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Author

Mark Pinese

Other affiliations: University of New South Wales
Bio: Mark Pinese is an academic researcher from Garvan Institute of Medical Research. The author has contributed to research in topics: Pancreatic cancer & Cancer. The author has an hindex of 33, co-authored 71 publications receiving 9551 citations. Previous affiliations of Mark Pinese include University of New South Wales.


Papers
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Journal ArticleDOI
Peter Bailey1, David K. Chang2, Katia Nones3, Katia Nones1, Amber L. Johns4, Ann-Marie Patch1, Ann-Marie Patch3, Marie-Claude Gingras5, David Miller1, David Miller4, Angelika N. Christ1, Timothy J. C. Bruxner1, Michael C.J. Quinn3, Michael C.J. Quinn1, Craig Nourse2, Craig Nourse1, Murtaugh Lc6, Ivon Harliwong1, Senel Idrisoglu1, Suzanne Manning1, Ehsan Nourbakhsh1, Shivangi Wani3, Shivangi Wani1, J. Lynn Fink1, Oliver Holmes1, Oliver Holmes3, Chin4, Matthew J. Anderson1, Stephen H. Kazakoff3, Stephen H. Kazakoff1, Conrad Leonard3, Conrad Leonard1, Felicity Newell1, Nicola Waddell1, Scott Wood1, Scott Wood3, Qinying Xu3, Qinying Xu1, Peter J. Wilson1, Nicole Cloonan1, Nicole Cloonan3, Karin S. Kassahn1, Karin S. Kassahn7, Karin S. Kassahn8, Darrin Taylor1, Kelly Quek1, Alan J. Robertson1, Lorena Pantano9, Laura Mincarelli2, Luis Navarro Sanchez2, Lisa Evers2, Jianmin Wu4, Mark Pinese4, Mark J. Cowley4, Jones2, Jones4, Emily K. Colvin4, Adnan Nagrial4, Emily S. Humphrey4, Lorraine A. Chantrill4, Lorraine A. Chantrill10, Amanda Mawson4, Jeremy L. Humphris4, Angela Chou4, Angela Chou11, Marina Pajic12, Marina Pajic4, Christopher J. Scarlett13, Christopher J. Scarlett4, Andreia V. Pinho4, Marc Giry-Laterriere4, Ilse Rooman4, Jaswinder S. Samra14, James G. Kench15, James G. Kench4, James G. Kench16, Jessica A. Lovell4, Neil D. Merrett12, Christopher W. Toon4, Krishna Epari17, Nam Q. Nguyen18, Andrew Barbour19, Nikolajs Zeps20, Kim Moran-Jones2, Nigel B. Jamieson2, Janet Graham21, Janet Graham2, Fraser Duthie22, Karin A. Oien22, Karin A. Oien4, Hair J22, Robert Grützmann23, Anirban Maitra24, Christine A. Iacobuzio-Donahue25, Christopher L. Wolfgang26, Richard A. Morgan26, Rita T. Lawlor, Corbo, Claudio Bassi, Borislav Rusev, Paola Capelli27, Roberto Salvia, Giampaolo Tortora, Debabrata Mukhopadhyay28, Gloria M. Petersen28, Munzy Dm5, William E. Fisher5, Saadia A. Karim, Eshleman26, Ralph H. Hruban26, Christian Pilarsky23, Jennifer P. Morton, Owen J. Sansom2, Aldo Scarpa27, Elizabeth A. Musgrove2, Ulla-Maja Bailey2, Oliver Hofmann9, Oliver Hofmann2, R. L. Sutherland4, David A. Wheeler5, Anthony J. Gill16, Anthony J. Gill4, Richard A. Gibbs5, John V. Pearson1, John V. Pearson3, Andrew V. Biankin, Sean M. Grimmond29, Sean M. Grimmond1, Sean M. Grimmond2 
03 Mar 2016-Nature
TL;DR: Detailed 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.
Abstract: 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.

