Sabatino Marianna, Zhao Yingdong, Voiculescu Sonia, Monaco Alessandro, Robbins Paul, Karai Laszlo, Nickoloff Brian J, Maio Michele, Selleri Silvia, Marincola Francesco M, Wang Ena
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, Biometrics Research Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892-1184, USA.
Cancer Res. 2008 Jan 1;68(1):122-31. doi: 10.1158/0008-5472.CAN-07-1939.
It is generally accepted that human cancers derive from a mutated single cell. However, the genetic steps characterizing various stages of progression remain unclear. Studying a unique case of metastatic melanoma, we observed that cell lines derived from metachronous metastases arising over a decade retained a central core of genetic stability in spite of divergent phenotypes. In the present study, we expanded our previous observations comparing these autologous cell lines of clonal derivation with allogeneic ones and correlated array comparative genomic hybridization (aCGH) with gene expression profiling to determine their relative contribution to the dynamics of disease progression. aCGH and gene expression profiling were performed on autologous cell lines and allogeneic melanoma cell lines originating from other patients. A striking correlation existed between total extent of genetic imbalances, global transcriptional patterns, and cellular phenotypes. They did not follow a strict temporal progression but stemmed independently at various time points from a central core of genetic stability best explained according to the cancer stem cell hypothesis. Although their contribution was intertwined, genomic imbalances detectable by aCGH contributed only 25% of the transcriptional traits determining autologous tumor distinctiveness. Our study provides important insights about the dynamics of cancer progression and supports the development of targeted anticancer therapies aimed against stable genetic factors that are maintained throughout the end stage of disease.
人们普遍认为人类癌症起源于单个突变细胞。然而，表征肿瘤进展各个阶段的遗传步骤仍不清楚。通过研究一例独特的转移性黑色素瘤病例，我们观察到，尽管表型不同，但源自十年间不同时间出现的异时转移灶的细胞系仍保留了遗传稳定性的核心。在本研究中，我们扩展了之前的观察结果，将这些克隆来源的自体细胞系与异体细胞系进行比较，并将阵列比较基因组杂交（aCGH）与基因表达谱相关联，以确定它们对疾病进展动态的相对贡献。对自体细胞系和源自其他患者的异体黑色素瘤细胞系进行了aCGH和基因表达谱分析。遗传失衡的总程度、整体转录模式和细胞表型之间存在显著相关性。它们并非遵循严格的时间进程，而是在不同时间点独立地源于遗传稳定性的核心，根据癌症干细胞假说来解释最为合理。尽管它们的作用相互交织，但aCGH可检测到的基因组失衡仅占决定自体肿瘤独特性的转录特征的25%。我们的研究为癌症进展的动态变化提供了重要见解，并支持针对在疾病终末期仍保持稳定的遗传因素开发靶向抗癌疗法。
