全基因组重新定义了胰腺癌的突变格局。
Whole genomes redefine the mutational landscape of pancreatic cancer.
作者信息
Waddell Nicola, Pajic Marina, Patch Ann-Marie, Chang David K, Kassahn Karin S, Bailey Peter, Johns Amber L, Miller David, Nones Katia, Quek Kelly, Quinn Michael C J, Robertson Alan J, Fadlullah Muhammad Z H, Bruxner Tim J C, Christ Angelika N, Harliwong Ivon, Idrisoglu Senel, Manning Suzanne, Nourse Craig, Nourbakhsh Ehsan, Wani Shivangi, Wilson Peter J, Markham Emma, Cloonan Nicole, Anderson Matthew J, Fink J Lynn, Holmes Oliver, Kazakoff Stephen H, Leonard Conrad, Newell Felicity, Poudel Barsha, Song Sarah, Taylor Darrin, Waddell Nick, Wood Scott, Xu Qinying, Wu Jianmin, Pinese Mark, Cowley Mark J, Lee Hong C, Jones Marc D, Nagrial Adnan M, Humphris Jeremy, Chantrill Lorraine A, Chin Venessa, Steinmann Angela M, Mawson Amanda, Humphrey Emily S, Colvin Emily K, Chou Angela, Scarlett Christopher J, Pinho Andreia V, Giry-Laterriere Marc, Rooman Ilse, Samra Jaswinder S, Kench James G, Pettitt Jessica A, Merrett Neil D, Toon Christopher, Epari Krishna, Nguyen Nam Q, Barbour Andrew, Zeps Nikolajs, Jamieson Nigel B, Graham Janet S, Niclou Simone P, Bjerkvig Rolf, Grützmann Robert, Aust Daniela, Hruban Ralph H, Maitra Anirban, Iacobuzio-Donahue Christine A, Wolfgang Christopher L, Morgan Richard A, Lawlor Rita T, Corbo Vincenzo, Bassi Claudio, Falconi Massimo, Zamboni Giuseppe, Tortora Giampaolo, Tempero Margaret A, Gill Anthony J, Eshleman James R, Pilarsky Christian, Scarpa Aldo, Musgrove Elizabeth A, Pearson John V, Biankin Andrew V, Grimmond Sean M
机构信息
1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.
1] The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2010, Australia.
出版信息
Nature. 2015 Feb 26;518(7540):495-501. doi: 10.1038/nature14169.
Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
胰腺癌仍然是最致命的恶性肿瘤之一，也是一项重大的健康负担。我们对100例胰腺导管腺癌（PDAC）进行了全基因组测序和拷贝数变异（CNV）分析。导致基因破坏的染色体重排很普遍，影响了已知在胰腺癌中起重要作用的基因（TP53、SMAD4、CDKN2A、ARID1A和ROBO2）以及胰腺癌发生的新候选驱动基因（KDM6A和PREX2）。结构变异模式（染色体结构变异）将PDAC分为4种具有潜在临床应用价值的亚型：这些亚型分别被称为稳定型、局部重排型、散在型和不稳定型。相当一部分病例存在局部扩增，其中许多包含可靶向治疗的致癌基因（ERBB2、MET、FGFR1、CDK6、PIK3R3和PIK3CA），但在个体患者中的发生率较低。基因组不稳定与DNA维持基因（BRCA1、BRCA2或PALB2）的失活以及DNA损伤修复缺陷的突变特征共同出现。在接受铂类治疗的8例患者中，5例具有这些DNA维持缺陷指标的患者中有4例有反应。
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