研究揭示：胰腺癌的转录表型受肿瘤进化过程中的基因组事件驱动
加拿大多伦多大学Faiyaz Notta、Steven Gallinger等研究人员合作揭示，胰腺癌的转录表型受肿瘤进化过程中的基因组事件驱动。该研究2020年1月13日在线发表于国际优异学术期刊《自然—遗传学》。
研究人员表示，胰腺癌表现为多种高度侵袭性疾病。该疾病异质性的基础已被证明由于不良的肿瘤细胞性和广泛的基因组不稳定性而难以解决。
为了解决这个问题，研究人员从原发性和转移性肿瘤纯化出的上皮细胞产生了全基因组和转录组的数据集。转录组分析表明分子亚型是由肿瘤内亚群的混合物驱动的基因表达连续体的产物，单细胞分析证实了这一点。综合的全基因组分析发现，分子亚型与基因（例如突变体KRAS和GATA6）中的特定拷贝数畸变有关。通过绘制肿瘤的遗传历史图谱，四倍体化成为这些事件背后的关键突变过程。综上所述，这些数据表明：肿瘤中的基因组畸变会产生分子亚型，并且疾病异质性是由于进展过程中持续的基因组不稳定所致。
附：英文原文
Title: Transcription phenotypes of pancreatic cancer are driven by genomic events during tumor evolution
Author: Michelle Chan-Seng-Yue, Jaeseung C. Kim, Gavin W. Wilson, Karen Ng, Eugenia Flores Figueroa, Grainne M. OKane, Ashton A. Connor, Robert E. Denroche, Robert C. Grant, Jessica McLeod, Julie M. Wilson, Gun Ho Jang, Amy Zhang, Sheng-Ben Liang, Ayelet Borgida, Dianne Chadwick, Sangeetha Kalimuthu, Ilinca Lungu, John M. S. Bartlett, Paul M. Krzyzanowski, Vandana Sandhu, Herv Tiriac, Fieke E. M. Froeling, Joanna M. Karasinska, James T. Topham, Daniel J. Renouf, David F. Schaeffer, Steven J. M. Jones, Marco A. Marra, Janessa Laskin, Runjan Chetty, Lincoln D. Stein, George Zogopoulos, Benjamin Haibe-Kains, Peter J. Campbell, David A. Tuveson, Jennifer J. Knox, Sandra E. Fischer, Steven Gallinger, Faiyaz Notta
Issue&Volume: 2020-01-13
Abstract: Pancreatic adenocarcinoma presents as a spectrum of a highly aggressive disease in patients. The basis of this disease heterogeneity has proved difficult to resolve due to poor tumor cellularity and extensive genomic instability. To address this, a dataset of whole genomes and transcriptomes was generated from purified epithelium of primary and metastatic tumors. Transcriptome analysis demonstrated that molecular subtypes are a product of a gene expression continuum driven by a mixture of intratumoral subpopulations, which was confirmed by single-cell analysis. Integrated whole-genome analysis uncovered that molecular subtypes are linked to specific copy number aberrations in genes such as mutant KRAS and GATA6. By mapping tumor genetic histories, tetraploidization emerged as a key mutational process behind these events. Taken together, these data support the premise that the constellation of genomic aberrations in the tumor gives rise to the molecular subtype, and that disease heterogeneity is due to ongoing genomic instability during progression.
DOI: 10.1038/s41588-019-0566-9
Source: https://www.nature.com/articles/s41588-019-0566-9
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