PO.CL09.01 · 临床研究
染色体外DNA塑造多发性骨髓瘤的侵袭性转录状态
Extrachromosomal DNA shapes aggressive transcriptional states in multiple myeloma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
染色体外DNA（ecDNA）日益被认为是各种实体瘤中致癌基因扩增、瘤内异质性和不良临床结局的关键驱动因素。然而，其在多发性骨髓瘤中的意义在很大程度上仍未被探究。多发性骨髓瘤的特征为显著的基因组不稳定，包括超二倍体或IgH易位，以及广泛的结构重排，这些是生物学异质性和治疗耐药的基础。因此，界定ecDNA是否在该疾病中贡献了额外一层基因组复杂性代表着一项重要的未满足需求。
方法：
使用AmpliconSuite流程分析多发性骨髓瘤研究基金会（MMRF）CoMMpass研究中患者肿瘤样本的全基因组测序（WGS）BAM文件，以识别提示ecDNA的环化DNA扩增子。整合同一队列中匹配的转录组（RNA-seq）数据和临床元数据，以评估与ecDNA携带位点相关的基因表达的预后影响。使用clusterProfiler R包进行基因集富集分析（GSEA），以评估与ecDNA阳性肿瘤相关的通路水平生物学特征。
结果：
我们在MMRF CoMMpass数据集的904例患者中的28例（3.1%）中识别出ecDNA。尽管患病率较低，但ecDNA阳性骨髓瘤患者相比无ecDNA的患者表现出显著更差的生存。频繁扩增的ecDNA位点包含致癌基因，如MYC、TNFRSF17（BCMA）和SNX29，以及促肿瘤lncRNA，包括CASC11和PVT1。GSEA显示，ecDNA阳性肿瘤中MYC和E2F靶点、氧化磷酸化以及PI3K-AKT-mTOR和mTORC1信号通路强烈富集，凸显了转录成瘾和代谢激活。这些通路与多发性骨髓瘤中已知的增殖、代谢重编程和治疗耐药机制一致。
结论：
ecDNA阳性骨髓瘤代表一个生物学上侵袭性的亚群，其特征为致癌基因富集的环状扩增子以及过度激活的增殖和代谢程序。伴ecDNA的骨髓瘤患者显示出显著更差的生存，支持ecDNA作为一个此前未被充分认识的高危特征。这些发现凸显ecDNA作为骨髓瘤中潜在的治疗易感性，值得进一步研究。
查看英文原文 English abstract
Background:
Extrachromosomal DNA (ecDNA) is increasingly recognized as a key driver of oncogene amplification, intratumoral heterogeneity, and poor clinical outcomes across solid tumors. However, its significance in multiple myeloma remains largely unexplored. Multiple myeloma is characterized by marked genomic instability including hyperdiploidy or IgH translocations, and widespread structural rearrangements that underlie biological heterogeneity and therapy resistance. Defining whether ecDNA contributes an additional layer of genomic complexity in this disease therefore represents an important unmet need.
Methods:
Whole-genome sequencing (WGS) BAM files of patient tumor samples from the Multiple Myeloma Research Foundation (MMRF) CoMMpass study were analyzed using the AmpliconSuite pipeline to identify circularized DNA amplicons indicative of ecDNA. Matched transcriptome (RNA-seq) data and clinical metadata from the same cohort were integrated to evaluate the prognostic impact of gene expression associated with ecDNA-harboring loci. Gene Set Enrichment Analysis (GSEA) was performed using the clusterProfiler R package to assess pathway-level biological signatures linked to ecDNA-positive tumors.
Results:
We identified ecDNA in 28 of 904 patients (3.1%) from the MMRF CoMMpass dataset. Despite the low prevalence, ecDNA-positive myeloma patients exhibited significantly inferior survival compared with patients without ecDNA. Frequently amplified ecDNA loci contained oncogenes such as MYC, TNFRSF17 (BCMA), and SNX29, as well as pro-tumoral lncRNAs including CASC11 and PVT1. GSEA revealed strong enrichment of MYC and E2F targets, oxidative phosphorylation, and PI3K-AKT-mTOR and mTORC1 signaling in ecDNA-positive tumors, highlighting transcriptional addiction and metabolic activation. These pathways align with known mechanisms of proliferation, metabolic rewiring, and treatment resistance in multiple myeloma.
Conclusions:
ecDNA-positive myeloma represents a biologically aggressive subset characterized by oncogene-enriched circular amplicons and hyperactivated proliferative and metabolic programs. Myeloma patients with ecDNA showed significantly worse survival, supporting ecDNA as a previously underrecognized high-risk feature. These findings highlight ecDNA as potential therapeutic vulnerabilities in myeloma and warrant further investigation.
利益披露 Disclosure
H. Jung, None..
S. Shin, None..
Y. Kim, None..
J. Byun, None..
Y. Koh, None..
J. Hong, None..
D. Shin, None..
I. Kim, None..
H. Kim, None..
H. Cho, None.