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Marie-Claude Gingras

Bio: Marie-Claude Gingras is an academic researcher from Baylor College of Medicine. The author has contributed to research in topics: Pancreatic cancer & Proto-oncogene tyrosine-protein kinase Src. The author has an hindex of 28, co-authored 65 publications receiving 7467 citations. Previous affiliations of Marie-Claude Gingras include Human Genome Sequencing Center & Laval University.


Papers
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Journal ArticleDOI
Peter Bailey1, David K. Chang2, Katia Nones3, Katia Nones1, Amber L. Johns4, Ann-Marie Patch3, Ann-Marie Patch1, Marie-Claude Gingras5, David Miller1, David Miller4, Angelika N. Christ1, Timothy J. C. Bruxner1, Michael C.J. Quinn1, Michael C.J. Quinn3, Craig Nourse1, Craig Nourse2, 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 Leonard3, Conrad Leonard1, Felicity Newell1, Nicola Waddell1, Scott Wood3, Scott Wood1, Qinying Xu3, Qinying Xu1, Peter J. Wilson1, Nicole Cloonan3, Nicole Cloonan1, Karin S. Kassahn7, Karin S. Kassahn1, 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. Chantrill10, Lorraine A. Chantrill4, 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. Kench4, James G. Kench15, 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 Graham2, Janet Graham21, 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. Pearson3, John V. Pearson1, 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
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. Chang3, David K. Chang2, David K. Chang1, 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. Scarlett2, Christopher J. Scarlett7, 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 Mead11, R. Scott Mead2, 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. Kench12, James G. Kench2, James G. Kench9, Jessica A. Lovell2, Roger J. Daly2, Neil D. Merrett3, Neil D. Merrett9, 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. Musgrove1, Elizabeth A. Musgrove2, Aldo Scarpa21, James R. Eshleman20, Thomas J. Hudson6, Robert L. Sutherland2, Robert L. Sutherland1, 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
TL;DR: An integrated multi-platform analysis of 150 pancreatic ductal adenocarcinoma specimens reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine.

1,259 citations

Journal ArticleDOI
Aldo Scarpa, David K. Chang, Katia Nones1, Katia Nones2, Vincenzo Corbo, Ann-Marie Patch1, Ann-Marie Patch2, Peter Bailey1, Peter Bailey3, Rita T. Lawlor, Amber L. Johns4, David Miller1, Andrea Mafficini, Borislav Rusev, Maria Scardoni, Davide Antonello, Stefano Barbi, Katarzyna O. Sikora, Sara Cingarlini, Caterina Vicentini, Skye McKay4, Michael C.J. Quinn2, Michael C.J. Quinn1, Timothy J. C. Bruxner1, Angelika N. Christ1, Ivon Harliwong1, Senel Idrisoglu1, Suzanne McLean1, Craig Nourse3, Craig Nourse1, Ehsan Nourbakhsh1, Peter J. Wilson1, Matthew J. Anderson1, J. Lynn Fink1, Felicity Newell1, Felicity Newell2, Nick Waddell1, Oliver Holmes1, Oliver Holmes2, Stephen H. Kazakoff1, Stephen H. Kazakoff2, Conrad Leonard2, Conrad Leonard1, Scott Wood2, Scott Wood1, Qinying Xu1, Qinying Xu2, Shivashankar H. Nagaraj1, Eliana Amato, Irene Dalai, Samantha Bersani, Ivana Cataldo, Angelo Paolo Dei Tos5, Paola Capelli, Maria Vittoria Davì, Luca Landoni, Anna Malpaga, Marco Miotto, Vicki L. J. Whitehall2, Vicki L. J. Whitehall1, Barbara A. Leggett2, Barbara A. Leggett6, Barbara A. Leggett1, Janelle L. Harris2, Jonathan M. Harris7, Marc D. Jones3, Jeremy L. Humphris4, Lorraine A. Chantrill4, Venessa T. Chin4, Adnan Nagrial4, Marina Pajic4, Christopher J. Scarlett8, Christopher J. Scarlett4, Andreia V. Pinho4, Ilse Rooman4, Christopher W. Toon4, Jianmin Wu9, Jianmin Wu4, Mark Pinese4, Mark J. Cowley4, Andrew Barbour10, Amanda Mawson4, Emily S. Humphrey4, Emily K. Colvin4, Angela Chou11, Angela Chou4, Jessica A. Lovell4, Nigel B. Jamieson3, Nigel B. Jamieson12, Fraser Duthie3, Marie-Claude Gingras13, Marie-Claude Gingras14, William E. Fisher13, Rebecca A. Dagg15, Loretta Lau15, Michael Lee16, Hilda A. Pickett16, Roger R. Reddel16, Jaswinder S. Samra17, Jaswinder S. Samra18, James G. Kench18, James G. Kench4, James G. Kench19, Neil D. Merrett20, Neil D. Merrett18, Krishna Epari21, Nam Q. Nguyen22, Nikolajs Zeps23, Nikolajs Zeps24, Massimo Falconi, Michele Simbolo, Giovanni Butturini, George Van Buren13, Stefano Partelli, Matteo Fassan, Kum Kum Khanna2, Anthony J. Gill18, Anthony J. Gill4, David A. Wheeler14, Richard A. Gibbs14, Elizabeth A. Musgrove3, Claudio Bassi, Giampaolo Tortora, Paolo Pederzoli, John V. Pearson1, John V. Pearson2, Nicola Waddell2, Nicola Waddell1, Andrew V. Biankin, Sean M. Grimmond25 
02 Mar 2017-Nature
TL;DR: In this paper, the authors performed whole-genome sequencing of 102 primary pancreatic neuroendocrine tumours and defined the genomic events that characterize their pathogenesis, including a deficiency in G:C,>T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase.
Abstract: 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.

