PO.BCS01.01 · 生物信息与计算
量化拷贝数扩增的选择优势以揭示卵巢癌治疗靶点
Quantifying the selective advantage of copy number amplifications to reveal therapeutic targets in ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
卵巢癌(OV)仍是最致命的恶性肿瘤之一,而致癌性体细胞单核苷酸突变有限、染色体不稳定性广泛,阻碍了靶点的发现。传统策略根据拷贝数扩增的频率和幅度来确定扩增基因的靶向优先级。然而,这些指标受区域基因组结构和大量搭车事件(passenger event)的混淆,难以识别在肿瘤演化过程中真正增加细胞增殖和存活的扩增。为解决这一问题,我们开发了一种演化模型,用以量化扩增的癌症效应量(CES),直接估计每个事件所赋予的选择优势,借鉴了针对单核苷酸变异所开发的方法。通过整合观察到的扩增模式与区域背景拷贝数改变(CNA)率以量化适应度贡献,我们将真正驱动肿瘤演化的扩增与因基因组不稳定性而升高的搭车事件区分开来。利用来自554例卵巢癌肿瘤序列队列的分段拷贝数图谱,我们量化了全基因组范围内扩增的癌症效应。已知的癌基因如MYC和CCNE1表现出高CES。一些常被报道的复发性扩增表现出低CES,与搭车状态一致;而若干中高频率的局灶性扩增则表现出强烈的选择优势,代表了被传统拷贝数指标所掩盖的关键CNA驱动因素。这种分层对治疗开发至关重要,因为高CES扩增标记了肿瘤既呈剂量增加又具有选择性依赖的位点。剂量增加、选择性依赖的位点对三链形成寡核苷酸(TFO)疗法具有直接的转化意义,该疗法在三链形成基序处触发DNA损伤,而扩增的位点提供了增加的靶点剂量。高CES位点同时提供了丰富的TFO结合位点并代表核心的癌症依赖性,体现了一种实现持久治疗效果的机制。对扩增选择的量化为癌症效应提供了严谨的、基于演化的依据,能够识别真正的致癌扩增驱动因素,并在以染色体不稳定性为主导的癌症中精确定位具有治疗可操作性的靶点。
查看英文原文 English abstract
Ovarian cancer (OV) remains one of the most lethal malignancies, and target discovery is hindered by limited oncogenic somatic single-nucleotide mutations and extensive chromosomal instability. Conventional strategies prioritize targeting of amplified genes based on frequency and amplitude of copy number amplification. However, these metrics are confounded by regional genomic architecture and abundant passenger events, rendering it difficult to identify the amplifications that truly increase cell proliferation and survival during tumor evolution. To address this problem, we developed an evolutionary model that quantifies the cancer effect size (CES) of amplifications, directly estimating the selective advantage conferred by each event, mirroring methodologies developed for single-nucleotide variants. By integrating observed amplification patterns with regional background copy number alteration (CNA) rates to quantify fitness contributions, we distinguished amplifications that genuinely drive tumor evolution from passengers elevated by genomic instability. Using segmented copy number profiles from a cohort of 554 ovarian cancer tumor sequences, we quantified cancer effects of amplifications across the genome. Known oncogenes like MYC and CCNE1 exhibit high CES. Some oft-reported recurrent amplifications exhibited low CES, consistent with a passenger status, whereas several moderately high-frequency focal amplifications exhibited strong selective advantage, representing key CNA drivers that are obscured by conventional copy-number metrics. This stratification is critical for therapeutic development because high-CES amplifications mark loci where tumors are both dosage-increased and selectively dependent. Dosage-increased, selectively dependent loci have direct translational relevance for triplex-forming oligonucleotide (TFO) therapies, which trigger DNA damage at triplex-forming motifs, with amplified loci providing increased target dosage. High-CES loci simultaneously provide abundant TFO-binding sites and represent core cancer dependencies, embodying a mechanism for durable therapeutic impact. Quantification of selection for amplifications provides a rigorous, evolutionarily grounded basis for cancer effect, identifying true amplification drivers of oncogenesis and precisely positioning therapeutically actionable targets in cancers dominated by chromosomal instability.
利益披露 Disclosure
M. Liu, None.