Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets
Agnieszka K. Witkiewicz,Elizabeth A. McMillan,Uthra Balaji,Guem Hee Baek,Wan Chi Lin,John C. Mansour,Mehri Mollaee,Kay Uwe Wagner,Prasad Koduru,Adam C. Yopp,Michael A. Choti,Charles J. Yeo,Peter McCue,Michael A. White,Erik S. Knudsen +14 more
TLDR
It is shown that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra, and multiple novel mutated genes in PDA are identified, with select genes harbouring prognostic significance.Abstract:
Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.read more
Citations
More filters
Journal ArticleDOI
Pan-cancer Immunogenomic Analyses Reveal Genotype-Immunophenotype Relationships and Predictors of Response to Checkpoint Blockade
Pornpimol Charoentong,Francesca Finotello,Mihaela Angelova,Clemens Mayer,Mirjana Efremova,Dietmar Rieder,Hubert Hackl,Zlatko Trajanoski +7 more
TL;DR: The immunophenoscore was a superior predictor of response to anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death protein 1 (anti-PD-1) antibodies in two independent validation cohorts and may help inform cancer immunotherapy and facilitate the development of precision immuno-oncology.
Integrative Genomics Viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Journal ArticleDOI
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma
Adrian Ally,Miruna Balasundaram,Rebecca Carlsen,Eric Chuah,Amanda Clarke,Noreen Dhalla,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Yussanne Ma,Marco A. Marra,Michael Mayo,Richard A. Moore,Andrew J. Mungall,Jacqueline E. Schein,Payal Sipahimalani,Angela Tam,Nina Thiessen,Dorothy Cheung,Tina Wong,Denise Brooks,A. Gordon Robertson,Reanne Bowlby,Karen Mungall,Sara Sadeghi,Liu Xi,Kyle R. Covington,Eve Shinbrot,David A. Wheeler,Richard A. Gibbs,Lawrence A. Donehower,Linghua Wang,Jay Bowen,Julie M. Gastier-Foster,Mark Gerken,Carmen Helsel,Kristen M. Leraas,Tara M. Lichtenberg,Nilsa C. Ramirez,Lisa Wise,Erik Zmuda,Stacey Gabriel,Matthew Meyerson,Carrie Cibulskis,Bradley A. Murray,Juliann Shih,Rameen Beroukhim,Andrew D. Cherniack,Steven E. Schumacher,Gordon Saksena,Chandra Sekhar Pedamallu,Lynda Chin,Gad Getz,Michael S. Noble,Hailei Zhang,David I. Heiman,Juok Cho,Nils Gehlenborg,Douglas Voet,Pei Lin,Scott Frazer,Timothy Defreitas,Sam Meier,Michael S. Lawrence,Jaegil Kim,Chad J. Creighton,Donna M. Muzny,Harshavardhan Doddapaneni,Jianhong Hu,Min Wang,Donna Morton,Viktoriya Korchina,Yi Han,Huyen Dinh,Lora Lewis,Michelle Bellair,Xiuping Liu,Jireh Santibanez,Robert Glenn,Sandra Lee,Walker Hale,Joel S. Parker,Matthew D. Wilkerson,D. Neil Hayes,Sheila Reynolds,Ilya Shmulevich,Wei Zhang,Yuexin Liu,Lisa Iype,Hala Makhlouf,Michael Torbenson,Sanjay Kakar,Matthew M. Yeh,Dhanpat Jain,David E. Kleiner,Renumathy Dhanasekaran,Hashem B. El-Serag,Sun Young Yim,John N. Weinstein,Lopa Mishra,Jianping Zhang,Rehan Akbani,Shiyun Ling,Zhenlin Ju,Xiaoping Su,Apurva M. Hegde,Gordon B. Mills,Yiling Lu,Jian Chen,Ju Seog Lee,Bo Hwa Sohn,Jae-Jun Shim,Pan Tong,Hiroyuki Aburatani,Shogo Yamamoto,Kenji Tatsuno,Wei Li,Zheng Xia,Nicolas Stransky,Eric Seiser,Federico Innocenti,Jianjiong Gao,Ritika Kundra,Hongxin Zhang,Zachary J. Heins,Angelica Ochoa,Chris Sander,Marc Ladanyi,Ronglai Shen,Arshi Arora,Francisco Sanchez-Vega,Nikolaus Schultz,Katayoon