%0 Journal Article %J Cell Rep %D 2016 %T Ampullary Cancers Harbor ELF3 Tumor Suppressor Gene Mutations and Exhibit Frequent WNT Dysregulation. %A Gingras, Marie-Claude %A Covington, Kyle R %A Chang, David K %A Donehower, Lawrence A %A Gill, Anthony J %A Ittmann, Michael M %A Creighton, Chad J %A Johns, Amber L %A Shinbrot, Eve %A Dewal, Ninad %A Fisher, William E %A Pilarsky, Christian %A Grützmann, Robert %A Overman, Michael J %A Jamieson, Nigel B %A Van Buren, George %A Drummond, Jennifer %A Walker, Kimberly %A Hampton, Oliver A %A Xi, Liu %A Muzny, Donna M %A Doddapaneni, Harsha %A Lee, Sandra L %A Bellair, Michelle %A Hu, Jianhong %A Han, Yi %A Dinh, Huyen H %A Dahdouli, Mike %A Samra, Jaswinder S %A Bailey, Peter %A Waddell, Nicola %A Pearson, John V %A Harliwong, Ivon %A Wang, Huamin %A Aust, Daniela %A Oien, Karin A %A Hruban, Ralph H %A Hodges, Sally E %A McElhany, Amy %A Saengboonmee, Charupong %A Duthie, Fraser R %A Grimmond, Sean M %A Biankin, Andrew V %A Wheeler, David A %A Gibbs, Richard A %K Adenocarcinoma %K Ampulla of Vater %K Base Sequence %K DNA-Binding Proteins %K Duodenal Neoplasms %K Genomic Instability %K Humans %K Microsatellite Repeats %K Molecular Sequence Data %K Mutation %K Pancreatic Neoplasms %K Proto-Oncogene Proteins c-ets %K Transcription Factors %K Wnt Signaling Pathway %X

The ampulla of Vater is a complex cellular environment from which adenocarcinomas arise to form a group of histopathologically heterogenous tumors. To evaluate the molecular features of these tumors, 98 ampullary adenocarcinomas were evaluated and compared to 44 distal bile duct and 18 duodenal adenocarcinomas. Genomic analyses revealed mutations in the WNT signaling pathway among half of the patients and in all three adenocarcinomas irrespective of their origin and histological morphology. These tumors were characterized by a high frequency of inactivating mutations of ELF3, a high rate of microsatellite instability, and common focal deletions and amplifications, suggesting common attributes in the molecular pathogenesis are at play in these tumors. The high frequency of WNT pathway activating mutation, coupled with small-molecule inhibitors of β-catenin in clinical trials, suggests future treatment decisions for these patients may be guided by genomic analysis.

%B Cell Rep %V 14 %P 907-919 %8 2016 Feb 02 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/26804919?dopt=Abstract %R 10.1016/j.celrep.2015.12.005 %0 Journal Article %J Nature %D 2016 %T Genomic analyses identify molecular subtypes of pancreatic cancer. %A Bailey, Peter %A Chang, David K %A Nones, Katia %A Johns, Amber L %A Patch, Ann-Marie %A Marie-Claude Gingras %A Miller, David K %A Christ, Angelika N %A Bruxner, Tim J C %A Quinn, Michael C %A Nourse, Craig %A Murtaugh, L Charles %A Harliwong, Ivon %A Idrisoglu, Senel %A Manning, Suzanne %A Nourbakhsh, Ehsan %A Wani, Shivangi %A Fink, Lynn %A Holmes, Oliver %A Chin, Venessa %A Anderson, Matthew J %A Kazakoff, Stephen %A Leonard, Conrad %A Newell, Felicity %A Waddell, Nick %A Wood, Scott %A Xu, Qinying %A Wilson, Peter J %A Cloonan, Nicole %A Kassahn, Karin S %A Taylor, Darrin %A Quek, Kelly %A Robertson, Alan %A Pantano, Lorena %A Mincarelli, Laura %A Sanchez, Luis N %A Evers, Lisa %A Wu, Jianmin %A Pinese, Mark %A Cowley, Mark J %A Jones, Marc D %A Colvin, Emily K %A Nagrial, Adnan M %A Humphrey, Emily S %A Chantrill, Lorraine A %A Mawson, Amanda %A Humphris, Jeremy %A Chou, Angela %A Pajic, Marina %A Scarlett, Christopher J %A Pinho, Andreia V %A Giry-Laterriere, Marc %A Rooman, Ilse %A Samra, Jaswinder S %A Kench, James G %A Lovell, Jessica A %A Merrett, Neil D %A Toon, Christopher W %A Epari, Krishna %A Nguyen, Nam Q %A Barbour, Andrew %A Zeps, Nikolajs %A Moran-Jones, Kim %A Jamieson, Nigel B %A Graham, Janet S %A Duthie, Fraser %A Oien, Karin %A Hair, Jane %A Grützmann, Robert %A Maitra, Anirban %A Iacobuzio-Donahue, Christine A %A Wolfgang, Christopher L %A Morgan, Richard A %A Lawlor, Rita T %A Corbo, Vincenzo %A Bassi, Claudio %A Rusev, Borislav %A Capelli, Paola %A Salvia, Roberto %A Tortora, Giampaolo %A Mukhopadhyay, Debabrata %A Petersen, Gloria M %A Munzy, Donna M %A Fisher, William E %A Karim, Saadia A %A Eshleman, James R %A Hruban, Ralph H %A Pilarsky, Christian %A Morton, Jennifer P %A Sansom, Owen J %A Scarpa, Aldo %A Musgrove, Elizabeth A %A Bailey, Ulla-Maja Hagbo %A Hofmann, Oliver %A Sutherland, Robert L %A Wheeler, David A %A Gill, Anthony J %A Richard A Gibbs %A Pearson, John V %A Waddell, Nicola %A Biankin, Andrew V %A Grimmond, Sean M %K Animals %K Basic Helix-Loop-Helix Transcription Factors %K Carcinoma, Pancreatic Ductal %K Cell Line, Tumor %K DNA Methylation %K DNA-Binding Proteins %K Gene Expression Regulation, Neoplastic %K Gene Regulatory Networks %K Genes, Neoplasm %K Genome, Human %K Genomics %K Hepatocyte Nuclear Factor 3-beta %K Hepatocyte Nuclear Factor 3-gamma %K Histone Demethylases %K Homeobox Protein Nkx-2.2 %K Homeodomain Proteins %K Humans %K Mice %K Mutation %K Nuclear Proteins %K Pancreatic Neoplasms %K Prognosis %K Receptors, Cytoplasmic and Nuclear %K Survival Analysis %K Trans-Activators %K Transcription Factors %K Transcription, Genetic %K Transcriptome %K Tumor Suppressor Protein p53 %K Tumor Suppressor Proteins %K Zebrafish Proteins %X

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

%B Nature %V 531 %P 47-52 %8 2016 Mar 03 %G eng %N 7592 %1 https://www.ncbi.nlm.nih.gov/pubmed/26909576?dopt=Abstract %R 10.1038/nature16965