%0 Journal Article %J Nature %D 2017 %T Whole-genome landscape of pancreatic neuroendocrine tumours. %A Scarpa, Aldo %A Chang, David K %A Nones, Katia %A Corbo, Vincenzo %A Patch, Ann-Marie %A Bailey, Peter %A Lawlor, Rita T %A Johns, Amber L %A Miller, David K %A Mafficini, Andrea %A Rusev, Borislav %A Scardoni, Maria %A Antonello, Davide %A Barbi, Stefano %A Sikora, Katarzyna O %A Cingarlini, Sara %A Vicentini, Caterina %A McKay, Skye %A Quinn, Michael C J %A Bruxner, Timothy J C %A Christ, Angelika N %A Harliwong, Ivon %A Idrisoglu, Senel %A McLean, Suzanne %A Nourse, Craig %A Nourbakhsh, Ehsan %A Wilson, Peter J %A Anderson, Matthew J %A Fink, J Lynn %A Newell, Felicity %A Waddell, Nick %A Holmes, Oliver %A Kazakoff, Stephen H %A Leonard, Conrad %A Wood, Scott %A Xu, Qinying %A Nagaraj, Shivashankar Hiriyur %A Amato, Eliana %A Dalai, Irene %A Bersani, Samantha %A Cataldo, Ivana %A Dei Tos, Angelo P %A Capelli, Paola %A Davì, Maria Vittoria %A Landoni, Luca %A Malpaga, Anna %A Miotto, Marco %A Whitehall, Vicki L J %A Leggett, Barbara A %A Harris, Janelle L %A Harris, Jonathan %A Jones, Marc D %A Humphris, Jeremy %A Chantrill, Lorraine A %A Chin, Venessa %A Nagrial, Adnan M %A Pajic, Marina %A Scarlett, Christopher J %A Pinho, Andreia %A Rooman, Ilse %A Toon, Christopher %A Wu, Jianmin %A Pinese, Mark %A Cowley, Mark %A Barbour, Andrew %A Mawson, Amanda %A Humphrey, Emily S %A Colvin, Emily K %A Chou, Angela %A Lovell, Jessica A %A Jamieson, Nigel B %A Duthie, Fraser %A Marie-Claude Gingras %A Fisher, William E %A Dagg, Rebecca A %A Lau, Loretta M S %A Lee, Michael %A Pickett, Hilda A %A Reddel, Roger R %A Samra, Jaswinder S %A Kench, James G %A Merrett, Neil D %A Epari, Krishna %A Nguyen, Nam Q %A Zeps, Nikolajs %A Falconi, Massimo %A Simbolo, Michele %A Butturini, Giovanni %A Van Buren, George %A Partelli, Stefano %A Fassan, Matteo %A Khanna, Kum Kum %A Gill, Anthony J %A Wheeler, David A %A Richard A Gibbs %A Musgrove, Elizabeth A %A Bassi, Claudio %A Tortora, Giampaolo %A Pederzoli, Paolo %A Pearson, John V %A Waddell, Nicola %A Biankin, Andrew V %A Grimmond, Sean M %K Base Sequence %K Calmodulin-Binding Proteins %K Carcinoma, Neuroendocrine %K Chromatin Assembly and Disassembly %K Chromosome Aberrations %K DNA Copy Number Variations %K DNA Glycosylases %K DNA Mutational Analysis %K DNA Repair %K Female %K Genome, Human %K Genomics %K Germ-Line Mutation %K Humans %K Male %K Pancreatic Neoplasms %K RNA-Binding Protein EWS %K RNA-Binding Proteins %K Telomere %K TOR Serine-Threonine Kinases %X