Kasaian,Amie Radenbaugh,Karl-Dimiter Bissig,David D. Moore,Yasushi Totoki,Hiromi Nakamura,Tatsuhiro Shibata,Christina Yau,Kiley Graim,Josh Stuart,David Haussler,Betty L. Slagle,Akinyemi I. Ojesina,Panagiotis Katsonis,Amanda Koire,Olivier Lichtarge,Teng-Kuei Hsu,Martin L. Ferguson,John A. Demchok,Ina Felau,Margi Sheth,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jean C. Zenklusen,Jiashan Zhang,Carolyn M. Hutter,Heidi J. Sofia,Roel G.W. Verhaak,Siyuan Zheng,Frederick Lang,Sudha Chudamani,Jia Liu,Laxmi Lolla,Ye Wu,Rashi Naresh,Todd Pihl,Charlie Sun,Yunhu Wan,Christopher C. Benz,Amy H. Perou,Leigh B. Thorne,Lori Boice,Mei Huang,W. Kimryn Rathmell,Houtan Noushmehr,Fabiano Pinto Saggioro,Daniela Pretti da Cunha Tirapelli,Carlos Gilberto Carlotti Junior,Enio David Mente,Orlando de Castro Silva,Felipe Amstalden Trevisan,Koo Jeong Kang,Keun Soo Ahn,Nasra H. Giama,Catherine D. Moser,Thomas J. Giordano,Michelle Vinco,Theodore H. Welling,Daniel Crain,Erin Curley,Johanna Gardner,David Mallery,Scott Morris,Joseph Paulauskis,Robert Penny,Candace Shelton,Troy Shelton,Robin Kate Kelley,Joong-Won Park,Vishal S. Chandan,Lewis R. Roberts,Oliver F. Bathe,Curt H. Hagedorn,J. Todd Auman,Daniel R. O'Brien,Jean-Pierre A. Kocher,Corbin D. Jones,Piotr A. Mieczkowski,Charles M. Perou,Tara Skelly,Donghui Tan,Umadevi Veluvolu,Saianand Balu,Tom Bodenheimer,Alan P. Hoyle,Stuart R. Jefferys,Shaowu Meng,Lisle E. Mose,Yan Shi,Janae V. Simons,Matthew G. Soloway,Jeffrey Roach,Katherine A. Hoadley,Stephen B. Baylin,Hui Shen,Toshinori Hinoue,Moiz S. Bootwalla,David Van Den Berg,Daniel J. Weisenberger,Phillip H. Lai,Andrea Holbrook,Mario Berrios,Peter W. Laird +235 more
TL;DR: Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts and development of a p53 target gene expression signature correlating with poor survival was enabled.
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.
Journal ArticleDOI
Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma
Benjamin J. Raphael,Ralph H. Hruban,Andrew J. Aguirre,Richard A. Moffitt,Jen Jen Yeh,Chip Stewart,A. Gordon Robertson,Andrew D. Cherniack,Manaswi Gupta,Gad Getz,Stacey Gabriel,Matthew Meyerson,Carrie Cibulskis,Suzanne S. Fei,Toshinori Hinoue,Hui Shen,Peter W. Laird,Shiyun Ling,Yiling Lu,Gordon B. Mills,Rehan Akbani,Phillipe Loher,Eric Londin,Isidore Rigoutsos,Aristeidis G. Telonis,Ewan A. Gibb,Anna Goldenberg,Aziz M. Mezlini,Katherine A. Hoadley,Eric A. Collisson,Eric S. Lander,Bradley A. Murray,Julian M. Hess,Mara Rosenberg,Louis Bergelson,Hailei Zhang,Juok Cho,Grace Tiao,Jaegil Kim,Dimitri Livitz,Ignaty Leshchiner,Brendan Reardon,Eliezer M. Van Allen,Atanas Kamburov,Rameen Beroukhim,Gordon Saksena,Steven E. Schumacher,Michael S. Noble,David I. Heiman,Nils Gehlenborg,Michael S. Lawrence,Volkan Adsay,Gloria M. Petersen,David S. Klimstra,Nabeel Bardeesy,Mark D.M. Leiserson,Reanne Bowlby,Katayoon Kasaian,Inanc Birol,Karen Mungall,Sara Sadeghi,John N. Weinstein,Paul T. Spellman,Yuexin Liu,Laufey T. Amundadottir,Joel E. Tepper,Aatur D. Singhi,Rajiv Dhir,Drwiega Paul,Thomas C. Smyrk,Lizhi Zhang,Paula Kim,Jay Bowen,Jessica Frick,Julie M. Gastier-Foster,Mark Gerken,Kevin Lau,Kristen M. Leraas,Tara M. Lichtenberg,Nilsa C. Ramirez,Jeremy Renkel,Mark E. Sherman,Lisa Wise,Peggy Yena,Erik Zmuda,Juliann Shih,Adrian