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Frequency of K-ras Mutations in Pancreatic Intraductal Neoplasias Associated with Pancreatic Ductal Adenocarcinoma and Chronic Pancreatitis: A Meta-Analysis
Open accessAbstract
Molecular analyses have demonstrated mutations in the K-ras gene at codon 12 in the majority of pancreatic ductal adenocarcinomas (PDACs). In order to determine whether the K-ras mutation rate increases parallel to the grade of dysplasia in duct lesions, we performed a meta-analysis of the studies published between 1988 and 2003 that provide information on K-ras mutations in hyperplastic and dysplastic duct lesions in the pancreas. The described duct lesions were reclassified according to the nomenclature for pancreatic intraepithelial neoplasia (PanIN), and the molecular methods for detecting K-ras were reviewed. In PanIN lesions from pancreata of patients with PDAC, there was a stepwise increase in K-ras mutations that correlated with the grade of dysplasia of the PanIN lesion. K-ras mutations were found in 36%, 44%, and 87% of PanIN-1a, 1b, and 2-3 lesions, respectively (trend statistic P <.001). Mutation-enriched polymerase chain reaction (PCR) resulted in higher rates of K-ras mutations in PanIN than plain PCR did. The incidence of K-ras mutations in PanIN lesions associated with chronic pancreatitis (CP) or normal pancreas was low (around 10%). In CP, K-ras mutations were only found after a disease duration of 3 years. The correlation of the incidence of K-ras mutations with the grade of dysplasia in PanIN and the occurrence of these mutations in CP with a duration of more than 3 years underlines the importance of this genetic change for the development of PDAC.
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In the citing paper
“KRAS mutations were found in 10% of CP lesions and 44% of PDAC lesions, with an increase in frequency with the progression of PanIN grade [102].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [102]
Experimental — accuracy not yet measuredIn the citing paper
“KRAS mutations are often early events in tumourigenesis in lung and pancreatic cancers [41, 42].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [42]
In the citing paper
“KRAS mutation is readily detectable in 25% and 38% of PanIN-1A and PanIN-1B, respectively (55).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [55]
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ResultSelf-citationSignificance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer
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BackgroundPast Medical History and Pancreatic Cancer Risk: Results From a Multicenter Case-Control Study
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“Patients with chronic pancreatitis often have similar premalignant changes such as pancreatic intraepithelial neoplasia lesions as are seen in patients with pancreatic cancers (24).”
BackgroundSelf-citationDemographics and Epidemiology of Pancreatic Cancer
Yeo, T. P., & Lowenfels, A. B. (2012) · The Cancer Journal · doi:10.1097/ppo.0b013e3182756803 · Cited by 78
“5 years, there was an association with a high level of K-ras mutation positivity.(67)”
BackgroundSelf-citationGenetic Progression of Pancreatic Cancer
Cowan, R. W., & Maitra, A. (2014) · The Cancer Journal · doi:10.1097/ppo.0000000000000011 · Cited by 76
“Principal among these mutations are activating point mutations in the KRAS oncogene, which are present in as many as 90% of all PDACs(4,5) and are considered an early event in the progression from normal ductal cells to invasive adenocarcinoma.(6,7) The inactivation of several tumor suppressor genes, such as those cod…”
BackgroundKipp, B. R., Fritcher, E. G. B., Clayton, A. C., Gores, G. J., Roberts, L. R., Zhang, J., Levy, M. J., & Halling, K. C. (2010) · Journal of Molecular Diagnostics · doi:10.2353/jmoldx.2010.100016 · Cited by 77
Haas, S., Jesnowski, R., Steiner, M., Hummel, F., Ringel, J., Burstein, C., Nizze, H., Liebe, S., & Löhr, M. J. (2006) · Europe PMC (PubMed Central) · doi:10.3748/wjg.v12.i30.4843 · Cited by 75
Self-citationBiliary intraepithelial neoplasia in patients without chronic biliary disease
Wu, T., Levy, M. L., Correa, A. M., Rosen, C. B. B., & Abraham, S. C. (2009) · Cancer · doi:10.1002/cncr.24471 · Cited by 74
“Oncogenic K-ras mutations, present in >90% of pancreatic ductal adenocarcinomas, are also found in 10% to 44% of PanIN-1 lesions, depending on whether there is coexistent carcinoma.(23) Loss of p16 expression—corresponding to inactivation of the CDKN2A/INK4A tumor suppressor gene—is seen in 29% of PanIN-1 from pancrea…”
BackgroundPancreatic adenocarcinoma pathology: changing "landscape".