2,443 citations

Journal ArticleDOI
Nicola Waddell1, Marina Pajic2, Ann-Marie Patch3, David K. Chang2, Karin S. Kassahn3, Peter Bailey3, Amber L. Johns2, David Miller3, Katia Nones3, Kelly Quek3, Michael C.J. Quinn3, Alan J. Robertson3, Muhammad Zaki Hidayatullah Fadlullah3, Timothy J. C. Bruxner3, Angelika N. Christ3, Ivon Harliwong3, Senel Idrisoglu3, Suzanne Manning3, Craig Nourse3, Ehsan Nourbakhsh3, Shivangi Wani3, Peter J. Wilson3, Emma Markham3, Nicole Cloonan1, Matthew J. Anderson3, J. Lynn Fink3, Oliver Holmes3, Stephen H. Kazakoff3, Conrad Leonard3, Felicity Newell3, Barsha Poudel3, Sarah Song3, Darrin Taylor3, Nick Waddell3, Scott Wood3, Qinying Xu3, Jianmin Wu2, Mark Pinese2, Mark J. Cowley2, Hong C. Lee2, Marc D. Jones2, Adnan Nagrial2, Jeremy L. Humphris2, Lorraine A. Chantrill2, Venessa T. Chin2, Angela Steinmann2, Amanda Mawson2, Emily S. Humphrey2, Emily K. Colvin2, Angela Chou2, Christopher J. Scarlett2, Andreia V. Pinho2, Marc Giry-Laterriere2, Ilse Rooman2, Jaswinder S. Samra4, James G. Kench2, Jessica A. Pettitt2, Neil D. Merrett5, Christopher W. Toon2, Krishna Epari6, Nam Q. Nguyen7, Andrew Barbour8, Nikolajs Zeps9, Nigel B. Jamieson10, Janet Graham11, Simone P. Niclou, Rolf Bjerkvig12, Robert Grützmann13, Daniela Aust13, Ralph H. Hruban14, Anirban Maitra15, Christine A. Iacobuzio-Donahue16, Christopher L. Wolfgang14, Richard A. Morgan14, Rita T. Lawlor17, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni17, Giampaolo Tortora, Margaret A. Tempero18, Anthony J. Gill2, James R. Eshleman14, Christian Pilarsky13, Aldo Scarpa17, Elizabeth A. Musgrove19, John V. Pearson1, Andrew V. Biankin2, Sean M. Grimmond3 
26 Feb 2015-Nature
TL;DR: Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency, and 4 of 5 individuals with these measures of defective DNA maintenance responded to platinum therapy.
Abstract: 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.

2,035 citations

Journal ArticleDOI
Andrew V. Biankin1, Andrew V. Biankin2, Andrew V. Biankin3, Nicola Waddell4, Karin S. Kassahn4, Marie-Claude Gingras5, Lakshmi Muthuswamy6, Amber L. Johns2, David Miller4, Peter Wilson4, Ann-Marie Patch4, Jianmin Wu2, David K. Chang2, David K. Chang1, David K. Chang3, Mark J. Cowley2, Brooke Gardiner4, Sarah Song4, Ivon Harliwong4, Senel Idrisoglu4, Craig Nourse4, Ehsan Nourbakhsh4, Suzanne Manning4, Shivangi Wani4, Milena Gongora4, Marina Pajic2, Christopher J. Scarlett7, Christopher J. Scarlett2, Anthony J. Gill8, Anthony J. Gill2, Anthony J. Gill9, Andreia V. Pinho2, Ilse Rooman2, Matthew J. Anderson4, Oliver Holmes4, Conrad Leonard4, Darrin Taylor4, Scott Wood4, Qinying Xu4, Katia Nones4, J. Lynn Fink4, Angelika N. Christ4, Timothy J. C. Bruxner4, Nicole Cloonan4, Gabriel Kolle10, Felicity Newell4, Mark Pinese2, R. Scott Mead2, R. Scott Mead11, Jeremy L. Humphris2, Warren Kaplan2, Marc D. Jones2, Emily K. Colvin2, Adnan Nagrial2, Emily S. Humphrey2, Angela Chou2, Angela Chou11, Venessa T. Chin2, Lorraine A. Chantrill2, Amanda Mawson2, Jaswinder S. Samra8, James G. Kench2, James G. Kench12, James G. Kench9, Jessica A. Lovell2, Roger J. Daly2, Neil D. Merrett9, Neil D. Merrett1, Christopher W. Toon2, Krishna Epari13, Nam Q. Nguyen14, Andrew Barbour4, Nikolajs Zeps15, Nipun Kakkar5, Fengmei Zhao5, Yuan Qing Wu5, Min Wang5, Donna M. Muzny5, William E. Fisher5, F. Charles Brunicardi16, Sally E. Hodges5, Jeffrey G. Reid5, Jennifer Drummond5, Kyle Chang5, Yi Han5, Lora Lewis5, Huyen Dinh5, Christian J. Buhay5, Timothy Beck6, Lee Timms6, Michelle Sam6, Kimberly Begley6, Andrew M.K. Brown6, Deepa Pai6, Ami Panchal6, Nicholas Buchner6, Richard de Borja6, Robert E. Denroche6, Christina K. Yung6, Stefano Serra17, Nicole Onetto6, Debabrata Mukhopadhyay18, Ming-Sound Tsao17, Patricia Shaw17, Gloria M. Petersen18, Steven Gallinger19, Steven Gallinger17, Ralph H. Hruban20, Anirban Maitra20, Christine A. Iacobuzio-Donahue20, Richard D. Schulick20, Christopher L. Wolfgang20, Richard A. Morgan20, Rita T. Lawlor, Paola Capelli21, Vincenzo Corbo, Maria Scardoni21, Giampaolo Tortora, Margaret A. Tempero22, Karen M. Mann23, Nancy A. Jenkins23, Pedro A. Perez-Mancera24, David J. Adams25, David A. Largaespada26, Lodewyk F. A. Wessels27, Alistair G. Rust25, Lincoln Stein6, David A. Tuveson24, Neal G. Copeland23, Elizabeth A. Musgrove2, Elizabeth A. Musgrove3, Aldo Scarpa21, James R. Eshleman20, Thomas J. Hudson6, Robert L. Sutherland2, Robert L. Sutherland3, David A. Wheeler5, John V. Pearson4, John Douglas Mcpherson6, Richard A. Gibbs5, Sean M. Grimmond4 
15 Nov 2012-Nature
TL;DR: It is found that frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, are also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement ofAxon guidance genes in pancreatic carcinogenesis.
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.

