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
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TLDR
It is found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations, which defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors.Abstract:
There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for approximately 10(6) single-nucleotide polymorphisms. We found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors. Analysis of these tumors' transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the importance of these pathways and processes. Our data indicate that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.read more
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Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.
Marco Gerlinger,Andrew Rowan,Stuart Horswell,James Larkin,David Endesfelder,Eva Grönroos,Pierre Martinez,Nicholas Matthews,Aengus Stewart,Patrick S. Tarpey,Ignacio Varela,Benjamin Phillimore,Sharmin Begum,Neil Q. McDonald,Adam Butler,David T. Jones,Keiran Raine,Calli Latimer,Claudio R. Santos,Mahrokh Nohadani,Aron Charles Eklund,Bradley Spencer-Dene,Graham Clark,Lisa Pickering,Gordon Stamp,Martin Gore,Zoltan Szallasi,Zoltan Szallasi,Julian Downward,P. Andrew Futreal,Charles Swanton +30 more
TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
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Cancer Genome Landscapes
Bert Vogelstein,Nickolas Papadopoulos,Victor E. Velculescu,Shibin Zhou,Luis A. Diaz,Kenneth W. Kinzler +5 more
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).
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An Integrated Genomic Analysis of Human Glioblastoma Multiforme
D. Williams Parsons,Siân Jones,Xiaosong Zhang,Jimmy Lin,Rebecca J. Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,I-Mei Siu,Gary L. Gallia,Alessandro Olivi,Roger E. McLendon,B.K. Ahmed Rasheed,Stephen T. Keir,Tatiana Nikolskaya,Yuri Nikolsky,Dana A. Busam,Hanna Tekleab,Luis A. Diaz,James Hartigan,Doug R. Smith,Robert L. Strausberg,Suely Kazue Nagahashi Marie,Sueli Mieko Oba Shinjo,Hai Yan,Gregory J. Riggins,Darell D. Bigner,Rachel Karchin,Nick Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E. Velculescu,Kenneth W. Kinzler +32 more
TL;DR: Recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival.
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Mutational landscape and significance across 12 major cancer types
Cyriac Kandoth,Michael D. McLellan,Fabio Vandin,Kai Ye,Beifang Niu,Charles Lu,Mingchao Xie,Qunyuan Zhang,Joshua F. McMichael,Matthew A. Wyczalkowski,Mark D.M. Leiserson,Christopher A. Miller,John S. Welch,Matthew J. Walter,Michael C. Wendl,Timothy J. Ley,Richard K. Wilson,Benjamin J. Raphael,Li Ding +18 more
TL;DR: Data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types are presented as part of the TCGA Pan-Cancer effort, and clinical association analysis identifies genes having a significant effect on survival.
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Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies
Chetan Bettegowda,Chetan Bettegowda,Mark Sausen,Rebecca J. Leary,Isaac Kinde,Yuxuan Wang,Nishant Agrawal,Nishant Agrawal,Bjarne Bartlett,Bjarne Bartlett,Hao Wang,Brandon Luber,Rhoda M. Alani,Emmanuel S. Antonarakis,Nilofer S. Azad,Alberto Bardelli,Henry Brem,John L. Cameron,Clarence Lee,Leslie A. Fecher,Leslie A. Fecher,Gary L. Gallia,Peter Gibbs,Dung T. Le,Dung T. Le,Robert L. Giuntoli,Michael Goggins,Michael D. Hogarty,Matthias Holdhoff,Seung-Mo Hong,Seung-Mo Hong,Yuchen Jiao,Hartmut Juhl,Jenny J. Kim,Giulia Siravegna,Daniel A. Laheru,Calogero Lauricella,Michael Lim,Evan J. Lipson,Suely Kazue Nagahashi Marie,George J. Netto,Kelly S. Oliner,Alessandro Olivi,Louise Olsson,Gregory J. Riggins,Andrea Sartore-Bianchi,Kerstin Schmidt,le-Ming Shih,Sueli Mieko Oba-Shinjo,Salvatore Siena,Dan Theodorescu,Jeanne Tie,Timothy T. Harkins,Silvio Veronese,Tian Li Wang,Jon D. Weingart,Christopher L. Wolfgang,Laura D. Wood,Dongmei Xing,Ralph H. Hruban,Jian Wu,Peter J. Allen,C. Max Schmidt,Michael A. Choti,Victor E. Velculescu,Kenneth W. Kinzler,Bert Vogelstein,Nickolas Papadopoulos,Luis A. Diaz,Luis A. Diaz +69 more
TL;DR: The ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types was evaluated and suggested that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes.
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