The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In 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
“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]
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
UCSF Chimera—A visualization system for exploratory research and analysis
Pettersen, E. F., Goddard, T. D., Huang, C. C., Couch, G. S., Greenblatt, D. M., Meng, E. C., & Ferrin, T. E. (2004) · Journal of Computational Chemistry · doi:10.1002/jcc.20084 · Cited by 45,882
Hanahan, D., & Weinberg, R. A. (2000) · Cell · doi:10.1016/s0092-8674(00)81683-9 · Cited by 29,219
Mapping and quantifying mammalian transcriptomes by RNA-Seq
Mortazavi, A., Williams, B. A., McCue, K., Schaeffer, L., & Wold, B. (2008) · Nature Methods · doi:10.1038/nmeth.1226 · Cited by 13,696
Jemal, A., Siegel, R. L., Ward, E., Hao, Y., Xu, J., Murray, T., & Thun, M. J. (2008) · CA A Cancer Journal for Clinicians · doi:10.3322/ca.2007.0010 · Cited by 10,184
SIFT: predicting amino acid changes that affect protein function
Ng, P. C. (2003) · Nucleic Acids Research · doi:10.1093/nar/gkg509 · Cited by 6,601
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Self-citationCancer genes and the pathways they control
Vogelstein, B., & Kinzler, K. W. (2004) · Nature Medicine · doi:10.1038/nm1087 · Cited by 4,346
Self-citationSerial Analysis of Gene Expression
Velculescu, V. E., Zhang, L., Vogelstein, B., & Kinzler, K. W. (1995) · Science · doi:10.1126/science.270.5235.484 · Cited by 3,713
Self-citationThe Consensus Coding Sequences of Human Breast and Colorectal Cancers
Sjöblom, T., Jones, S., Wood, L. D., Parsons, D. W., Lin, J., Barber, T. D., Mandelker, D. L., Leary, R. J., Ptak, J., Silliman, N., et al. (2006) · Science · doi:10.1126/science.1133427 · Cited by 3,161
Self-citationHighly Integrated Single-Base Resolution Maps of the Epigenome in Arabidopsis
Lister, R., O’Malley, R. C., Tonti‐Filippini, J., Gregory, B. D., Berry, C. C., Millar, A. H., & Ecker, J. R. (2008) · Cell · doi:10.1016/j.cell.2008.03.029 · Cited by 2,424
Cancer burden in the year 2000. The global picture
Parkin, D. M., Bray, F. I., & Devesa, S. S. (2001) · European Journal of Cancer · doi:10.1016/s0959-8049(01)00267-2 · Cited by 2,169
Sultan, M., Schulz, M. H., Richard, H., Magen, A., Klingenhoff, A., Scherf, M., Seifert, M., Borodina, T., Soldatov, A., Parkhomchuk, D., et al. (2008) · Science · doi:10.1126/science.1160342 · Cited by 1,293
Maitra, A., & Hruban, R. H. (2008) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathmechdis.3.121806.154305 · Cited by 707
Self-citationMorin, R. D., Bainbridge, M. N., Fejes, A. P., Hirst, M., Krzywinski, M. I., Pugh, T. J., McDonald, H., Varhol, R., Jones, S. J. M., & Marra, M. A. (2008) · BioTechniques · doi:10.2144/000112900 · Cited by 433
Self-citationImmortal Human Pancreatic Duct Epithelial Cell Lines with Near Normal Genotype and Phenotype
Ouyang, H., Mou, L.-J., Luk, C. K., Liu, N., Karásková, J., Squire, J. A., & Tsao, M. (2000) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64800-6 · Cited by 317
Pathway Mapping Tools for Analysis of High Content Data
Ekins, S., Nikolsky, Y., Bugrim, A. E., Kirillov, E., & Nikolskaya, T. (2006) · Humana Press eBooks · doi:10.1385/1-59745-217-3:319 · Cited by 266