Ally,Miruna Balasundaram,Rebecca Carlsen,Andy Chu,Eric Chuah,Amanda Clarke,Noreen Dhalla,Robert A. Holt,Steven J.M. Jones,Darlene Lee,Yussanne Ma,Marco A. Marra,Michael Mayo,Richard A. Moore,Andrew J. Mungall,Jacqueline E. Schein,Payal Sipahimalani,Angela Tam,Nina Thiessen,Kane Tse,Tina Wong,Denise Brooks,J. Todd Auman,Saianand Balu,Tom Bodenheimer,D. Neil Hayes,Alan P. Hoyle,Stuart R. Jefferys,Corbin D. Jones,Shaowu Meng,Piotr A. Mieczkowski,Lisle E. Mose,Charles M. Perou,Amy H. Perou,Jeffrey Roach,Yan Shi,Janae V. Simons,Tara Skelly,Matthew G. Soloway,Donghui Tan,Umadevi Veluvolu,Joel S. Parker,Matthew D. Wilkerson,Anil Korkut,Yasin Senbabaoglu,Patrick Burch,Robert R. McWilliams,Kari G. Chaffee,Ann L. Oberg,Wei Zhang,Marie-Claude Gingras,David A. Wheeler,Liu Xi,Monique Albert,John M. S. Bartlett,Harman Sekhon,Yeager Stephen,Zaren Howard,Miller Judy,Anne Breggia,Rachna T. Shroff,Sudha Chudamani,Jia Liu,Laxmi Lolla,Rashi Naresh,Todd Pihl,Qiang Sun,Yunhu Wan,Ye Wu,Smith Jennifer,Kevin Roggin,Karl-Friedrich Becker,Madhusmita Behera,Joseph J. Bennett,Lori Boice,Eric J. Burks,Carlos Gilberto Carlotti Junior,John Chabot,Daniela Pretti da Cunha Tirapelli,Jose Sebastião dos Santos,Michael Dubina,Jennifer M. Eschbacher,Mei Huang,Lori Huelsenbeck-Dill,Roger Jenkins,Alexey Karpov,Rafael Kemp,Vladimir Lyadov,Shishir K. Maithel,Georgy Manikhas,Eric Montgomery,Houtan Noushmehr,Adeboye O. Osunkoya,Taofeek K. Owonikoko,Oxana Paklina,Olga Potapova,Suresh S. Ramalingam,W. Kimryn Rathmell,Kimberly M. Rieger-Christ,Charles Saller,Galiya Setdikova,Alexey Shabunin,Gabriel Sica,Tao Su,Travis Sullivan,Pat Swanson,Katherine Tarvin,Michael Tavobilov,Leigh B. Thorne,Stefan Urbanski,Olga Voronina,Timothy C. Wang,Daniel Crain,Erin Curley,Johanna Gardner,David Mallery,Scott J. Morris,Joseph Paulauskis,Robert Penny,Candace Shelton,Troy Shelton,Klaus-Peter Janssen,Oliver F. Bathe,Nathan Bahary,Julia Slotta-Huspenina,Amber L. Johns,Hanina Hibshoosh,Rosa F. Hwang,Antonia R. Sepulveda,Amie Radenbaugh,Stephen B. Baylin,Mario Berrios,Moiz S. Bootwalla,Andrea Holbrook,Phillip H. Lai,Dennis T. Maglinte,Swapna Mahurkar,Timothy J. Triche,David Van Den Berg,Daniel J. Weisenberger,Lynda Chin,Raju Kucherlapati,Melanie H. Kucherlapati,Angeliki Pantazi,Peter J. Park,Doug Voet,Pei Lin,Scott Frazer,Timothy Defreitas,Sam Meier,Sun Young Kwon,Yong Hoon Kim,Sang Jae Park,Sung Sik Han,Seong Hoon Kim,Hark Kyun Kim,Emma E. Furth,Margaret A. Tempero,Chris Sander,Andrew V. Biankin,David K. Chang,Peter Bailey,Anthony J. Gill,James G. Kench,Sean M. Grimmond,Russell Postier,Rosemary E. Zuna,Hugues Sicotte,John A. Demchok,Martin L. Ferguson,Carolyn M. Hutter,Kenna R. Mills Shaw,Margi Sheth,Heidi J. Sofia,Roy Tarnuzzer,Zhining Wang,Liming Yang,Jiashan Zhang,Ina Felau,Jean C. Zenklusen +265 more
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.
References
More filters
Journal ArticleDOI
Fast and accurate short read alignment with Burrows–Wheeler transform
Heng Li,Richard Durbin +1 more
TL;DR: Burrows-Wheeler Alignment tool (BWA) is implemented, a new read alignment package that is based on backward search with Burrows–Wheeler Transform (BWT), to efficiently align short sequencing reads against a large reference sequence such as the human genome, allowing mismatches and gaps.
