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: 33.61). 10/2008; 321(5897):1801-6. DOI: 10.1126/science.1164368
Source: PubMed


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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    • "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 · 2.32 Impact Factor
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    • "Conversely, ADAMTS-15 is detected in colon cancer cells rather than in stromal cells, and its expression inversely correlates with the histopathological grade of tumors [42]. Notably, ADAMTS15 gene is not epigenetically silenced, but it has been found frequently mutated not only in colon but also in pancreatic carcinomas [42] [61] [62]. Tumor-suppressive effects elicited by ADAMTS-15 have also been described in breast carcinomas and its detection is associated with a better clinical outcome in breast cancer patients [59] [63]. "
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    ABSTRACT: ADAMTSs (A Disintegrin And Metalloprotease domains with ThromboSpondins) are complex extracellular proteases that have been related to both oncogenic and tumor-protective functions. These enzymes can be secreted by cancer and stromal cells and may contribute to modify the tumor microenvironment by multiple mechanisms. Thus, ADAMTSs can cleave or interact with a wide range of extracellular matrix components or regulatory factors, and therefore affect cell adhesion, migration, proliferation and angiogenesis. The balance of protumor versus antitumor effects of ADAMTSs may depend on the nature of their substrates or interacting-partners upon secretion from the cell. Moreover, different ADAMTS genes have been found overexpressed, mutated or epigenetically silenced in tumors from different origins, suggesting the direct impact of these metalloproteases in cancer development. However, despite the important advances on the tumor biology of ADAMTSs in recent years, more mechanistic and functional studies are necessary to fully understand how these proteases can influence tumor microenvironment to potentiate cancer growth or to induce tumor regression. This review outlines current and emerging connections between ADAMTSs and cancer.
    Matrix Biology 01/2015; 272. DOI:10.1016/j.matbio.2015.01.013 · 5.07 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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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease.
    Pancreatology 10/2014; 15(1). DOI:10.1016/j.pan.2014.10.001 · 2.84 Impact Factor
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