Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
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DOI：
10.1038/nature11547
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发表时间：
2012-11-15
期刊：
影响因子：
64.8
通讯作者：
Grimmond, Sean M.
中科院分区：
文献类型：
--
作者：
Biankin, Andrew V.;Waddell, Nicola;Kassahn, Karin S.;Gingras, Marie-Claude;Muthuswamy, Lakshmi B.;Johns, Amber L.;Miller, David K.;Wilson, Peter J.;Patch, Ann-Marie;Wu, Jianmin;Chang, David K.;Cowley, Mark J.;Gardiner, Brooke B.;Song, Sarah;Harliwong, Ivon;Idrisoglu, Senel;Nourse, Craig;Nourbakhsh, Ehsan;Manning, Suzanne;Wani, Shivangi;Gongora, Milena;Pajic, Marina;Scarlett, Christopher J.;Gill, Anthony J.;Pinho, Andreia V.;Rooman, Ilse;Anderson, Matthew;Holmes, Oliver;Leonard, Conrad;Taylor, Darrin;Wood, Scott;Xu, Qinying;Nones, Katia;Fink, J. Lynn;Christ, Angelika;Bruxner, Tim;Cloonan, Nicole;Kolle, Gabriel;Newell, Felicity;Pinese, Mark;Mead, R. Scott;Humphris, Jeremy L.;Kaplan, Warren;Jones, Marc D.;Colvin, Emily K.;Nagrial, Adnan M.;Humphrey, Emily S.;Chou, Angela;Chin, Venessa T.;Chantrill, Lorraine A.;Mawson, Amanda;Samra, Jaswinder S.;Kench, James G.;Lovell, Jessica A.;Daly, Roger J.;Merrett, Neil D.;Toon, Christopher;Epari, Krishna;Nguyen, Nam Q.;Barbour, Andrew;Zeps, Nikolajs;Kakkar, Nipun;Zhao, Fengmei;Wu, Yuan Qing;Wang, Min;Muzny, Donna M.;Fisher, William E.;Brunicardi, F. Charles;Hodges, Sally E.;Reid, Jeffrey G.;Drummond, Jennifer;Chang, Kyle;Han, Yi;Lewis, Lora R.;Dinh, Huyen;Buhay, Christian J.;Beck, Timothy;Timms, Lee;Sam, Michelle;Begley, Kimberly;Brown, Andrew;Pai, Deepa;Panchal, Ami;Buchner, Nicholas;De Borja, Richard;Denroche, Robert E.;Yung, Christina K.;Serra, Stefano;Onetto, Nicole;Mukhopadhyay, Debabrata;Tsao, Ming-Sound;Shaw, Patricia A.;Petersen, Gloria M.;Gallinger, Steven;Hruban, Ralph H.;Maitra, Anirban;Iacobuzio-Donahue, Christine A.;Schulick, Richard D.;Wolfgang, Christopher L.;Morgan, Richard A.;Lawlor, Rita T.;Capelli, Paola;Corbo, Vincenzo;Scardoni, Maria;Tortora, Giampaolo;Tempero, Margaret A.;Mann, Karen M.;Jenkins, Nancy A.;Perez-Mancera, Pedro A.;Adams, David J.;Largaespada, David A.;Wessels, Lodewyk F. A.;Rust, Alistair G.;Stein, Lincoln D.;Tuveson, David A.;Copeland, Neal G.;Musgrove, Elizabeth A.;Scarpa, Aldo;Eshleman, James R.;Hudson, Thomas J.;Sutherland, Robert L.;Wheeler, David A.;Pearson, John V.;McPherson, John D.;Gibbs, Richard A.;Grimmond, Sean M.
胰腺癌是一种高致命性的恶性肿瘤，几乎没有有效的治疗方法。我们进行了外显子组测序和拷贝数分析，以确定基因组畸变的前瞻性积累的临床队列（n = 142）的早期（I期和II期）散发性胰腺导管腺癌。对99个信息肿瘤的详细分析发现了2,016个非沉默突变和1,628个拷贝数变异的实质性异质性。我们定义了16个显著突变的基因，重申了已知的突变（KRAS，TP 53，CDKN 2A，SMAD 4，MLL 3，TGFBR 2，ARID 1A和SF 3B 1），并发现了新的突变基因，包括参与染色质修饰（EPC 1和ARID 2），DNA损伤修复（ATM）和其他机制（ZIM 2，MAP 2K 4，NALCN，SLC 16 A4和MAGEA 6）的其他基因。体外功能数据和动物模型的综合分析为这些遗传畸变在癌变中的潜在作用提供了支持性证据。基于通路的复发突变基因分析概括了胰腺导管腺癌核心信号通路的聚类，并在每个通路中鉴定了新的突变基因。我们还确定了频繁和多样的体细胞畸变的基因传统上被描述为胚胎调节轴突的指导，特别是SLIT/ROBO信号，这也是明显的小鼠睡美人转座子介导的体细胞突变模型的胰腺癌，提供了进一步的支持性证据轴突导向基因在胰腺癌的发生的潜在参与。
Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
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影响因子：
8.8
作者：
Bamford, S;Dawson, E;Forbes, S;Clements, J;Pettett, R;Dogan, A;Flanagan, A;Teague, J;Futreal, PA;Stratton, MR;Wooster, R
通讯作者：
Wooster, R
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
3.7
作者：
Jamieson, Nigel B.;Denley, Simon M.;McMillan, Donald C.
通讯作者：
McMillan, Donald C.
影响因子：
15.9
作者：
Comoglio, PM;Trusolino, L
通讯作者：
Trusolino, L