Self-citationJaffee, E. M., Hruban, R. H., Canto, M. I., & Kern, S. E. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00093-4 · Cited by 222
Self-citationKoorstra, J.-B. M., Hustinx, S. R., Offerhaus, G. J. A., & Maitra, A. (2008) · Pancreatology · doi:10.1159/000123838 · Cited by 190
Self-citationHussain, S. P., & Harris, C. C. (1999) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s1383-5742(99)00028-9 · Cited by 164
Statistical Analysis of Pathogenicity of Somatic Mutations in Cancer
Greenman, C., Wooster, R., Futreal, P. A., Stratton, M. R., & Easton, D. F. (2006) · Genetics · doi:10.1534/genetics.105.044677 · Cited by 163
Knudson, A. G. (2002) · American Journal of Medical Genetics · doi:10.1002/ajmg.10320 · Cited by 160
The molecular epidemiology of P53 gene mutations in human breast cancer
Hartmann, A., Blaszyk, H., Kovach, J. S., & Sommer, S. S. (1997) · Trends in Genetics · doi:10.1016/s0168-9525(96)10043-3 · Cited by 139
A multidimensional analysis of genes mutated in breast and colorectal cancersPreprint
Lin, J., Gan, C. M., Zhang, X., Jones, S., Sjöblom, T., Wood, L. D., Parsons, D. W., Papadopoulos, N., Kinzler, K. W., Vogelstein, B., et al. (2007) · Genome Research · doi:10.1101/gr.6431107 · Cited by 136
Self-citationKlein, W. M., Hruban, R. H., Klein–Szanto, A. J., & Wilentz, R. E. (2002) · Modern Pathology · doi:10.1038/modpathol.3880544 · Cited by 131
Self-citationHustinx, S. R., Leoni, L. M., Yeo, C. J., Brown, P. N., Goggins, M., Kern, S. E., Hruban, R. H., & Maitra, A. (2005) · Modern Pathology · doi:10.1038/modpathol.3800377 · Cited by 125
Self-citationRecent Advances on the Molecular Mechanisms Involved in Pancreatic Cancer Progression and Therapies
Mimeault, M., Brand, R. E., Sasson, A. A., & Batra, S. K. (2005) · Pancreas · doi:10.1097/01.mpa.0000175893.04660.1b · Cited by 99
Ductal Pancreatic Cancer in Humans and MicePreprint
Tuveson, D. A., & Hingorani, S. R. (2005) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.2005.70.040 · Cited by 86
Modeling Cancer Progression via Pathway Dependencies
Edelman, E. J., Guinney, J., Chi, J., Febbo, P. G., & Mukherjee, S. (2008) · PLoS Computational Biology · doi:10.1371/journal.pcbi.0040028 · Cited by 76
Chittenden, T. W., Howe, E., Culhane, A. C., Sultana, R., Taylor, J. M., Holmes, C. C., & Quackenbush, J. F. (2008) · Genomics · doi:10.1016/j.ygeno.2008.03.002 · Cited by 54
Targeting the absence: Homozygous DNA deletions as immutable signposts for cancer therapy
Varshavsky, A. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706546104 · Cited by 31
Efthimiou, E., Crnogorac‐Jurcevic, T., & Lemoine, N. R. (2001) · Pancreatology · doi:10.1159/000055865 · Cited by 19
Winter, J. M., Brody, J. R., & Kern, S. E. (2006) · Cancer Biology & Therapy · doi:10.4161/cbt.5.4.2552 · Cited by 14
Self-citation
Flagged first, then by citations
Research works printed but not linked: 10
- D. M. Parkin, F. I. Bray, S. S. Devesa, Eur. J. Cancer37 (suppl.), S4 (2001).
- 10.1158/1078-0432.CCR-06-0113 · DOI
- 10.1073/pnas.0712345105 · DOI
- 10.1126/science.1145720 · DOI · Paper page
- H.-P. Elsasser, G. Adler, H. F. Kern, in The Pancreas, V. L. W. Go et al., Eds. (Raven, New York, 1993), pp. 75–86.
- R. J. Learyet al. Proc. Natl. Acad. Sci. U.S.A. in press.
