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

Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Science (Impact Factor: 31.48). 10/2008; 321(5897):1801-6. DOI: 10.1126/science.1164368
Source: PubMed

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 ∼106 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.

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Available from: Giovanni Parmigiani, Jul 10, 2015
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    • "It is almost always fatal despite maximal treatment, with fewer than 1 % of patients surviving 5 years after diagnosis (Carpelan-Holmström et al. 2005). Analysis of pancreatic ductal adenocarcinomas has revealed complex and diverse patterns of genetic lesions (Jones et al. 2008), but KRAS mutations are present in 90–95 % of cases (Caldas and Kern 1995) and widely understood to be the initiating event (reviewed by Deramaudt and Rustgi 2005). This is supported by the experimental replication of pancreatic cancer in mice, from neoplasia to invasive disease using mutant Kras G12D alone (Hingorani et al. 2003), which can be accelerated by combination with mutant Trp53 R172H (Hingorani et al. 2005). "
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    ABSTRACT: Oncogenic mutations of KRAS play a major role in human carcinogenesis. Here we describe viable gene-targeted pigs carrying a latent KRAS (G12D) mutant allele that can be activated by Cre recombination. These have been produced as part of a program to model human cancers in pigs by replicating genetic lesions known to initiate and drive human disease. Cre-activated KRAS (G12D) animals add to a growing set of gene-targeted pigs that includes a Cre-activated oncogenic mutant TP53, a Cre-responsive dual fluorescent reporter and two truncating mutations of APC (adenomatous polyposis coli). These alleles can be combined and activated in various tissues to produce new models for cancer research.
    Transgenic Research 02/2015; 24(3). DOI:10.1007/s11248-015-9866-8 · 2.28 Impact Factor
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    • "M. Hidalgo et al. / Pancreatology 15 (2015) 8e18 14 average of 63 mutations [22]. However, while the need for molecular characterization of different cancers is well recognized and has been highlighted by the American Society for Clinical Oncology as a key factor for accelerating progress in cancer [137], the organization and society in general have paid little attention to PDAC to date. "
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    • "It is also becoming clear that pancreatic cancer tumors are highly heterogeneous, with results from a global landmark genomic analysis of 24 advanced pancreatic adenocarcinomas showing that tumors contain on average 63 genetic alterations. This heterogeneity may partially explain the notorious resistance of pancreatic cancer to chemotherapy and, unfortunately, it may also render the idea of targeted therapies to specific tumor mutations as largely unrealistic [21]. "
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