Journal ArticleDOI
Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks
Paul Shannon,Andrew Markiel,Owen Ozier,Nitin S. Baliga,Jonathan T. Wang,Daniel Ramage,Nada Amin,Benno Schwikowski,Trey Ideker +8 more
TL;DR: Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
Integrative genomics viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: In this article, the authors present an approach for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Journal ArticleDOI
Signatures of mutational processes in human cancer
Ludmil B. Alexandrov,Serena Nik-Zainal,Serena Nik-Zainal,David C. Wedge,Samuel Aparicio,Sam Behjati,Sam Behjati,Andrew V. Biankin,Graham R. Bignell,Niccolo Bolli,Niccolo Bolli,Åke Borg,Anne Lise Børresen-Dale,Anne Lise Børresen-Dale,Sandrine Boyault,Birgit Burkhardt,Adam Butler,Carlos Caldas,Helen Davies,Christine Desmedt,Roland Eils,Jorunn E. Eyfjord,John A. Foekens,Mel Greaves,Fumie Hosoda,Barbara Hutter,Tomislav Ilicic,Sandrine Imbeaud,Sandrine Imbeaud,Marcin Imielinsk,Natalie Jäger,David T. W. Jones,David T. Jones,Stian Knappskog,Stian Knappskog,Marcel Kool,Sunil R. Lakhani,Carlos López-Otín,Sancha Martin,Nikhil C. Munshi,Nikhil C. Munshi,Hiromi Nakamura,Paul A. Northcott,Marina Pajic,Elli Papaemmanuil,Angelo Paradiso,John V. Pearson,Xose S. Puente,Keiran Raine,Manasa Ramakrishna,Andrea L. Richardson,Andrea L. Richardson,Julia Richter,Philip Rosenstiel,Matthias Schlesner,Ton N. Schumacher,Paul N. Span,Jon W. Teague,Yasushi Totoki,Andrew Tutt,Rafael Valdés-Mas,Marit M. van Buuren,Laura van ’t Veer,Anne Vincent-Salomon,Nicola Waddell,Lucy R. Yates,Icgc PedBrain,Jessica Zucman-Rossi,Jessica Zucman-Rossi,P. Andrew Futreal,Ultan McDermott,Peter Lichter,Matthew Meyerson,Matthew Meyerson,Sean M. Grimmond,Reiner Siebert,Elias Campo,Tatsuhiro Shibata,Stefan M. Pfister,Stefan M. Pfister,Peter J. Campbell,Peter J. Campbell,Peter J. Campbell,Michael R. Stratton,Michael R. Stratton +84 more
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.
Related Papers (5)
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Siân Jones,Xiaosong Zhang,D. Williams Parsons,D. Williams Parsons,Jimmy Lin,Rebecca J. Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,Hirohiko Kamiyama,Antonio Jimeno,Seung-Mo Hong,Baojin Fu,Ming Tseh Lin,Eric S. Calhoun,Mihoko Kamiyama,Kimberly Walter,Tatiana Nikolskaya,Yuri Nikolsky,James Hartigan,Douglas Smith,Manuel Hidalgo,Steven D. Leach,Alison P. Klein,Elizabeth M. Jaffee,Michael Goggins,Anirban Maitra,Anirban Maitra,Christine A. Iacobuzio-Donahue,James R. Eshleman,Scott E. Kern,Ralph H. Hruban,Rachel Karchin,Nickolas Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E. Velculescu,Kenneth W. Kinzler +37 more
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Thierry Conroy,Françoise Desseigne,Marc Ychou,Olivier Bouché,Rosine Guimbaud,Yves Becouarn,Antoine Adenis,Jean-Luc Raoul,Sophie Gourgou-Bourgade,Jaafar Bennouna,Jean-Baptiste Bachet,Faiza Khemissa-Akouz,Denis Péré-Vergé,Catherine Delbaldo,Eric Assenat,Bruno Chauffert,C. Montoto-Grillot,Michel Ducreux +17 more
Increased Survival in Pancreatic Cancer with nab-Paclitaxel plus Gemcitabine
Daniel D. Von Hoff,Thomas J. Ervin,Francis P. Arena,E. Gabriela Chiorean,Jeffrey R. Infante,Malcolm J. Moore,Thomas E. Seay,Sergei Tjulandin,Wen Wee Ma,Mansoor N. Saleh,Marion Harris,Michele Reni,Scot Dowden,Daniel A. Laheru,Nathan Bahary,Ramesh K. Ramanathan,Josep Tabernero,Manuel Hidalgo,David Goldstein,Eric Van Cutsem,Xinyu Wei,Jose Iglesias,Markus F. Renschler +22 more