伦敦大学学院癌症研究所Nicholas McGranahan小组的一项最新研究揭示了克隆拷贝数多样性与肺癌患者的生存有关。这一研究成果于2025年8月13日发表在国际顶尖学术期刊《自然》上。

在这里，该课题组人员提出了等位基因特异性拷贝数改变系统发育分析（ALPACA），这是一种通过利用以SNV频率为主题的多样本大肿瘤测序数据重建的系统发育树来推断SNV和SCNA共同进化的方法。与目前最先进的方法相比，ALPACA估计模拟肿瘤的SCNA进化具有更高的准确性。ALPACA揭示了可能错过标准方法的小克隆的杂合性缺失和扩增事件，并揭示了体细胞改变的时间顺序。通过分析TRACERx421肺癌患者的克隆特异性拷贝数，该团队发现了转移播种克隆中染色体不稳定性增加的证据，以及影响肿瘤抑制基因的缺失和影响CCND1的扩增的富集。

此外，该团队还发现，在多克隆转移扩散的肿瘤和胸外转移的肿瘤中，SCNA率都增加了，并且在肺癌患者中，更高的克隆拷贝数多样性与降低的无病生存率之间存在关联。

研究人员表示，在肿瘤发育过程中，单核苷酸变异（SNV）和体细胞拷贝数改变（SCNAs）在癌细胞中积累，促进克隆进化。然而，从大量DNA测序数据中准确估计克隆特异性拷贝数是具有挑战性的。

附：英文原文

Title: Clone copy number diversity is linked to survival in lung cancer

Author: Pawlik, Piotr, Grigoriadis, Kristiana, Bunkum, Abigail, Coggan, Helena, Frankell, Alexander M., Martinez-Ruiz, Carlos, Karasaki, Takahiro, Huebner, Ariana, Rowan, Andrew, Fisher, Jasmin, Hackshaw, Allan, Swanton, Charles, Zaccaria, Simone, McGranahan, Nicholas

Issue&Volume: 2025-08-13

Abstract: Both single nucleotide variants (SNVs) and somatic copy number alterations (SCNAs) accumulate in cancer cells during tumour development, fuelling clonal evolution. However, accurate estimation of clone-specific copy numbers from bulk DNA-sequencing data is challenging. Here we present allele-specific phylogenetic analysis of copy number alterations (ALPACA), a method to infer SNV and SCNA coevolution by leveraging phylogenetic trees reconstructed from multi-sample bulk tumour sequencing data using SNV frequencies. ALPACA estimates the SCNA evolution of simulated tumours with a higher accuracy than current state-of-the-art methods1,2,3,4. ALPACA uncovers loss-of-heterozygosity and amplification events in minor clones that may be missed using standard approaches and reveals the temporal order of somatic alterations. Analysing clone-specific copy numbers in TRACERx421 lung tumours5,6, we find evidence of increased chromosomal instability in metastasis-seeding clones and enrichment for losses affecting tumour suppressor genes and amplification affecting CCND1. Furthermore, we identify increased SCNA rates in both tumours with polyclonal metastatic dissemination and tumours with extrathoracic metastases, and an association between higher clone copy number diversity and reduced disease-free survival in patients with lung cancer.

DOI: 10.1038/s41586-025-09398-w

Source: https://www.nature.com/articles/s41586-025-09398-w