Whole genomes redefine the mutational landscape of pancreatic cancer.
Nicola Waddell,Marina Pajic,Ann-Marie Patch,David K. Chang,Karin S. Kassahn,Peter Bailey,Amber L. Johns,David Miller,Katia Nones,Kelly Quek,Michael C.J. Quinn,Alan J. Robertson,Muhammad Zaki Hidayatullah Fadlullah,Timothy J. C. Bruxner,Angelika N. Christ,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Craig Nourse,Ehsan Nourbakhsh,Shivangi Wani,Peter J. Wilson,Emma Markham,Nicole Cloonan,Matthew J. Anderson,J. Lynn Fink,Oliver Holmes,Stephen H. Kazakoff,Conrad Leonard,Felicity Newell,Barsha Poudel,Sarah Song,Darrin Taylor,Nick Waddell,Scott Wood,Qinying Xu,Jianmin Wu,Mark Pinese,Mark J. Cowley,Hong C. Lee,Marc D. Jones,Adnan Nagrial,Jeremy L. Humphris,Lorraine A. Chantrill,Venessa T. Chin,Angela Steinmann,Amanda Mawson,Emily S. Humphrey,Emily K. Colvin,Angela Chou,Christopher J. Scarlett,Andreia V. Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S. Samra,James G. Kench,Jessica A. Pettitt,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew Barbour,Nikolajs Zeps,Nigel B. Jamieson,Janet Graham,Simone P. Niclou,Rolf Bjerkvig,Robert Grützmann,Daniela Aust,Ralph H. Hruban,Anirban Maitra,Christine A. Iacobuzio-Donahue,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Vincenzo Corbo,Claudio Bassi,Massimo Falconi,Giuseppe Zamboni,Giampaolo Tortora,Margaret A. Tempero,Anthony J. Gill,James R. Eshleman,Christian Pilarsky,Aldo Scarpa,Elizabeth A. Musgrove,John V. Pearson,Andrew V. Biankin,Sean M. Grimmond +88 more
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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.read more
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Genomic analyses identify molecular subtypes of pancreatic cancer
Peter Bailey,David K. Chang,Katia Nones,Katia Nones,Amber L. Johns,Ann-Marie Patch,Ann-Marie Patch,Marie-Claude Gingras,David Miller,David Miller,Angelika N. Christ,Timothy J. C. Bruxner,Michael C.J. Quinn,Michael C.J. Quinn,Craig Nourse,Craig Nourse,Murtaugh Lc,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Ehsan Nourbakhsh,Shivangi Wani,Shivangi Wani,J. Lynn Fink,Oliver Holmes,Oliver Holmes,Chin,Matthew J. Anderson,Stephen H. Kazakoff,Stephen H. Kazakoff,Conrad Leonard,Conrad Leonard,Felicity Newell,Nicola Waddell,Scott Wood,Scott Wood,Qinying Xu,Qinying Xu,Peter J. Wilson,Nicole Cloonan,Nicole Cloonan,Karin S. Kassahn,Karin S. Kassahn,Karin S. Kassahn,Darrin Taylor,Kelly Quek,Alan J. Robertson,Lorena Pantano,Laura Mincarelli,Luis Navarro Sanchez,Lisa Evers,Jianmin Wu,Mark Pinese,Mark J. Cowley,Jones,Jones,Emily K. Colvin,Adnan Nagrial,Emily S. Humphrey,Lorraine A. Chantrill,Lorraine A. Chantrill,Amanda Mawson,Jeremy L. Humphris,Angela Chou,Angela Chou,Marina Pajic,Marina Pajic,Christopher J. Scarlett,Christopher J. Scarlett,Andreia V. Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S. Samra,James G. Kench,James G. Kench,James G. Kench,Jessica A. Lovell,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew Barbour,Nikolajs Zeps,Kim Moran-Jones,Nigel B. Jamieson,Janet Graham,Janet Graham,Fraser Duthie,Karin A. Oien,Karin A. Oien,Hair J,Robert Grützmann,Anirban Maitra,Christine A. Iacobuzio-Donahue,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Corbo,Claudio Bassi,Borislav Rusev,Paola Capelli,Roberto Salvia,Giampaolo Tortora,Debabrata Mukhopadhyay,Gloria M. Petersen,Munzy Dm,William E. Fisher,Saadia A. Karim,Eshleman,Ralph H. Hruban,Christian Pilarsky,Jennifer P. Morton,Owen J. Sansom,Aldo Scarpa,Elizabeth A. Musgrove,Ulla-Maja Bailey,Oliver Hofmann,Oliver Hofmann,R. L. Sutherland,David A. Wheeler,Anthony J. Gill,Anthony J. Gill,Richard A. Gibbs,John V. Pearson,John V. Pearson,Andrew V. Biankin,Sean M. Grimmond,Sean M. Grimmond,Sean M. Grimmond +128 more
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.