Brosens, L. A. A., Hackeng, W. M., Offerhaus, G. J. A., Hruban, R. H., & Wood, L. D. (2015) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2078-6891.2015.032 · Cited by 73
Mori, A., Moser, C., Lang, S. A., Hackl, C., Gottfried, E., Kreutz, M. P., Schlitt, H. J., Geissler, E. K., & Stoeltzing, O. (2009) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-08-0525 · Cited by 71
“Because pancreatic cancers frequently harbor activating KRAS mutations (11), which consecutively activate MEK/MAPK/Erk signaling (12), we hypothesized that”
BackgroundPanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration
Bell, A. T. F., Mitchell, J. T., Kiemen, A. L., Lyman, M. R., Fujikura, K., Lee, J. W., Coyne, E. M., Shin, S. M., Nagaraj, S., Deshpande, A. M., et al. (2024) · Cell Systems · doi:10.1016/j.cels.2024.07.001 · Cited by 77
Computational Model Predicts the Effects of Targeting Cellular Metabolism in Pancreatic Cancer
Roy, M., & Finley, S. D. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00217 · Cited by 70
“Mutations mediated by the KRAS or MYC oncogenes, found in 95% of cases of PDAC (Almoguera et al., 1988; Uemura et al., 2004; Löhr et al., 2005; Hezel et al., 2006; Kimmelman, 2015), promote reprogramming of the cellular metabolism, enabling the cancer cells to optimally use available resources…”
BackgroundHarrison, M., Jameson, C., & Gore, M. E. (2007) · International Journal of Gynecological Cancer · doi:10.1111/j.1525-1438.2007.01022.x · Cited by 68
Classification, morphology and molecular pathology of premalignant lesions of the pancreas
Cooper, C. L., O'Toole, S. A., & Kench, J. G. (2013) · Pathology · doi:10.1097/pat.0b013e32835f2205 · Cited by 71
“Mutations Mutation of KRAS in 33% of PanIN-1, 44% of PanIN-2 and 87% PanIN-3.(190) Inactivating mutation of CDKN2 in PanIN-2 and telomere shortening in PanIN-1.”
BackgroundAberrant signaling pathways in pancreatic cancer: A two compartment view
McCleary‐Wheeler, A. L., McWilliams, R. R., & Fernández-Zapico, M. E. (2011) · Molecular Carcinogenesis · doi:10.1002/mc.20827 · Cited by 69
“KRAS mutations can be seen in the earliest of lesions in which there is minimal atypia, and these mutations only increase in frequency as the lesions progress through the PanIN lesions to invasive carcinomas [31,32].”
BackgroundCarcinogenesis of Pancreatic Adenocarcinoma: Precursor Lesions
Gnoni, A., Licchetta, A., Scarpa, A., Azzariti, A., Brunetti, A. E., Simone, G., Nardulli, P., Santini, D., Aieta, M., Delcuratolo, S., et al. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141019731 · Cited by 64
“Oncogenic KRAS mutations are observed in early pancreatic lesions as previously described [63].”
