atlas were acquired from the cbioportal.ResultsThere were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared with UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. Patients with UTUC had lower PD-L1 than those with UCB. There was no significant difference in the number of DDR mutations, copy number variation counts, and tumor mutational burden between UTUC and UCB.ConclusionUTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.Implications for practiceThis study's findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.

Dataset Information

Genomic Sequencing for Bladder Urothelial Carcinoma and Its Clinical Implications for Immunotherapy.

Purpose

Materials and methods

Results

Conclusion

Publications

Genomic Sequencing for Bladder Urothelial Carcinoma and Its Clinical Implications for Immunotherapy.

Similar Datasets

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