外染色体DNA驱动的瘤基因空间异质性和质母细胞瘤的进化
Imran Noorani1,2,3, Magnus Haughey4, Jens Luebeck5
1Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, United Kingdom.
Cancer discovery
|September 8, 2025
概括
染色体外DNA (ecDNA) 瘤基因放大驱动癌症耐药性. 这项研究揭示了瘤细胞母细胞瘤中的瘤特异性ecDNA演变,表明EGFR-ecDNA积累之前的克隆扩张,影响治疗耐药性.
科学领域:
- 基因组学就是基因组学.
- 癌症生物学 癌症生物学
- 计算生物学 计算生物学
背景情况:
- 癌基因的异染色体DNA (ecDNA) 放大是癌症的标志,与治疗耐药性和不良预后有关.
- 对于ecDNA的时空进化和异质性,人们对其了解甚少,这阻碍了治疗策略.
研究的目的:
- 研究人类质母细胞瘤 (GBM) 中ecDNA的时空演变.
- 了解ecDNA异质性的癌基因特异性模式及其进化轨迹.
主要方法:
- 将计算建模与来自94个未经治疗的人类GBM样本的基因组数据集成在一起.
- 对ecDNA增强型瘤基因的空间模式和进化性质的分析.
主要成果:
- 在ecDNA中观察到瘤基因特定的空间异质性,由随机分离和差异性适应性优势驱动.
- 与PDGFRA-ecDNA不同的是,EGFR-ecDNA在克隆扩张之前会积累,从而带来显著的健康优势和高丰度.
- 包括EGFRvIII在内的EGFR-ecDNA变异源自野生型EGFR-ecDNA,早期出现并达到高水平.
结论:
- 在GBM中,ecDNA的致癌成分决定了不同的进化路径.
- 像ecDNA克隆性和异质体等新概念需要对GBM基因组数据进行精细的进化解释.
更多相关视频
相关概念视频
Cancers Originate from Somatic Mutations in a Single Cell
14.6K
Cancer arises from mutations in the critical genes that allow healthy cells to escape cell cycle regulation and acquire the ability to proliferate indefinitely. Though originating from a single mutation event in one of the originator cells, cancer progresses when the mutant cell lines continue to gain more and more mutations, and finally, become malignant. For example, chronic myelogenous leukemia (CML) develops initially as a non-lethal increase in white blood cells, which progressively...
14.6K
Tumor Progression
7.2K
Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
7.2K
Adaptive Mechanisms in Cancer Cells
7.0K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
7.0K
Cancer-Critical Genes I: Proto-oncogenes
11.2K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
11.2K
Induced Pluripotent Stem Cells
5.4K
Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
Somatic...
5.4K


