PO.MCB08.05 · 分子与细胞生物学

通过全面的多组学分析深化对非肌层浸润性膀胱癌（NMIBC）疾病生物学的认识

Advancing insights into disease biology of non-muscle invasive bladder cancer (NMIBC) through comprehensive multi-omics analysis

编号 7266 展板 6 时间 4/22 09:00–12:00 区域 Section 21 主讲 Longen Zhou, PhD

分会场 Genomic Approaches to Define Tumor Biology and Clinical Stratification

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作者与单位 Authors & Affiliations

Siew Kee Low¹, Yoshiyuki Nagumo², Xuesong Lyu¹, Jiarui Zhang³, Jie Zhao¹, Kozaburo Tanuma², Satoka Kinase², Karen Urtishak³, Neil Beeharry³, Shibu THOMAS³, Longen Zhou³, Hiroyuki Nishiyama²

¹Johnson & Johnson, Shanghai, China,²Department of Urology, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan,³Johnson & Johnson, Spring House, PA

摘要 Abstract

中文摘要

非肌层浸润性膀胱癌（NMIBC）约占所有膀胱癌病例的75%，具有高复发率并可能进展为肌层浸润性疾病。NMIBC的治疗策略包括经尿道膀胱肿瘤切除术（TURBT），随后主要辅以卡介苗（BCG）免疫治疗或化疗。尽管NMIBC的管理已取得进展，但理解其分子基础及治疗后的变化对于改善预后、患者分层和制定合理治疗策略仍然至关重要。在此，我们开展了全外显子组和转录组测序，以阐明分子图谱和肿瘤微环境，并发掘与BCG应答相关的潜在预后生物标志物。利用转录组测序数据，通过BCG应答亚型预测器评估了三种不同的BCG应答亚型（BRS）。评估了高危组与低/中危组之间基因组改变的患病率以及通过ssGSEA（单样本基因集富集分析）分析的京都基因与基因组百科全书（KEGG）转录组特征的比较。共分析了37例治疗前NMIBC患者的数据（N=37），包括接受TURBT后辅以BCG治疗的患者〔N=16〕和仅接受TURBT的患者〔N=21〕。37例患者的基因组分析显示突变频率与已发表文献一致，患病率最高的为端粒酶逆转录酶（TERT）（78.4%），其次为结节性硬化复合体1（TSC1）（64.9%）和赖氨酸（K）特异性甲基转移酶（KMT）2D（51.4%）。值得注意的是，成纤维细胞生长因子受体3（FGFR3）的突变频率在低危和中危组中（66.7%，N=15）高于高危组（36.4%，N=22）。利用转录组分析通过ssGSEA计算的通路评分显示，高危组相比低危和中危组，细胞周期通路富集的基因表达谱显著更高（p=0.033）。BRS3肿瘤患者在接受BCG治疗后，其无进展生存期（PFS）较BRS1/2显著缩短（p=0.0095，HR=5.92）。BRS3肿瘤表现出上皮-间质转化和基底标志物的高表达，并以免疫抑制特征为特点。我们发现FGFR3突变率在低危和中危组中更高。细胞周期失调已知会促进膀胱癌的肿瘤进展和侵袭性；我们的通路分析发现高危NMIBC中存在细胞周期通路富集，这加深了我们对NMIBC疾病生物学的认识。我们的数据验证了BRS3亚型在预测不良BCG应答方面的价值，证明了该分类方法的稳健性。鉴于本研究队列较小，尚需进一步研究以证实这些发现。