637 citations

Journal ArticleDOI
TL;DR: A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis.
Abstract: Diverse epidemiological factors are associated with hepatocellular carcinoma (HCC) prevalence in different populations. However, the global landscape of the genetic changes in HCC genomes underpinning different epidemiological and ancestral backgrounds still remains uncharted. Here a collection of data from 503 liver cancer genomes from different populations uncovered 30 candidate driver genes and 11 core pathway modules. Furthermore, a collaboration of two large-scale cancer genome projects comparatively analyzed the trans-ancestry substitution signatures in 608 liver cancer cases and identified unique mutational signatures that predominantly contribute to Asian cases. This work elucidates previously unexplored ancestry-associated mutational processes in HCC development. A combination of hotspot TERT promoter mutation, TERT focal amplification and viral genome integration occurs in more than 68% of cases, implicating TERT as a central and ancestry-independent node of hepatocarcinogenesis. Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities.

589 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

Journal Article
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
Abstract: AACR Centennial Conference: Translational Cancer Medicine-- Nov 4-8, 2007; Singapore PL02-05 All cancers are due to abnormalities in DNA. The availability of the human genome sequence has led to the proposal that resequencing of cancer genomes will reveal the full complement of somatic mutations and hence all the cancer genes. To explore the nature of the information that will be derived from cancer genome sequencing we have sequenced the coding exons of the family of 518 protein kinases, ~1.3Mb DNA per cancer sample, in 210 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that has previously been strongly implicated in oncogenesis, the results indicate that the majority of somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This systematic mutation screen and others have previously yielded a number of cancer genes that are frequently mutated in one or more cancer types and which are now anticancer drug targets (for example BRAF , PIK3CA , and EGFR ). However, detailed analyses of the data from our screen additionally suggest that there exist a large number of additional “driver” mutations which are distributed across a substantial number of genes. It therefore appears that cells may be able to utilise mutations in a large repertoire of potential cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed only infrequently. These findings may have implications for future anticancer drug development.

2,737 citations

Journal ArticleDOI
Peter Bailey1, David K. Chang2, Katia Nones3, Katia Nones1, Amber L. Johns4, Ann-Marie Patch3, Ann-Marie Patch1, 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 Leonard3, Conrad Leonard1, Felicity Newell1, Nicola Waddell1, Scott Wood1, Scott Wood3, Qinying Xu3, Qinying Xu1, Peter J. Wilson1, Nicole Cloonan1, Nicole Cloonan3, Karin S. Kassahn7, Karin S. Kassahn8, Karin S. Kassahn1, Darrin Taylor1, Kelly Quek1, Alan J. Robertson1, Lorena Pantano9, Laura Mincarelli2, Luis Navarro Sanchez2, Lisa Evers2, Jianmin Wu4, Mark Pinese4, Mark J. Cowley4, Jones4, Jones2, Emily K. Colvin4, Adnan Nagrial4, Emily S. Humphrey4, Lorraine A. Chantrill4, Lorraine A. Chantrill10, Amanda Mawson4, Jeremy L. Humphris4, Angela Chou4, Angela Chou11, 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 Hofmann2, Oliver Hofmann9, R. L. Sutherland4, David A. Wheeler5, Anthony J. Gill15, Anthony J. Gill4, Richard A. Gibbs5, John V. Pearson1, John V. Pearson3, Andrew V. Biankin, Sean M. Grimmond2, Sean M. Grimmond1, Sean M. Grimmond29 
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