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Science 321 (5897): 1801-1806

Copyright © 2008 by the American Association for the Advancement of Science

Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

Siân Jones1*, Xiaosong Zhang1*, D. Williams Parsons1,2*, Jimmy Cheng-Ho Lin1*, Rebecca J. Leary1*, Philipp Angenendt1*, Parminder Mankoo3, Hannah Carter3, Hirohiko Kamiyama4, Antonio Jimeno1, Seung-Mo Hong4, Baojin Fu4, Ming-Tseh Lin4, Eric S. Calhoun1, Mihoko Kamiyama4, Kimberly Walter4, Tatiana Nikolskaya5, Yuri Nikolsky6, James Hartigan7, Douglas R. Smith7, Manuel Hidalgo1, Steven D. Leach1,8, Alison P. Klein1,4, Elizabeth M. Jaffee1,4, Michael Goggins1,4, Anirban Maitra1,4, Christine Iacobuzio-Donahue1,4, James R. Eshleman1,4, Scott E. Kern1,4, Ralph H. Hruban1,4, Rachel Karchin3, Nickolas Papadopoulos1, Giovanni Parmigiani1,9, Bert Vogelstein1{dagger}, Victor E. Velculescu1{dagger}, and Kenneth W. Kinzler1{dagger}

1 Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
2 Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston, TX 77030, USA.
3 Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21218, USA.
4 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
5 Vavilov Institute for General Genetics, Moscow B333, 117809, Russia.
6 GeneGo, Incorporated, St. Joseph, MI 49085, USA.
7 Agencourt Bioscience Corporation, Beverly, MA 01915, USA.
8 Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
9 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.


Figure 1 Fig. 1.. Examples of structural models of mutations. (A). The x-ray crystal structure of the C2 domain of protein kinase C {gamma} (PKCG) [Protein Data Bank identification number (PDBID) 2UZP]. R252 (41) is shown as yellow space-fills; Ca2+ ions are shown as red spheres. The ligands 1,2-ethanediol and pyridoxal-5-phosphate are shown in white and purple ball-and-stick representations, respectively. The R252->H252 (R252H) mutation could reduce the membrane binding of the C2 domain of PRKCG and thereby affect function. (B) The nuclear magnetic resonance solution structure of the three tandem repeats of zf-C2H2 domains from human Kruppel-like factor 5 (KLF5) (PDBID 2EBT). H389 is shown as yellow space-fills; Zn2+ ions are shown as cyan spheres. The residues comprising the C2H2 group that coordinate the nearby Zn2+ ion are shown as ball-and-stick representations, H393 and H397 are shown in green and white, whereas C380 and C375 are shown in orange and red. The mutation at position 389 (H389N) may disrupt the structure of the zinc finger or nearby zinc coordination site. (C) The x-ray crystal structure of the heterotrimer of SMAD3 (two subunits shown as blue ribbons) and SMAD4 (one subunit shown as pink ribbons) (PDBID 1U7F). The residues corresponding to two of the mutant positions (F260S and S422F, shown as red and yellow space-fills, respectively, in chain A) are located at interfaces and could perturb Smad3-Smad3 or Smad3-Smad4 interactions. In chain B, F260 is shown as cyan space-fills and S422 as green space-fills. (D) The x-ray crystal structure of the extracellular domain of human DPP6 as a homodimer (PDBID 1XFD). Two of the mutated residues found in this study, T409I (shown as red space-fills) and D475N (shown in yellow space-fills) are in spatial proximity and are close to one of the glycosylation sites, N471 (shown as white space-fills). These mutations fall in the β-propeller domain of the protein (residues 142 to 322 and 351 to 581) thought to be involved in protein-protein interactions. The A778T mutation (shown as blue space-fills) falls in the */β hydrolase domain (residues 127 to 142 and 581 to 849) and is close to the homodimer region of the protein and could perturb the homodimer association. Carbohydrates with glycosylation sites are shown in stick representation. Images created with UCSF Chimera version 1.2422 for Linux (42). [View Larger Version of this Image (43K GIF file)]
 

Figure 2 Fig. 2.. Number of genetic alterations detected through sequencing and copy number analyses in each of the 24 cancers. [View Larger Version of this Image (22K GIF file)]
 

Figure 3 Fig. 3.. Signaling pathways and processes. (A) The 12 pathways and processes whose component genes were genetically altered in most pancreatic cancers. (B and C) Two pancreatic cancers (Pa14C and Pa10X) and the specific genes that are mutated in them. The positions around the circles in (B) and (C) correspond to the pathways and processes in (A). Several pathway components overlapped, as illustrated by the BMPR2 mutation that presumably disrupted both the SMAD4 and Hedgehog signaling pathways in Pa10X. Additionally, not all 12 processes and pathways were altered in every pancreatic cancer, as exemplified by the fact that no mutations known to affect DNA damage control were observed in Pa10X. N.O. indicates not observed. [View Larger Version of this Image (38K GIF file)]
 


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