BackgroundWatts, J. A., Zhang, C., Klein–Szanto, A. J., Kormish, J. D., Fu, J., Zhang, M. Q., & Zaret, K. S. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002277 · Cited by 63
Oncogenic transcription factors: cornerstones of inflammation-linked pancreatic carcinogenesis
Baumgart, S., Ellenrieder, V., & Fernández-Zapico, M. E. (2011) · Gut · doi:10.1136/gutjnl-2011-301008 · Cited by 64
“The most common genetic abnormality in pancreatic cancer is the activating mutation of KRAS, which is an initial key event in pancreatic carcinogenesis and found in virtually all invasively growing tumours.(1) However, mutation of KRAS alone is not sufficient for full neoplastic progression, and additional abnormaliti…”
BackgroundHennig, R., Kehl, T., Noor, S., Ding, X., Rao, S. M., Bergmann, F., Fürstenberger, G., Büchler, M. W., Frieß, H., Krieg, P., et al. (2007) · Neoplasia · doi:10.1593/neo.07565 · Cited by 62
Satellite RNAs promote pancreatic oncogenic processes via the dysfunction of YBX1
Kishikawa, T., Otsuka, M., Yoshikawa, T., Ohno, M., Ijichi, H., & Koike, K. (2016) · Nature Communications · doi:10.1038/ncomms13006 · Cited by 45
Nanofluidic Digital PCR for KRAS Mutation Detection and Quantification in Gastrointestinal Cancer
Azuara, D., Morell, M., Gausachs, M., Rodríguez‐Moranta, F., Fabregat, J., Busquets, J., Peláez, N., Boadas, J., Galter, S., Moreno, V. R., et al. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2012.186577 · Cited by 60
Hong, S., Vincent, A., Kanda, M., Leclerc, J., Omura, N., Borges, M. W., Klein, A. P., Canto, M. I., Hruban, R. H., & Goggins, M. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-1075 · Cited by 59
Esposito, I., Kleeff, J. H., Abiatari, I., Shi, X., Giese, N. A., Bergmann, F., Roth, W., Frieß, H., & Schirmacher, P. (2006) · Journal of Clinical Pathology · doi:10.1136/jcp.2006.038257 · Cited by 58
The Role of Mitochondria in the Chemoresistance of Pancreatic Cancer Cells
Fu, Y., Ricciardiello, F., Yang, G., Qiu, J., Huang, H., Xiao, J., Cao, Z., Zhao, F., Liu, Y., Luo, W., et al. (2021) · Cells · doi:10.3390/cells10030497 · Cited by 59
“On the other hand, CP tissues also generally contain early PanIN that often carries mutated K-RAS [46,47].”
BackgroundBattini, S., Faitot, F., Impériale, A., Çiçek, A. E., Heimburger, C., Avérous, G., Bachellier, P., & Namer, I. J. (2017) · BMC Medicine · doi:10.1186/s12916-017-0810-z · Cited by 57
Ras Activity in Acinar Cells Links Chronic Pancreatitis and Pancreatic Cancer
Logsdon, C. D., & Ji, B. (2009) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2009.07.040 · Cited by 57
Pancreatic Intraepithelial Neoplasia and Pancreatic Tumorigenesis: Of Mice and Men
Ottenhof, N. A., Milne, A. N., Morsink, F. H. M., Drillenburg, P., ten Kate, F. J. W., Maitra, A., & Offerhaus, G. J. A. (2009) · Archives of Pathology & Laboratory Medicine · doi:10.5858/133.3.375 · Cited by 57
NF-κB and Pancreatic Cancer; Chapter and Verse
Silke, J., & O’Reilly, L. A. (2021) · Cancers · doi:10.3390/cancers13184510 · Cited by 55
“Chronic pancreatitis is a PDAC precursor lesion [26], associated with excess alcohol consumption [21,102,106] and with a 13.”
BackgroundInfluentialRubenstein, J. H., Scheiman, J. M., & Anderson, M. A. (2007) · Pancreatology · doi:10.1159/000108969 · Cited by 55
KRAS Mutation Subtypes and Their Association with Other Driver Mutations in Oncogenic Pathways
Mondal, K., Posa, M. K., Shenoy, R. P., & Roychoudhury, S. (2024) · Cells · doi:10.3390/cells13141221 · Cited by 58
“A study on pancreatic cancer reported that about 25% and 38% of KRAS mutations detected at the PanIN-1A and PanIN-1B stages, respectively [32].”
BackgroundMorphogenesis of pancreatic cancer: role of pancreatic intraepithelial neoplasia (PanINs)
Koorstra, J.-B. M., Feldmann, G., Habbe, N., & Maitra, A. (2008) · Langenbeck s Archives of Surgery · doi:10.1007/s00423-008-0282-x · Cited by 54
“Mutations of the KRAS gene are one of the earliest genetic abnormalities observed in the progression model of pancreatic cancer, demonstrable in approximately 36%, 44%, and 87% of cancer-associated PanIN-1A, PanIN-1B, and PanIN-2/3 lesions, respectively [31].”