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

%B Nature %V 543 %P 65-71 %8 2017 Mar 02 %G eng %N 7643 %1 https://www.ncbi.nlm.nih.gov/pubmed/28199314?dopt=Abstract %R 10.1038/nature21063 %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 %0 Journal Article %J Nature %D 2012 %T Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. %A Biankin, Andrew V %A Waddell, Nicola %A Kassahn, Karin S %A Gingras, Marie-Claude %A Muthuswamy, Lakshmi B %A Johns, Amber L %A Miller, David K %A Wilson, Peter J %A Patch, Ann-Marie %A Wu, Jianmin %A Chang, David K %A Cowley, Mark J %A Gardiner, Brooke B %A Song, Sarah %A Harliwong, Ivon %A Idrisoglu, Senel %A Nourse, Craig %A Nourbakhsh, Ehsan %A Manning, Suzanne %A Wani, Shivangi %A Gongora, Milena %A Pajic, Marina %A Scarlett, Christopher J %A Gill, Anthony J %A Pinho, Andreia V %A Rooman, Ilse %A Anderson, Matthew %A Holmes, Oliver %A Leonard, Conrad %A Taylor, Darrin %A Wood, Scott %A Xu, Qinying %A Nones, Katia %A Fink, J Lynn %A Christ, Angelika %A Bruxner, Tim %A Cloonan, Nicole %A Kolle, Gabriel %A Newell, Felicity %A Pinese, Mark %A Mead, R Scott %A Humphris, Jeremy L %A Kaplan, Warren %A Jones, Marc D %A Colvin, Emily K %A Nagrial, Adnan M %A Humphrey, Emily S %A Chou, Angela %A Chin, Venessa T %A Chantrill, Lorraine A %A Mawson, Amanda %A Samra, Jaswinder S %A Kench, James G %A Lovell, Jessica A %A Daly, Roger J %A Merrett, Neil D %A Toon, Christopher %A Epari, Krishna %A Nguyen, Nam Q %A Barbour, Andrew %A Zeps, Nikolajs %A Kakkar, Nipun %A Zhao, Fengmei %A Wu, Yuan Qing %A Wang, Min %A Muzny, Donna M %A Fisher, William E %A Brunicardi, F Charles %A Hodges, Sally E %A Reid, Jeffrey G %A Drummond, Jennifer %A Chang, Kyle %A Han, Yi %A Lewis, Lora R %A Dinh, Huyen %A Buhay, Christian J %A Beck, Timothy %A Timms, Lee %A Sam, Michelle %A Begley, Kimberly %A Brown, Andrew %A Pai, Deepa %A Panchal, Ami %A Buchner, Nicholas %A De Borja, Richard %A Denroche, Robert E %A Yung, Christina K %A Serra, Stefano %A Onetto, Nicole %A Mukhopadhyay, Debabrata %A Tsao, Ming-Sound %A Shaw, Patricia A %A Petersen, Gloria M %A Gallinger, Steven %A Hruban, Ralph H %A Maitra, Anirban %A Iacobuzio-Donahue, Christine A %A Schulick, Richard D %A Wolfgang, Christopher L %A Morgan, Richard A %A Lawlor, Rita T %A Capelli, Paola %A Corbo, Vincenzo %A Scardoni, Maria %A Tortora, Giampaolo %A Tempero, Margaret A %A Mann, Karen M %A Jenkins, Nancy A %A Perez-Mancera, Pedro A %A Adams, David J %A Largaespada, David A %A Wessels, Lodewyk F A %A Rust, Alistair G %A Stein, Lincoln D %A Tuveson, David A %A Copeland, Neal G %A Musgrove, Elizabeth A %A Scarpa, Aldo %A Eshleman, James R %A Hudson, Thomas J %A Sutherland, Robert L %A Wheeler, David A %A Pearson, John V %A McPherson, John D %A Gibbs, Richard A %A Grimmond, Sean M %K Animals %K Axons %K Carcinoma, Pancreatic Ductal %K Gene Dosage %K Gene Expression Regulation, Neoplastic %K Genome %K Humans %K Kaplan-Meier Estimate %K Mice %K Mutation %K Pancreatic Neoplasms %K Proteins %K Signal Transduction %X

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.

%B Nature %V 491 %P 399-405 %8 2012 Nov 15 %G eng %N 7424 %1 https://www.ncbi.nlm.nih.gov/pubmed/23103869?dopt=Abstract %R 10.1038/nature11547