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Pancreatic Neoplasms: HELP
Articles by David A. Largaespada
Based on 4 articles published since 2010
(Why 4 articles?)
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Between 2010 and 2020, David A. Largaespada wrote the following 4 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Case-oriented pathways analysis in pancreatic adenocarcinoma using data from a sleeping beauty transposon mutagenesis screen. 2016

Ho, Yen-Yi / Starr, Timothy K / LaRue, Rebecca S / Largaespada, David A. ·Division of Biostatistics, School of Public Health, University of Minnesota, 420 Delaware St. SE, Minneapolis, Minnesota, USA. yho@umn.edu. · Masonic Cancer Center, University of Minnesota, 425 E River Pkwy, Minneapolis, Minnesota, USA. yho@umn.edu. · Masonic Cancer Center, University of Minnesota, 425 E River Pkwy, Minneapolis, Minnesota, USA. · Department of Obstetrics, Gynecology & Women's Health, MMC 395, 420 Delaware St SE, Minneapolis, MN 55455, Minnesota, USA. · Minnesota Super Computing Institute, 599 Walter Library, 117 Pleasant Street SE, Minneapolis, MN 55455, Minnesota, USA. · Department of Pediatrics, 2231 6th St. SE, Minneapolis, MN 55455, Minnesota, USA. ·BMC Med Genomics · Pubmed #27038937.

ABSTRACT: BACKGROUND: Mutation studies of pancreatic ductal adenocarcinoma (PDA) have revealed complicated heterogeneous genomic landscapes of the disease. These studies cataloged a number of genes mutated at high frequencies, but also report a very large number of genes mutated in lower percentages of tumors. Taking advantage of a well-established forward genetic screening technique, with the Sleeping Beauty (SB) transposon, several studies produced PDA and discovered a number of common insertion sites (CIS) and associated genes that are recurrently mutated at high frequencies. As with human mutation studies, a very large number of genes were found to be altered by transposon insertion at low frequencies. These low frequency CIS associated genes may be very valuable to consider for their roles in cancer, since collectively they might emerge from a core group of genetic pathways. RESULT: In this paper, we determined whether the genetic mutations in SB-accelerated PDA occur within a collated group of biological processes defined as gene sets. The approach considered both genes mutated in high and lower frequencies. We implemented a case-oriented, gene set enrichment analysis (CO-GSEA) on SB altered genes in PDA. Compared to traditional GSEA, CO-GSEA enables us to consider individual characteristics of mutation profiles of each PDA tumor. We identified genetic pathways with higher numbers of genetic mutations than expected by chance. We also present the correlations between these significant enriched genetic pathways, and their associations with CIS genes. CONCLUSION: These data suggest that certain pathway alterations cooperate in PDA development.

2 Article Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. 2012

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 / Anonymous5580740 / 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. ·The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia. ·Nature · Pubmed #23103869.

ABSTRACT: 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.

3 Article The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma. 2012

Pérez-Mancera, Pedro A / Rust, Alistair G / van der Weyden, Louise / Kristiansen, Glen / Li, Allen / Sarver, Aaron L / Silverstein, Kevin A T / Grützmann, Robert / Aust, Daniela / Rümmele, Petra / Knösel, Thomas / Herd, Colin / Stemple, Derek L / Kettleborough, Ross / Brosnan, Jacqueline A / Li, Ang / Morgan, Richard / Knight, Spencer / Yu, Jun / Stegeman, Shane / Collier, Lara S / ten Hoeve, Jelle J / de Ridder, Jeroen / Klein, Alison P / Goggins, Michael / Hruban, Ralph H / Chang, David K / Biankin, Andrew V / Grimmond, Sean M / Anonymous31051 / Wessels, Lodewyk F A / Wood, Stephen A / Iacobuzio-Donahue, Christine A / Pilarsky, Christian / Largaespada, David A / Adams, David J / Tuveson, David A. ·Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK. ·Nature · Pubmed #22699621.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

4 Article Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. 2011

Varela, Ignacio / Tarpey, Patrick / Raine, Keiran / Huang, Dachuan / Ong, Choon Kiat / Stephens, Philip / Davies, Helen / Jones, David / Lin, Meng-Lay / Teague, Jon / Bignell, Graham / Butler, Adam / Cho, Juok / Dalgliesh, Gillian L / Galappaththige, Danushka / Greenman, Chris / Hardy, Claire / Jia, Mingming / Latimer, Calli / Lau, King Wai / Marshall, John / McLaren, Stuart / Menzies, Andrew / Mudie, Laura / Stebbings, Lucy / Largaespada, David A / Wessels, L F A / Richard, Stephane / Kahnoski, Richard J / Anema, John / Tuveson, David A / Perez-Mancera, Pedro A / Mustonen, Ville / Fischer, Andrej / Adams, David J / Rust, Alistair / Chan-on, Waraporn / Subimerb, Chutima / Dykema, Karl / Furge, Kyle / Campbell, Peter J / Teh, Bin Tean / Stratton, Michael R / Futreal, P Andrew. ·Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. ·Nature · Pubmed #21248752.

ABSTRACT: The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.