Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Tri-Institutional PhD Program in Computational Biology and Medicine, Weill Cornell Medicine, New York, NY, USA.
Nat Commun. 2024 Oct 1;15(1):8512. doi: 10.1038/s41467-024-52544-7.
Dysregulated DNA replication is a cause and a consequence of aneuploidy in cancer, yet the interplay between copy number alterations (CNAs), replication timing (RT) and cell cycle dynamics remain understudied in aneuploid tumors. We developed a probabilistic method, PERT, for simultaneous inference of cell-specific replication and copy number states from single-cell whole genome sequencing (scWGS) data. We used PERT to investigate clone-specific RT and proliferation dynamics in >50,000 cells obtained from aneuploid and clonally heterogeneous cell lines, xenografts and primary cancers. We observed bidirectional relationships between RT and CNAs, with CNAs affecting X-inactivation producing the largest RT shifts. Additionally, we found that clone-specific S-phase enrichment positively correlated with ground-truth proliferation rates in genomically stable but not unstable cells. Together, these results demonstrate robust computational identification of S-phase cells from scWGS data, and highlight the importance of RT and cell cycle properties in studying the genomic evolution of aneuploid tumors.
DNA 复制失调是癌症非整倍体的原因和结果，但在非整倍体肿瘤中，拷贝数改变 (CNAs)、复制时间 (RT) 和细胞周期动力学之间的相互作用仍研究不足。我们开发了一种概率方法 PERT，用于从单细胞全基因组测序 (scWGS) 数据中同时推断细胞特异性复制和拷贝数状态。我们使用 PERT 来研究来自非整倍体和克隆异质性细胞系、异种移植物和原发性癌症的超过 50,000 个细胞中的克隆特异性 RT 和增殖动力学。我们观察到 RT 和 CNAs 之间存在双向关系，其中 CNAs 影响 X 染色体失活导致最大的 RT 偏移。此外，我们发现克隆特异性 S 期富集与基因组稳定但不稳定细胞中的真实增殖率呈正相关。这些结果共同证明了从 scWGS 数据中稳健地识别 S 期细胞，并强调了 RT 和细胞周期特性在研究非整倍体肿瘤的基因组进化中的重要性。
