综合多组学分析揭示了DNA甲基化景观在形成转移性黑色素瘤的生物学异质性和临床行为中的作用。

IF 12.8 1区 医学 Q1 ONCOLOGY
Andrea Anichini, Francesca P Caruso, Vincenzo Lagano, Teresa M R Noviello, Rossella Tufano, Gabriella Nicolini, Alessandra Molla, Ilaria Bersani, Francesco Sgambelluri, Alessia Covre, Maria F Lofiego, Sandra Coral, Anna Maria Di Giacomo, Elena Simonetti, Barbara Valeri, Mara Cossa, Filippo Ugolini, Sara Simi, Daniela Massi, Massimo Milione, Andrea Maurichi, Roberto Patuzzo, Mario Santinami, Michele Maio, Michele Ceccarelli, Roberta Mortarini
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引用次数: 0

摘要

背景:我们在转移性黑色素瘤(MM)队列中开展了一项综合多组学分析,以将DNA甲基化谱与肿瘤进展、生存、对辅助免疫治疗的反应、肿瘤免疫微环境结构以及免疫和黑色素瘤分化的转录程序联系起来。方法:对165例AJCC第8期III和IV期黑色素瘤患者(EPICA队列)进行全面注释,回顾性队列(n = 191)的病变进行亚硫酸氢盐还原测序,RNA测序,全外显子组测序,定量免疫组织化学和多重免疫荧光分析。使用TCGA黑色素瘤数据集进行验证。来自一组接受辅助免疫检查点阻断治疗的MM患者的治疗前病变(n = 28)被鉴定为DNA甲基化谱。通过EPIC阵列和Clariom S阵列研究了DNMT抑制剂对黑色素瘤细胞系DNA甲基化和转录组谱的影响。结果:在EPICA、TCGA MM和TCGA原发性黑色素瘤队列中发现了DNA甲基化水平逐渐升高的四个肿瘤亚群(即去甲基化、低甲基化、中甲基化和CIMP)。与CIMP肿瘤患者相比,EPICA低甲基化肿瘤患者表现出更长的生存期和更低的AJCC晚期进展率。在一项辅助免疫检查点阻断队列中,治疗前患有DEM/LOW病变的患者比患有INT/CIMP病变的患者的无复发生存期明显更长。RNA-seq数据分析显示,LOW和CIMP EPICA肿瘤表现出相反的影响预后靶基因的主分子激活,以及免疫治疗反应和黑色素瘤分化特征的差异表达。与CIMP肿瘤相比,LOW病变表现出CD8+ TCF-1+ PD-1+ TIM-3-预耗尽和CD8+ TCF-1- PD-1+ TIM-3+耗尽T细胞的富集,HLA I类抗原的更频繁保留和去分化黑色素瘤表型。与LOW和CIMP病变相关的分化和免疫相关转录特征是黑色素瘤细胞系在体外保留的肿瘤固有程序。一致地,用DNMT抑制剂治疗分化的黑色素瘤细胞系诱导了全球DNA去甲基化,促进了去分化,上调了病毒模仿和免疫治疗反应的IFNG预测特征。结论:这些结果揭示了DNA甲基化类别在MM中的生物学、预后和治疗相关性,并支持甲基组靶向策略用于精确免疫治疗。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Integrated multi-omics profiling reveals the role of the DNA methylation landscape in shaping biological heterogeneity and clinical behaviour of metastatic melanoma.

Background: We developed an integrated multi-omics analysis in metastatic melanoma (MM) cohorts to associate DNA methylation profiles with tumor progression, survival, response to adjuvant immunotherapy, structure of the tumor immune microenvironment and transcriptional programs of immunity and melanoma differentiation.

Methods: Lesions (n = 191) from a fully annotated, retrospective cohort of 165 AJCC 8th Stage III and IV melanoma patients (EPICA cohort) were characterized by reduced representation bisulfite sequencing, RNA sequencing, whole exome sequencing, quantitative immunohistochemistry and multiplex immunofluorescence analysis. The TCGA melanoma datasets were used for validation. Pre-therapy lesions (n = 28) from a cohort of MM patients treated with adjuvant immune checkpoint blockade were characterized for the DNA methylation profile. Impact of a DNMT inhibitor on DNA methylation and transcriptomic profiles of melanoma cell lines was investigated by EPIC arrays and Clariom S arrays.

Results: Four tumor subsets (i.e. DEMethylated, LOW, INTermediate and CIMP) with progressively increasing levels of DNA methylation were identified in EPICA, TCGA MM and TCGA primary melanoma cohorts. EPICA patients with LOW methylation tumors exhibited a significantly longer survival and a lower progression rate to more advanced AJCC stages, compared to patients with CIMP tumors. In an adjuvant immune checkpoint blockade cohort, patients with DEM/LOW pre-therapy lesions showed significantly longer relapse-free survival compared to those with INT/CIMP lesions. RNA-seq data analysis revealed that LOW and CIMP EPICA tumors showed opposite activation of master molecules influencing prognostic target genes, and differential expression of immunotherapy response and melanoma differentiation signatures. Compared to CIMP tumors, LOW lesions showed enrichment for CD8+ TCF-1+ PD-1+ TIM-3- pre-exhausted and CD8+ TCF-1- PD-1+ TIM-3+ exhausted T cells, more frequent retention of HLA Class I antigens and a de-differentiated melanoma phenotype. The differentiation and immune-related transcriptional features associated with LOW vs CIMP lesions were tumor-intrinsic programs retained in-vitro by melanoma cell lines. Consistently, treatment of differentiated melanoma cell lines with a DNMT inhibitor induced global DNA de-methylation, promoted de-differentiation and upregulated viral mimicry and IFNG predictive signatures of immunotherapy response.

Conclusions: These results reveal the biological, prognostic and therapeutic relevance of DNA methylation classes in MM and support methylome targeting strategies for precision immunotherapy.

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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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