Journal ArticleDOI
Inflammatory responses and inflammation-associated diseases in organs
Linlin Chen,Huidan Deng,Hengmin Cui,Jing Fang,Zhicai Zuo,Junliang Deng,Yinglun Li,Xun Wang,Ling Zhao +8 more
TL;DR: Inflammation is a biological response of the immune system that can be triggered by a variety of factors, including pathogens, damaged cells and toxic compounds, potentially leading to tissue damage or disease.
Journal ArticleDOI
Landscape of somatic mutations in 560 breast cancer whole-genome sequences
Serena Nik-Zainal,Serena Nik-Zainal,Helen Davies,Johan Staaf,Manasa Ramakrishna,Dominik Glodzik,Xueqing Zou,Inigo Martincorena,Ludmil B. Alexandrov,Sancha Martin,David C. Wedge,Peter Van Loo,Young Seok Ju,Michiel M. Smid,Arie B. Brinkman,Sandro Morganella,Miriam Ragle Aure,Ole Christian Lingjærde,Anita Langerød,Markus Ringnér,Sung-Min Ahn,Sandrine Boyault,Jane E. Brock,Annegien Broeks,Adam Butler,Christine Desmedt,Luc Dirix,Serge Dronov,Aquila Fatima,John A. Foekens,Moritz Gerstung,Gerrit Gk Hooijer,Se Jin Jang,David Jones,Hyung-Yong Kim,Tari Ta King,Savitri Krishnamurthy,Hee Jin Lee,Jeong-Yeon Lee,Yang Li,Stuart McLaren,Andrew Menzies,Ville Mustonen,Sarah O’Meara,Iris Pauporté,Xavier Pivot,Colin Ca Purdie,Keiran Raine,Kamna Ramakrishnan,Germán Fg Rodríguez-González,Gilles Romieu,Anieta M. Sieuwerts,Peter Pt Simpson,Rebecca Shepherd,Lucy Stebbings,Olafur Oa Stefansson,Jon W. Teague,Stefania Tommasi,Isabelle Treilleux,Gert Van den Eynden,Peter B. Vermeulen,Anne Vincent-Salomon,Lucy R. Yates,Carlos Caldas,Laura Van't Veer,Andrew Tutt,Andrew Tutt,Stian Knappskog,Benita Kiat Tee Bk Tan,Jos Jonkers,Åke Borg,Naoto T. Ueno,Christos Sotiriou,Alain Viari,P. Andrew Futreal,Peter J. Campbell,Paul N. Span,Steven Van Laere,Sunil R. Lakhani,Jorunn E. Eyfjord,Alastair M Thompson,Ewan Birney,Hendrik G. Stunnenberg,Marc J. van de Vijver,John W.M. Martens,Anne Lise Børresen-Dale,Andrea L. Richardson,Gu Kong,Gilles Thomas,Michael R. Stratton +89 more
TL;DR: This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operative, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
Journal ArticleDOI
PARP inhibitors: Synthetic lethality in the clinic
TL;DR: Current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness are discussed, and interesting lessons for the development of other therapies are provided.
Journal ArticleDOI
Virtual microdissection identifies distinct tumor- and stroma-specific subtypes of pancreatic ductal adenocarcinoma
Richard A. Moffitt,Raoud Marayati,Elizabeth L. Flate,Keith E. Volmar,S. Gabriela Herrera Loeza,Katherine A. Hoadley,Naim U. Rashid,Lindsay A. Williams,Samuel C. Eaton,Alexander H. Chung,Jadwiga K. Smyla,Judy M. Anderson,Hong Jin Kim,David J. Bentrem,Mark S. Talamonti,Christine A. Iacobuzio-Donahue,Michael A. Hollingsworth,Jen Jen Yeh +17 more
TL;DR: By digitally separating tumor, stromal and normal gene expression, two tumor subtypes are identified and validated, including a 'basal-like' subtype that has worse outcome and is molecularly similar to basal tumors in bladder and breast cancers.
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TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
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