1,752 citations

Journal ArticleDOI
Peter J. Campbell1, Gad Getz2, Jan O. Korbel3, Joshua M. Stuart4  +1329 moreInstitutions (238)
06 Feb 2020-Nature
TL;DR: The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.
Abstract: Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale1,2,3. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter4; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation5,6; analyses timings and patterns of tumour evolution7; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity8,9; and evaluates a range of more-specialized features of cancer genomes8,10,11,12,13,14,15,16,17,18.

1,600 citations

Journal ArticleDOI
23 Nov 2017-Nature
TL;DR: In this paper, the authors used genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer.
Abstract: Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

774 citations


Cited by
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29 Mar 2013-Science
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
Abstract: Over the past decade, comprehensive sequencing efforts have revealed the genomic landscapes of common forms of human cancer. For most cancer types, this landscape consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of “hills” (genes altered infrequently). To date, these studies have revealed ~140 genes that, when altered by intragenic mutations, can promote or “drive” tumorigenesis. A typical tumor contains two to eight of these “driver gene” mutations; the remaining mutations are passengers that confer no selective growth advantage. Driver genes can be classified into 12 signaling pathways that regulate three core cellular processes: cell fate, cell survival, and genome maintenance. A better understanding of these pathways is one of the most pressing needs in basic cancer research. Even now, however, our knowledge of cancer genomes is sufficient to guide the development of more effective approaches for reducing cancer morbidity and mortality.

6,441 citations

Journal ArticleDOI
TL;DR: The Reactome Knowledgebase provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations—an extended version of a classic metabolic map, in a single consistent data model.
Abstract: The Reactome Knowledgebase (www.reactome.org) provides molecular details of signal transduction, transport, DNA replication, metabolism and other cellular processes as an ordered network of molecular transformations-an extended version of a classic metabolic map, in a single consistent data model. Reactome functions both as an archive of biological processes and as a tool for discovering unexpected functional relationships in data such as gene expression pattern surveys or somatic mutation catalogues from tumour cells. Over the last two years we redeveloped major components of the Reactome web interface to improve usability, responsiveness and data visualization. A new pathway diagram viewer provides a faster, clearer interface and smooth zooming from the entire reaction network to the details of individual reactions. Tool performance for analysis of user datasets has been substantially improved, now generating detailed results for genome-wide expression datasets within seconds. The analysis module can now be accessed through a RESTFul interface, facilitating its inclusion in third party applications. A new overview module allows the visualization of analysis results on a genome-wide Reactome pathway hierarchy using a single screen page. The search interface now provides auto-completion as well as a faceted search to narrow result lists efficiently.

