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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International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors
Jörg Hamann,Gabriela Aust,Demet Araç,Felix B. Engel,Caroline J. Formstone,Robert Fredriksson,Randy A. Hall,Breanne L. Harty,Christiane Kirchhoff,Barbara Knapp,Arunkumar Krishnan,Ines Liebscher,Hsi-Hsien Lin,David C. Martinelli,Kelly Monk,Miriam C. Peeters,Xianhua Piao,Simone Prömel,Torsten Schöneberg,Thue W. Schwartz,Kathleen Singer,Martin Stacey,Yuri A. Ushkaryov,Mario Vallon,Uwe Wolfrum,Mathew W. Wright,Lei Xu,Tobias Langenhan,Helgi B. Schiöth +28 more
TL;DR: This review covers all major biologic aspects of Adhesion GPCRs, including evolutionary origins, interaction partners, signaling, expression, physiologic functions, and therapeutic potential.
Journal ArticleDOI
Personalized genomic analyses for cancer mutation discovery and interpretation
Siân Jones,Valsamo Anagnostou,Karli Lytle,Sonya Parpart-Li,Monica Nesselbush,David R. Riley,Manish Shukla,Bryan Chesnick,Maura Kadan,Eniko Papp,Kevin Galens,Derek Murphy,Theresa Zhang,Lisa Kann,Mark Sausen,Samuel V. Angiuoli,Luis A. Diaz,Victor E. Velculescu +17 more
TL;DR: Analysis of matched tumor and normal DNA from the same patient improves accuracy of identification of actionable mutations, allowing better targeting of potential treatments, and suggests matched normal DNA analyses are essential for precise identification and interpretation of somatic and germline alterations.
Journal ArticleDOI
A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.
Demet Araç,Demet Araç,Antony A. Boucard,Marc F. Bolliger,Jenna Nguyen,Jenna Nguyen,S. Michael Soltis,Thomas C. Südhof,Thomas C. Südhof,Axel T. Brunger,Axel T. Brunger +10 more
TL;DR: The GAIN domain embodies a unique, evolutionarily ancient and widespread autoproteolytic fold whose function is likely relevant for GPCR signalling and for multiple human diseases.
Journal ArticleDOI
Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice
Michael P. Kim,Douglas B. Evans,Huamin Wang,James L. Abbruzzese,Jason B. Fleming,Gary E. Gallick +5 more
TL;DR: These protocols for the orthotopic and heterotopic implantation of pancreatic cancer cell lines and freshly isolated patient tumors into immunodeficient mice and procedures for the digestion of tumors into single-cell suspensions for the isolation of subpopulations of tumor cells are described.
Journal ArticleDOI
Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis
Oliver G. McDonald,Xin Li,Tyler Saunders,Rakel Tryggvadottir,Samantha J. Mentch,Marc O. Warmoes,Anna E Word,Alessandro Carrer,Tal Salz,Sonoko Natsume,Kimberly M. Stauffer,Alvin Makohon-Moore,Yi Zhong,Hao Wu,Kathryn E. Wellen,Jason W. Locasale,Christine A. Iacobuzio-Donahue,Andrew P. Feinberg,Andrew P. Feinberg +18 more
TL;DR: Large-scale reprogramming of chromatin modifications during the natural evolution of distant metastasis is reported, suggesting a model whereby linked metabolic–epigenetic programs are selected for enhanced tumorigenic fitness during the evolution of remote metastasis.
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