- S. Ekins, Y. Nikolsky, A. Bugrim, E. Kirillov, T. Nikolskaya, Methods Mol. Biol.356, 319 (2007).
- T. Furukawaet al., Am. J. Pathol.148, 1763 (1996).
- A. H. Owens D. S. Coffey S. B. Baylin Tumor Cell Heterogeneity (Academic Press New York 1982).
- Contact information for the authors who directed the major components of this project is as follows: J. R. Eshleman S. E. Kern (clinical and sample coordination) jeshlem@jhmi.edu sk@mail.jhmi.edu; R. H. Hruban (pathological review) rhruban@jhmi.edu; R. Karchin (bioinformatic analysis) karchin@jhu.edu; N. Papadopoulos (gene expression analysis) npapado1@jhmi.edu; G. Parmigiani (statistical analysis) gp@jhu.edu; B. Vogelstein V. E. Velculescu K. W. Kinzler (sequencing and copy number analysis) bertvog@gmail.com velculescu@jhmi.edu kinzlke@jhmi.edu. We thank J. Ptak N. Silliman L. Dobbyn M. Whalen M. Borges G. Cusatis M. Griffith C. Henderson C. Karikari G. Mo M. Mullendore E. Palmisano M. Raben S. Solt and D. Trusty for expert technical assistance; T. Sjöblom for help with database management for mutational analyses; Y. Ding for help with bioinformatic analyses; and J. Cameron G. Feldmann S. Salaria L. Hua and C. Yeo for helpful discussions. This project was performed under the auspices of the Goldman Pancreatic Cancer Genome Initiative and was funded by the Sol Goldman Charitable Trust; the Lillian Goldman Charitable Trust; the Lustgarten Foundation for Pancreatic Cancer Research; the Virginia and D. K. Ludwig Fund for Cancer Research; the Susan G. Komen Foundation; the Michael Rolfe Pancreatic Cancer Foundation; the Joseph C. Monastra Foundation for Pancreatic Cancer; the family and friends of George Rubis; the Viragh Family Foundation; the Broad Foundation; the Emerald Foundation; NIH grants CA62924 CA43460 CA57345 and CA121113; and Beckman Coulter Corporation. Under separate licensing agreements between the Johns Hopkins University and Genzyme Beckman Coulter and Exact Sciences Corporations K.W.K. B.V. and V.E.V. are entitled to a share of royalties received by the university on sales of products related to research described in this paper. These authors and the university own Genzyme and Exact Sciences stock which is subject to certain restrictions under university policy. The terms of these arrangements are managed by the Johns Hopkins University in accordance with its conflict-of-interest policies.
Cited by
Sorted by citations
Vogelstein, B., Papadopoulos, N., Velculescu, V. E., Zhou, S., Diaz, L. A., & Kinzler, K. W. (2013) · Science · doi:10.1126/science.1235122 · Cited by 7,863
Self-citationIntratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing
Gerlinger, M., Rowan, A. J., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1113205 · Cited by 7,774
An Integrated Genomic Analysis of Human Glioblastoma Multiforme
Parsons, D. W., Jones, S., Zhang, X., Lin, J. C.-H., Leary, R. J., Angenendt, P., Mankoo, P., Carter, H., Siu, I.-M., Gallia, G. L., et al. (2008) · Science · doi:10.1126/science.1164382 · Cited by 5,857
Self-citationDetection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies
Bettegowda, C., Sausen, M., Leary, R. J., Kinde, I., Wang, Y., Agrawal, N., Bartlett, B. R., Wang, H., Luber, B., Alani, R. M., et al. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3007094 · Cited by 5,067
Self-citationMutational landscape and significance across 12 major cancer types
Kandoth, C., McLellan, M. D., Vandin, F., Ye, K., Niu, B., Lu, C., Xie, M., Zhang, Q., McMichael, J. F., Wyczalkowski, M. A., et al. (2013) · Nature · doi:10.1038/nature12634 · Cited by 4,419
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