5,065 citations

Journal ArticleDOI
17 Apr 2018-Immunity
TL;DR: An extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA identifies six immune subtypes that encompass multiple cancer types and are hypothesized to define immune response patterns impacting prognosis.

3,246 citations

01 Jan 2013
TL;DR: In this article, the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs) was described, including several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA.
Abstract: We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

2,616 citations

Journal ArticleDOI
Peter Bailey1, David K. Chang2, Katia Nones1, Katia Nones3, Amber L. Johns4, Ann-Marie Patch1, Ann-Marie Patch3, Marie-Claude Gingras5, David Miller1, David Miller4, Angelika N. Christ1, Timothy J. C. Bruxner1, Michael C.J. Quinn1, Michael C.J. Quinn3, Craig Nourse2, Craig Nourse1, Murtaugh Lc6, Ivon Harliwong1, Senel Idrisoglu1, Suzanne Manning1, Ehsan Nourbakhsh1, Shivangi Wani3, Shivangi Wani1, J. Lynn Fink1, Oliver Holmes3, Oliver Holmes1, Chin4, Matthew J. Anderson1, Stephen H. Kazakoff1, Stephen H. Kazakoff3, Conrad Leonard1, Conrad Leonard3, Felicity Newell1, Nicola Waddell1, Scott Wood1, Scott Wood3, Qinying Xu1, Qinying Xu3, Peter J. Wilson1, Nicole Cloonan1, Nicole Cloonan3, Karin S. Kassahn1, Karin S. Kassahn7, Karin S. Kassahn8, Darrin Taylor1, Kelly Quek1, Alan J. Robertson1, Lorena Pantano9, Laura Mincarelli2, Luis Navarro Sanchez2, Lisa Evers2, Jianmin Wu4, Mark Pinese4, Mark J. Cowley4, Jones2, Jones4, Emily K. Colvin4, Adnan Nagrial4, Emily S. Humphrey4, Lorraine A. Chantrill4, Lorraine A. Chantrill10, Amanda Mawson4, Jeremy L. Humphris4, Angela Chou11, Angela Chou4, Marina Pajic4, Marina Pajic12, Christopher J. Scarlett4, Christopher J. Scarlett13, Andreia V. Pinho4, Marc Giry-Laterriere4, Ilse Rooman4, Jaswinder S. Samra14, James G. Kench15, James G. Kench16, James G. Kench4, Jessica A. Lovell4, Neil D. Merrett12, Christopher W. Toon4, Krishna Epari17, Nam Q. Nguyen18, Andrew Barbour19, Nikolajs Zeps20, Kim Moran-Jones2, Nigel B. Jamieson2, Janet Graham2, Janet Graham21, Fraser Duthie22, Karin A. Oien4, Karin A. Oien22, Hair J22, Robert Grützmann23, Anirban Maitra24, Christine A. Iacobuzio-Donahue25, Christopher L. Wolfgang26, Richard A. Morgan26, Rita T. Lawlor, Corbo, Claudio Bassi, Borislav Rusev, Paola Capelli27, Roberto Salvia, Giampaolo Tortora, Debabrata Mukhopadhyay28, Gloria M. Petersen28, Munzy Dm5, William E. Fisher5, Saadia A. Karim, Eshleman26, Ralph H. Hruban26, Christian Pilarsky23, Jennifer P. Morton, Owen J. Sansom2, Aldo Scarpa27, Elizabeth A. Musgrove2, Ulla-Maja Bailey2, Oliver Hofmann9, Oliver Hofmann2, R. L. Sutherland4, David A. Wheeler5, Anthony J. Gill4, Anthony J. Gill16, Richard A. Gibbs5, John V. Pearson1, John V. Pearson3, Andrew V. Biankin, Sean M. Grimmond2, Sean M. Grimmond29, Sean M. Grimmond1 
03 Mar 2016-Nature
TL;DR: Detailed 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.
Abstract: 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.

2,443 citations