BackgroundA genetic roadmap of pancreatic cancer: still evolving
Notta, F., Hahn, S. A., & Real, F. X. (2017) · Gut · doi:10.1136/gutjnl-2016-313317 · Cited by 54
Sandini, M., Ruscic, K. J., Ferrone, C. R., Qadan, M., Eikermann, M., Warshaw, A. L., Lillemoe, K. D., & Castillo, C. F. F.-D. (2018) · Journal of Gastrointestinal Surgery · doi:10.1007/s11605-018-3939-y · Cited by 53
Roles of Commensal Microbiota in Pancreas Homeostasis and Pancreatic Pathologies
Leal‐Lopes, C., Velloso, F. J., Campopiano, J. C., Sogayar, M. C., & Correa, R. G. (2015) · Journal of Diabetes Research · doi:10.1155/2015/284680 · Cited by 54
Current State of “Omics” Biomarkers in Pancreatic Cancer
Turanlı, B., Yildirim, E., Gülfidan, G., Arğa, K. Y., & Sinha, R. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11020127 · Cited by 52
“Previous studies pointed out the most prominent genetic features of PDAC, such as oncogenic activation of K-RAS, which is a standard feature in more than 90% of the patients, and with the early onset mutation of that gene, it is considered a critical driver of PDAC initiation and progression [27].”
BackgroundCurrent understanding of precursors to pancreatic cancer
Takaori, K. (2007) · Journal of Hepato-Biliary-Pancreatic Surgery · doi:10.1007/s00534-006-1165-6 · Cited by 51
Tong, G., Geng, Q., Chai, J., Cheng, J., Chen, P., Liang, H., Shen, X.-R., & Wang, D. (2014) · Asian Pacific Journal of Cancer Prevention · doi:10.7314/apjcp.2014.15.12.5029 · Cited by 50
“A meta-analysis of 15 studies documented that K-ras mutations, which play an important role in the evolution of PC, had been detected in subjects with chronic pancreatitis (Löhr et al., 2005).”
MethodAfghani, E., & Klein, A. P. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.07.002 · Cited by 54
Germline Variants and Risk for Pancreatic Cancer
Zhan, W., Shelton, C. A., Greer, P. J., Brand, R. E., & Whitcomb, D. C. (2018) · Pancreas · doi:10.1097/mpa.0000000000001136 · Cited by 50
Guo, J., Xie, K., & Zheng, S. (2016) · International Journal of Biological Sciences · doi:10.7150/ijbs.14995 · Cited by 47
Metadata
- Authors
- Löhr, M., Klöppel, G., Maisonneuve, P., Lowenfels, A. B., & Lüttges, J.
- Affiliations
- Heidelberg University (DE)
- European Institute of Oncology (IT)
- New York Medical College (US)
- Corresponding author
- Löhr, Matthias
- Venue
- Neoplasia
- Publisher
- Elsevier BV
- Published
- 2005-01
- Volume
- 7
- Issue
- 1
- Pages
- 17-23
- ISSN
- 1476-5586 (ISSN-L)
- PMC
- PMC1490318
- OpenAlex
- W2108100098
- Cited by
- 343
- References
- 66
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 15 · 2023: 15 · 2022: 16 · 2021: 16 · 2020: 17 · 2019: 13 · 2018: 24 · 2017: 22 · 2016: 15 · 2015: 18 · 2014: 26 · 2013: 21 · 2012: 16
- FWCI
- 1.51
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Neoplasia (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Deutsche Forschungsgemeinschaft
- Deutsche Krebshilfe
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS mutation, pancreatic ductal adenocarcinoma, pancreatic intraepithelial neoplasia, chronic pancreatitis, pancreatic dysplasia, disease duration
- MeSH terms
- Adenocarcinoma, Humans, Mutation, Pancreatic Ducts, Pancreatic Neoplasms, Pancreatitis, Genes, ras, Carcinoma, Pancreatic Ductal
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