查看英文原文 English abstract

Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 75% of all bladder cancer cases and has high rate of recurrence and potential progression to muscle-invasive disease. Treatment strategies for NMIBC include transurethral resection of bladder tumor (TURBT) followed mainly by Bacillus Calmette-Guérin (BCG) immunotherapy or chemotherapy. Although NMIBC management has progressed, understanding its molecular basis and changes after treatment remains critical for better prognosis, patient stratification and informed treatment strategies. Here, we conducted whole exome and transcriptomic sequencing to elucidate molecular landscape and tumor microenvironment and uncover potential prognostic biomarkers associated with BCG response. Three distinct BCG response subtypes (BRS) were assessed by BCG response subtype predictor using transcriptomic sequencing data. Comparison of genomic alterations' prevalence and transcriptomic signatures in Kyoto Encyclopedia of Genes and Genomes (KEGG) via ssGSEA (single sample Gene Set Enrichment Analysis) between high vs low/intermediate risk were evaluated. Data from 37 pre-treatment NMIBC patients were analyzed (N = 37); including patients treated with TURBT followed by BCG [N = 16], and with TURBT only [N= 21]. Genomic profiling of 37 patients demonstrated mutation frequencies consistent with published literature, with highest prevalence observed in Telomerase Reverse Transcriptase (TERT) (78.4%), followed by Tuberous Sclerosis Complex 1 (TSC1) (64.9%) and Lysine (K)-Specific Methyltransferase (KMT)2D (51.4%). Notably, mutation frequency of Fibroblast Growth Factor Receptor 3 (FGFR3) was higher among low- and intermediate-risk groups (66.7%, N = 15) compared to high-risk groups (36.4%, N = 22). Pathway score calculated using ssGSEA from transcriptomic profiling revealed a markedly higher gene expression profile enriched in cell-cycle pathway in among high- compared to low- and intermediate-risk groups (p = 0.033). Patients with BRS3 tumors exhibited significantly reduced progression free survival (PFS) versus BRS1/2 (p= 0.0095, HR = 5.92), following BCG treatment. BRS3 tumors demonstrated elevated expression of epithelial-mesenchymal transition and basal markers and were characterized by an immunosuppressive profile. We identified that FGFR3 mutation rate is higher among low- and intermediate risk. Cell cycle dysregulation is known to contribute in tumor progression and aggressiveness of bladder cancer; our pathway analysis identified cell cycle pathway enrichment among high-risk NMIBC, which enhances our understanding of NMIBC disease biology. Our data validated BRS3 subtyping in predicting poor BCG response, demonstrating robustness of this classification approach. Further investigation is warranted to confirm these findings, considering smaller cohort in this study

利益披露 Disclosure

S. Low, Johnson & Johnson Employment, Are employee of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. Y. Nagumo, Astellas ). Chugai Pharma ). Johnson & Johnson ). AstraZeneca Other, consulting fees. Merck Sharp & Dohme Other, consulting fees. Ono Pharmaceutical consulting fees. AstraZeneca Other, honoraria for speakers’ bureaus. Astellas honoraria for speakers’ bureaus. Bristol Myers Squibb honoraria for speakers’ bureaus. Merck Biopharma Co. Ltd., honoraria for speakers’ bureaus. Merck Sharp & Dohme honoraria for speakers’ bureaus. Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus. Ono Pharmaceutical honoraria for speakers’ bureaus. Pfizer honoraria for speakers’ bureaus. X. Lyu, Johnson & Johnson Employment, Are employee of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. J. Zhang, Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. J. Zhao, Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. K. Tanuma, Astellas ). Chugai Pharma ). Johnson & Johnson ). AstraZeneca consulting fees. Johnson & Johnson consulting fees. Merck Sharp & Dohme consulting fees. Ono Pharmaceutical consulting fees. AstraZeneca honoraria for speakers’ bureaus. Astellas honoraria for speakers’ bureaus. Bristol Myers Squibb honoraria for speakers’ bureaus. Merck Biopharma Co. Ltd honoraria for speakers’ bureaus. Merck Sharp & Dohme honoraria for speakers’ bureaus. Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus. Ono Pharmaceutical honoraria for speakers’ bureaus. Pfizer honoraria for speakers’ bureaus. S. Kinase, Astellas ). Chugai Pharma ). Johnson & Johnson ). AstraZeneca consulting fees. Johnson & Johnson consulting fees. Merck Sharp & Dohme consulting fees. Ono Pharmaceutical consulting fees. AstraZeneca honoraria for speakers’ bureaus. Astellas honoraria for speakers’ bureaus. Bristol Myers Squibb honoraria for speakers’ bureaus. Merck Biopharma Co. Ltd honoraria for speakers’ bureaus. Merck Sharp & Dohme honoraria for speakers’ bureaus. Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus. Ono Pharmaceutical honoraria for speakers’ bureaus. Pfizer honoraria for speakers’ bureaus. K. Urtishak, Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. N. Beeharry, Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. S. Thomas, Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. L. Zhou, Johnson & Johnson Employment, Are employees of Johnson & Johnson and may hold stocks or stock options in Johnson & Johnson. H. Nishiyama, Astellas ). Chugai Pharma ). Johnson & Johnson ). AstraZeneca consulting fees. Johnson & Johnson consulting fees. Merck Sharp & Dohme consulting fees. Ono Pharmaceutical consulting fees. AstraZeneca honoraria for speakers’ bureaus. Astellas honoraria for speakers’ bureaus. Bristol Myers Squibb honoraria for speakers’ bureaus. Merck Biopharma Co. Ltd honoraria for speakers’ bureaus. Merck Sharp & Dohme honoraria for speakers’ bureaus. Nippon Kayaku Co. Ltd honoraria for speakers’ bureaus. Ono Pharmaceutical honoraria for speakers’ bureaus. Pfizer honoraria for speakers’ bureaus.

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