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

By Siân Jones, Xiaosong Zhang, D. W. Parsons, Jimmy Lin, R. Leary, P. Angenendt, P. Mankoo, Hannah Carter, H. Kamiyama, A. Jimeno and 26 more. Science, 2008

4,022 citations recorded by the source corpus.

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.

Subfields: Cancer Research, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/e1c1beead2f1bd31d9701aec11d3aa2740784e15

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Citations in the corpus

iArc monogrAphs on the evAluAtion oF cArcinogenic risks to humAns (2012, background): “For example, in 24 pancreatic cancers, a total of 12 genetic pathways were identified (Jones et al., 2008).”
Cancer as a metabolic disease (2010, background): “Although mitochondrial function and oxidative phosphorylation is impaired in tumor cells, it remains unclear how these impairments relate to carcinogenesis and to the large number of somatic mutations and chromosomal abnormalities found in tumors [7,15,91-93].”
KRAS: The Critical Driver and Therapeutic Target for Pancreatic Cancer (2018, methodology): “…data of pancreatic cancer patients shows that 93% of the rare PIK3CA mutations co-occur with aKRASmutation, suggesting activated KRAS alone is not sufficient to effectively activate PI3K (Jones et al. 2008; Biankin et al. 2012; Sausen et al. 2015; Waddell et al. 2015; Witkiewicz et al. 2015).”
A decade of exploring the cancer epigenome — biological and translational implications (2011, background): “Similar to DNA mutations that frequently occur in specific genes, such as TP53 or KRAS , which act as major drivers for cancer initiation and progressio”
Molecular networks as sensors and drivers of common human diseases (2009, background): “The genes affected were shown to be significantly more likely to belong to pathways known to be involved in tumorigenesis or tumour progression than was the case for the set of all genes that were resequenced as part of this stud”
Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (2014, positive): “The PDAC genome is characterized by a number of signaturemutations involving theKRAS oncogene and the CDKN2A, TP53, and SMAD4 tumor suppressor genes and by significant chromosomal aberrations resulted from telomere dysfunction and centrosome abnormalities, among other mechanisms (Hezel et al., 2006;”