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Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Open accessAbstract
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 ∼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.
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“the genomic landscape of PDAC is also dominated by loss of function alterations of TP53, SMAD4 (also known as DPC4), and CDKN2A45,48–50.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [48]
Experimental — accuracy not yet measuredIn the citing paper
“Among the identified genomic alterations (GAs) in PDAC, oncogenic KRAS mutations are the most common, occurring in close to 90% of patients, followed by TP53, CDKN2A, and SMAD47,8.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [8]
In the citing paper
“Chromatin remodeling and SWI/SNF complex genes are one of the most frequently altered class of genes in PDAC45,48–50, and can occur via somatic deletions of the associated chromosomal loci94.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [48]
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Metadata
- Authors
- Jones, S., Zhang, X., Parsons, D. W., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., Hong, S.-M., Fu, B., Lin, M.-T., Calhoun, E. S., Kamiyama, M., Walter, K., Nikolskaya, T., Nikolsky, Y., Hartigan, J., Smith, D. R., Hidalgo, M., Leach, S. D., Klein, A. P., Jaffee, E. M., Goggins, M., Maitra, A., Iacobuzio-Donahue, C., Eshleman, J. R., Kern, S. E., Hruban, R. H., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V. E., & Kinzler, K. W.
- Affiliations
- Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
- Howard Hughes Medical Institute (US)
- Russian Academy of Sciences (RU)
- Corresponding author
- Zhang, Xiaosong
- Parsons, D. Williams
- Lin, Jimmy Cheng-Ho
- Leary, Rebecca J.
- Angenendt, Philipp
- Vogelstein, Bert
- Velculescu, Victor E.
- Kinzler, Kenneth W.
- ORCID
- Zhang, Xiaosong
- Parsons, D. Williams
- Lin, Jimmy Cheng-Ho
- Leary, Rebecca J.
- Kamiyama, Hirohiko
- Jimeno, Antonio
- Hong, Seung-Mo
- Lin, Ming-Tseh
- Walter, Kimberly
- Smith, Douglas R.
- Hidalgo, Manuel
- Leach, Steven D.
- Klein, Alison P.
- Jaffee, Elizabeth M.
- Goggins, Michael
- Maitra, Anirban
- Eshleman, James R.
- Kern, Scott E.
- Hruban, Ralph H.
- Karchin, Rachel
- Papadopoulos, Nickolas
- Parmigiani, Giovanni
- Vogelstein, Bert
- Velculescu, Victor E.
- Kinzler, Kenneth W.
- Venue
- Science
- Published
- 2008-09-26
- Volume
- 321
- Issue
- 5897
- Pages
- 1801-1806
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC2848990
- OpenAlex
- W2138155367
- Cited by
- 3,969
- References
- 32
- Citations by year
- 2026: 53 · 2025: 88 · 2024: 148 · 2023: 198 · 2022: 133 · 2021: 225 · 2020: 218 · 2019: 208 · 2018: 210 · 2017: 244 · 2016: 249 · 2015: 307 · 2014: 315 · 2013: 272 · 2012: 314
- FWCI
- 137.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health (5r01ca121113-15)
- National Cancer Institute (CA 57345, R01-CA121113, CA-121113, CA43460, R37CA043460, P50CA062924, R37CA057345, CA 62924)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- pancreatic cancer, genetic alterations, point mutations, homozygous deletion, gene amplification, transcriptome, carcinogenesis, single nucleotide polymorphism array, next-generation sequencing
- MeSH terms
- Adenocarcinoma, Algorithms, Gene Amplification, Humans, Models, Molecular, Mutation, Pancreatic Neoplasms, Signal Transduction, Genome, Human, Point Mutation, Sequence Deletion, Computational Biology, Mutation, Missense, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Gene Expression Profiling, Carcinoma, Pancreatic Ductal
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