Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.
Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.
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DOI：
10.1158/2159-8290.cd-22-0786
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发表时间：
2023-03-01
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影响因子：
28.2
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中科院分区：
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恶性周围神经鞘肿瘤的多组学分析揭示了肿瘤进化背后的基因组事件，包括广泛的体细胞拷贝数改变（SCNA），检测游离DNA中的特定SCNA能够预测预后。恶性周围神经鞘瘤 (MPNST) 是一种侵袭性软组织肉瘤，偶发发生于 1 型神经纤维瘤病 (NF1) 患者中。对 95 个肿瘤样本的全基因组和多区域外显子组测序、转录组和甲基化分析揭示了肿瘤进化中基因组事件的顺序。 NF1 双等位基因失活后，CDKN2A 或 TP53 丢失，无论多梳抑制复合物 2 (PRC2) 失活，都会导致广泛的体细胞拷贝数畸变 (SCNA)。肿瘤进化的不同途径与 PRC2 基因失活和 H3K27 三甲基化 (H3K27me3) 状态相关。 H3K27me3 缺失的肿瘤通过广泛的染色体缺失、随后的全基因组加倍和 8 号染色体扩增而进化，并显示出较低水平的免疫细胞浸润。 H3K27me3 的保留会导致广泛的基因组不稳定，但会导致免疫细胞丰富的表型。在肿瘤样本和游离 DNA (cfDNA) 中检测到的特定 SCNA 可作为 H3K27me3 缺失和免疫浸润的替代指标，并预测预后。 MPNST 是 NF1（一种相对常见的肿瘤易感综合征）患者最常见的死亡和发病原因。我们的结果表明，肿瘤或 cfDNA 的体细胞拷贝数和甲基化谱可以作为早期诊断的生物标志物，并将患者分为预后相关亚组和治疗相关亚组。 这篇文章在本期特稿中重点介绍，第 17 页。第517章
Multiomic profiling of malignant peripheral nerve sheath tumors reveals genomic events that underlie tumor evolution including extensive somatic copy-number alterations (SCNA), with detection of specific SCNAs in cell-free DNA being able to predict prognosis. Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517