PO.MCB08.02 · 分子与细胞生物学
整合性多组学分析揭示染色体外DNA在黑色素瘤中的亚型特异性影响
Integrative multi-omic analysis reveals subtype-specific impact of extrachromosomal DNA in melanoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
染色体外DNA（ecDNA）驱动癌症中的癌基因扩增、转录失调和治疗耐药，但其在黑色素瘤中的患病率和影响仍不明确。我们分析了470例TCGA-SKCM样本，包括全基因组（n=223）、全外显子组（n=247）和RNA测序（n=469）。肿瘤被分类为BRAF/NRAS/NF1突变型（BNN，n=396）或三重野生型（TWT，n=74）。ecDNA检测使用AmpliconArchitect（AA）和基因水平环状扩增子预测（GCAP）进行。多组学分析评估了转录、免疫和临床相关性。在133例肿瘤中检测到ecDNA（28%；AA检出47例，GCAP检出133例，39例重叠），在TWT肿瘤中的患病率（51%）高于BNN肿瘤（26%；χ²=17.88，p=2.4×10⁻⁵）。频繁扩增的ecDNA基因包括MDM2、CDK4、CCND1、BIRC2/3、PAK1、GAB2和RSF1，涉及增殖、凋亡逃逸和染色质调控。为评估其推定的功能影响，我们进行了多种转录组学分析，鉴定出扩增癌基因（GAB2、MDM2、RSF1、CCND1、PAK1）的上调。此外，使用MutSigDB（针对Hallmark基因）进行的基因集富集分析显示，在ecDNA+肿瘤中与增强细胞增殖相关的通路（如MYC和E2F靶标）强烈富集。此外，细胞去卷积方法揭示免疫细胞组成在各亚型间存在差异，凸显了潜在的独特免疫调节效应。生存分析表明ecDNA+肿瘤的总生存期较差（p=0.016），主要由TWT病例所驱动（p=0.0048）。ecDNA在黑色素瘤中普遍存在，尤其是在TWT肿瘤中，在此它促进癌基因扩增、免疫调节重编程和不良预后。这些结果突出ecDNA作为TWT黑色素瘤中分层的潜在生物标志物和可靶向的脆弱性。
查看英文原文 English abstract
Extrachromosomal DNA (ecDNA) drives oncogene amplification, transcriptional deregulation, and therapeutic resistance in cancer, but its prevalence and impact in melanoma remain unclear. We analyzed 470 TCGA-SKCM samples with whole-genome ( n = 223), whole-exome ( n = 247), and RNA sequencing ( n = 469). Tumors were classified as BRAF/NRAS/NF1-mutant (BNN, n = 396) or triple wild-type (TWT, n = 74). ecDNA detection was performed using AmpliconArchitect (AA) and Gene-level Circular Amplicon Prediction (GCAP). Multi-omic analyses assessed transcriptional, immunologic, and clinical correlates. ecDNA was detected in 133 tumors (28%; 47 by AA, 133 by GCAP, 39 overlapping), with higher prevalence in TWT tumors (51%) than BNN tumors (26%; χ² = 17.88, p = 2.4 × 10⁻⁵). Frequently amplified ecDNA genes included MDM2, CDK4, CCND1, BIRC2/3, PAK1, GAB2, and RSF1 , implicating proliferation, apoptosis evasion, and chromatin regulation. In an effort to assess putative functional impact, we performed various transcriptomic analyses which identified upregulation of amplified oncogenes ( GAB2, MDM2, RSF1, CCND1, PAK1 ). In addition, gene set enrichment analyses with MutSigDB (against Hallmark genes) shows strong enrichment of pathways associated with enhanced cell proliferation, such as MYC and E2F targets in ecDNA+ tumors. In addition, cell deconvolution methods reveal immune cell composition varies across subtypes, highlighting potential unique immunomodulatory effects. Survival analysis indicated worse overall survival in ecDNA+ tumors ( p = 0.016), driven by TWT cases ( p = 0.0048). ecDNA is prevalent in melanoma, particularly in TWT tumors, where it promotes oncogene amplification, immunomodulatory reprogramming, and poor prognosis. These results highlight ecDNA as a potential biomarker for stratification and targetable vulnerability in TWT melanoma.
利益披露 Disclosure
S. Sakthikumar, None..
B. Turner, None..
J. Trent, None.
A. Sekulic,
Regeneron Other, Advisory Board.
Replimune Other, Advisory Board.