美国纪念斯隆-凯特琳癌症中心Sohrab P. Shah课题组在研究中取得进展。他们开发出正在进行的基因组加倍塑造卵巢癌的可进化性和免疫力。相关论文于2025年7月16日发表在《自然》杂志上。

在这里，研究团队研究了WGD对患者肿瘤单细胞分辨率下的体细胞进化和免疫逃避的影响。使用单细胞全基因组测序，小组分析了来自41例患者的70个高级别血清卵巢癌样本（30260个肿瘤基因组），并观察到几乎无处不存在的证据表明WGD是一个持续的突变过程。WGD与细胞-细胞多样性增加和染色体错分离率升高以及随之而来的微核有关。研究团队开发了一种基于突变的WGD计时方法，称为doubleTime，以描述WGD驱动肿瘤进化的特定模式，包括早期固定随后的大量多样化，在拷贝数多样性的预先存在背景下的多个平行WGD事件，以及小克隆和单个细胞的进化晚期WGD。

此外，主题匹配单细胞RNA测序和高分辨率免疫荧光显微镜，该研究团队发现炎症信号和cGAS-STING途径激活是由持续的染色体不稳定性引起的，但这主要局限于二倍体肿瘤（WGD-low）。相比之下，主要是WGD肿瘤（WGD-高），尽管错误分离增加，但表现出细胞周期失调，STING1抑制和免疫抑制表型状态。总之，这些发现表明WGD是一个持续的突变过程，促进了高级别血清性卵巢癌的可进化性和免疫失调。

据了解，全基因组加倍（WGD）是人类癌症的共同特征，与肿瘤进展、耐药性和转移有关。

附：英文原文

Title: Ongoing genome doubling shapes evolvability and immunity in ovarian cancer

Author: McPherson, Andrew, Vzquez-Garca, Ignacio, Myers, Matthew A., Al-Rawi, Duaa H., Zatzman, Matthew, Weiner, Adam C., Freeman, Samuel, Mohibullah, Neeman, Satas, Gryte, Williams, Marc J., Ceglia, Nicholas, Norknait, Danguol, Zhang, Allen W., Li, Jun, Lim, Jamie L. P., Wu, Michelle, Choi, Seongmin, Havasov, Eliyahu, Grewal, Diljot, Shi, Hongyu, Kim, Minsoo, Schwarz, Roland F., Kaufmann, Tom, Dinh, Khanh Ngoc, Uhlitz, Florian, Tran, Julie, Wu, Yushi, Patel, Ruchi, Ramakrishnan, Satish, Kim, DooA, Clarke, Justin, Green, Hunter, Ali, Emily, DiBona, Melody, Varice, Nancy, Kundra, Ritika, Broach, Vance, Gardner, Ginger J., Roche, Kara Long, Sonoda, Yukio, Zivanovic, Oliver, Kim, Sarah H., Grisham, Rachel N., Liu, Ying L., Viale, Agnes, Rusk, Nicole, Lakhman, Yulia, Ellenson, Lora H., Tavar, Simon, Aparicio, Samuel, Chi, Dennis S., Aghajanian, Carol, Abu-Rustum, Nadeem R., Friedman, Claire F., Zamarin, Dmitriy, Weigelt, Britta

Issue&Volume: 2025-07-16

Abstract: Whole-genome doubling (WGD) is a common feature of human cancers and is linked to tumour progression, drug resistance, and metastasis1,2,3,4,5,6. Here we examine the impact of WGD on somatic evolution and immune evasion at single-cell resolution in patient tumours. Using single-cell whole-genome sequencing, we analysed 70 high-grade serous ovarian cancer samples from 41 patients (30,260 tumour genomes) and observed near-ubiquitous evidence that WGD is an ongoing mutational process. WGD was associated with increased cell–cell diversity and higher rates of chromosomal missegregation and consequent micronucleation. We developed a mutation-based WGD timing method called doubleTime to delineate specific modes by which WGD can drive tumour evolution, including early fixation followed by considerable diversification, multiple parallel WGD events on a pre-existing background of copy-number diversity, and evolutionarily late WGD in small clones and individual cells. Furthermore, using matched single-cell RNA sequencing and high-resolution immunofluorescence microscopy, we found that inflammatory signalling and cGAS-STING pathway activation result from ongoing chromosomal instability, but this is restricted to predominantly diploid tumours (WGD-low). By contrast, predominantly WGD tumours (WGD-high), despite increased missegregation, exhibited cell-cycle dysregulation, STING1 repression, and immunosuppressive phenotypic states. Together, these findings establish WGD as an ongoing mutational process that promotes evolvability and dysregulated immunity in high-grade serous ovarian cancer.

DOI: 10.1038/s41586-025-09240-3

Source: https://www.nature.com/articles/s41586-025-09240-3