研究揭示：胰腺癌的轉(zhuǎn)錄表型受腫瘤進(jìn)化過(guò)程中的基因組事件驅(qū)動(dòng)
2020-01-16
來(lái)源：小柯機(jī)器人
加拿大多倫多大學(xué)Faiyaz Notta、Steven Gallinger等研究人員合作揭示，胰腺癌的轉(zhuǎn)錄表型受腫瘤進(jìn)化過(guò)程中的基因組事件驅(qū)動(dòng)。該研究2020年1月13日在線(xiàn)發(fā)表于國(guó)際優(yōu)異學(xué)術(shù)期刊《自然—遺傳學(xué)》。
研究人員表示，胰腺癌表現(xiàn)為多種高度侵襲性疾病。該疾病異質(zhì)性的基礎(chǔ)已被證明由于不良的腫瘤細(xì)胞性和廣泛的基因組不穩(wěn)定性而難以解決。
為了解決這個(gè)問(wèn)題，研究人員從原發(fā)性和轉(zhuǎn)移性腫瘤純化出的上皮細(xì)胞產(chǎn)生了全基因組和轉(zhuǎn)錄組的數(shù)據(jù)集。轉(zhuǎn)錄組分析表明分子亞型是由腫瘤內(nèi)亞群的混合物驅(qū)動(dòng)的基因表達(dá)連續(xù)體的產(chǎn)物，單細(xì)胞分析證實(shí)了這一點(diǎn)。綜合的全基因組分析發(fā)現(xiàn)，分子亞型與基因（例如突變體KRAS和GATA6）中的特定拷貝數(shù)畸變有關(guān)。通過(guò)繪制腫瘤的遺傳歷史圖譜，四倍體化成為這些事件背后的關(guān)鍵突變過(guò)程。綜上所述，這些數(shù)據(jù)表明：腫瘤中的基因組畸變會(huì)產(chǎn)生分子亞型，并且疾病異質(zhì)性是由于進(jìn)展過(guò)程中持續(xù)的基因組不穩(wěn)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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