PO.CL01.09 · 临床研究

基于尿液游离DNA甲基化的去卷积在局限性泌尿道癌症中鉴定肿瘤特异性细胞类型

Urine cell-free DNA methylation-based deconvolution identifies tumor-specific cell types in localized urinary tract cancers

编号 3848 展板 9 时间 4/20 02:00–05:00 区域 Section 45 主讲 Ze Zhang, MBBS;MS;PhD

分会场 Liquid Biopsies: Circulating Nucleic Acids 3

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作者与单位 Authors & Affiliations

Ze Zhang¹, Rashad Nawfal¹, Gunsagar Gulati¹, Damien Vasseur¹, Ji-Heui Seo¹, Hunter Savignano¹, Razane El Hajj Chehade¹, Karl Semaan¹, Tamara Merhej², John Canniff¹, Noa Phillips¹, Ning Shen³, Phillip Adams¹, Ilana Epstein¹, Jack Horst¹, Alexis Zinselmeier¹, Rachel Throwbridge¹, Gwo-Shu Mary Lee¹, Jamil Azzi⁴, Michelle S. Hirsch⁴, Martin Kathrins⁴, Timothy N. Clinton⁴, Matthew Mossanen⁴, Keegan Korthauer³, Toni K. Choueiri⁵, Matthew L. Freedman¹, Sylvan C. Baca¹

¹DFCI/Harvard Medical School, Boston, MA,²Harvard Medical School, Boston, MA,³Department of Statistics, The University of British Columbia, Vancouver, BC, Canada,⁴Brigham Women's Hospital, Boston, MA,⁵Dana-Farber Cancer Institute, Boston, MA

摘要 Abstract

中文摘要

背景：尿液是一种有前景的液体活检来源，可用于泌尿系统癌症的无创检测与监测，而这类癌症目前缺乏用于早期诊断的筛查工具。游离DNA甲基化免疫沉淀测序（cfMeDIP-seq）是一种成熟的工具，用于分析游离DNA（cfDNA）中富集的5-甲基胞嘧啶（5mC）信号。近期开发的decemedip计算框架可实现从cfMeDIP-seq数据进行细胞类型去卷积，提供了一种推断肿瘤来源与免疫来源cfDNA贡献的策略。方法：我们设计了一个定制的泌尿系统癌症cfMeDIP-seq去卷积panel，并将其与decemedip框架整合，以估算九种细胞类型的比例，包括免疫亚群（B细胞、CD4⁺ T细胞、CD8⁺ T细胞、单核细胞、中性粒细胞和自然杀伤细胞）以及前列腺、肾脏和尿路上皮癌的肿瘤特异性特征。通过cfMeDIP-seq分析了Dana-Farber癌症研究所54名患者的尿液cfDNA，包括19例局限性膀胱癌（BLCA）、18例局限性肾细胞癌（RCC）、9例局限性上尿路尿路上皮癌（UTUC）和8例非癌性肾脏疾病病例。应用去卷积以推断这些组别的细胞类型组成。结果：RCC样本表现出显著高于BLCA和UTUC的肾癌来源cfDNA信号（p = 3e-06），而尿路上皮癌显示出显著高于RCC的尿路上皮癌来源信号（p = 1e-05）。肾癌与尿路上皮癌cfDNA信号比值区分RCC与尿路上皮癌的AUC为0.984。在膀胱癌队列中，五名尿路上皮癌信号较低的患者曾接受新辅助治疗，提示去卷积能够捕捉治疗相关变化。排除这些病例进一步改善了鉴别性能（AUC = 0.987）。RCC患者的肾癌来源信号也显著高于非癌性肾脏疾病患者（p = 0.03），支持该方法在良恶性鉴别中的效用。结论：通过cfMeDIP-seq进行的尿液cfDNA去卷积能够检测肿瘤特异性信号并分析局限性泌尿系统癌症的免疫细胞组成。这种无创液体活检方法展现了在早期检测、疾病分型、微小残留病评估和治疗反应监测方面的潜力，值得在更大规模的前瞻性队列中进行验证。

查看英文原文 English abstract

Background: Urine is a promising liquid biopsy source for non-invasive detection and monitoring of cancers of the urinary system, which currently lack screening tools for early diagnosis. Cell-free DNA methylation immunoprecipitation sequencing (cfMeDIP-seq) is a well-established tool to profile enriched 5-methylcytosine (5mC) signals in cell-free DNA (cfDNA). Recently, the decemedip computational framework was developed to enable cell-type deconvolution from cfMeDIP-seq data, providing a strategy to infer tumor- and immune-derived cfDNA contributions. Methods: We designed a customized urinary cancer cfMeDIP-seq deconvolution panel and integrated it with the decemedip framework to estimate the proportions of nine cell types, including immune subsets (B cells, CD4⁺ T cells, CD8⁺ T cells, monocytes, neutrophils, and natural killer cells) as well as tumor-specific signatures for prostate, kidney, and urothelial cancers. Urine cfDNA from 54 patients at Dana-Farber Cancer Institute was profiled by cfMeDIP-seq, comprising 19 localized bladder cancers (BLCA), 18 localized renal cell carcinomas (RCC), 9 localized upper tract urothelial carcinomas (UTUC), and 8 non-cancerous kidney disease cases. Deconvolution was applied to infer cell-type composition across these groups. Results: RCC samples exhibited significantly higher kidney cancer-derived cfDNA signal than BLCA and UTUC (p = 3e-06), while urothelial cancers showed significantly higher urothelial cancer-derived signal compared to RCC (p = 1e-05). The kidney-to-urothelial cancer cfDNA signal ratio distinguished RCC from urothelial cancers with an AUC of 0.984. In the bladder cancer cohort, five patients with low urothelial cancer signal had received neoadjuvant therapy, suggesting that deconvolution captures treatment-related changes. Excluding these cases further improved the discriminatory performance (AUC = 0.987). RCC patients also demonstrated significantly higher kidney cancer-derived signal than those with non-cancerous kidney disease (p = 0.03), supporting the utility of this approach for benign-malignant differentiation. Conclusions: Urine cfDNA deconvolution via cfMeDIP-seq enables detection of tumor-specific signals and profiling of immune cell composition across localized urinary cancers. This noninvasive liquid biopsy approach demonstrates potential for early detection, disease subtyping, minimal residual disease assessment, and treatment response monitoring and warrants validation in larger prospective cohorts.

利益披露 Disclosure

Z. Zhang, None.. R. Nawfal, None.. G. Gulati, None.. D. Vasseur, None.. J. Seo, None.. H. Savignano, None.. R. El Hajj Chehade, None.. K. Semaan, None.. T. Merhej, None.. J. Canniff, None.. N. Phillips, None.. N. Shen, None.. P. Adams, None.. I. Epstein, None.. J. Horst, None.. A. Zinselmeier, None.. R. Throwbridge, None.. G. Lee, None.. J. Azzi, None.. M. S. Hirsch, None.. M. Kathrins, None.. T. N. Clinton, None.. M. Mossanen, None.. K. Korthauer, None.. M. L. Freedman, None.. S. C. Baca, None.

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