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Clinical Significance of the Genetic Landscape of Pancreatic Cancer and Implications for Identification of Potential Long-term Survivors
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Abstract
Purpose: Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome. Experimental Design: Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan–Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors. Results: The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53). Conclusions: Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status. Clin Cancer Res; 18(22); 6339–47. ©2012 AACR.
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“Coexistent alterations in CDKN2A, KRAS, TP53 and SMAD4 were observed in pancreatic cancer, with frequent loss of tumor suppressors like CDKN2A, ARID1A, APC and ID3 [26,44].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [26]
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“Genetic analysis indicates complex interactions among KRAS, CDKN2A, TP53 and SMAD4 alterations, influencing metastatic burden and survival [26].”
From Significance of TP53, CDKN2A, SMAD4 and KRAS in Pancreatic Cancer (2024) · cites this paper as [26]
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Cites
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Self-citationDistant metastasis occurs late during the genetic evolution of pancreatic cancer
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“Furthermore, although genetically engineeredmousemodels indicate that the concomitant expression of thesemutated genes is crucial to progress to invasion and metastasis in PDACs (15–19), the extent to which the coexistence of 3 or more of these altered genes in the same PDAC influence thebiologic behavior and survival…”
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Metadata
- Authors
- Yachida, S., White, C. M., Naito, Y., Zhong, Y., Brosnan, J. A., Macgregor-Das, A. M., Morgan, R. A., Saunders, T., Laheru, D. A., Herman, J. M., Hruban, R. H., Klein, A. P., Jones, S., Velculescu, V., Wolfgang, C. L., & Iacobuzio-Donahue, C. A.
- Affiliations
- Kurume University (JP)
- Authors' Affiliations: Departments of 1Pathology, 2Oncology, 3Surgery, and 4Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, 5The Lugwig Center for Cancer Genetics and Therapeutics, Johns Hopkins Medical Institutions, Baltimore, Maryland; 6National Cancer Center Research Institute, Tokyo; and 7Kurume University School of Medicine, Kurume, Fukuoka, Japan
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2012-11-14
- Volume
- 18
- Issue
- 22
- Pages
- 6339-6347
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC3500447
- OpenAlex
- W2155563954
- Cited by
- 280
- References
- 43
- Citations by year
- 2026: 16 · 2025: 18 · 2024: 17 · 2023: 22 · 2022: 27 · 2021: 33 · 2020: 25 · 2019: 15 · 2018: 20 · 2017: 23 · 2016: 15 · 2015: 22 · 2014: 15 · 2013: 12
- FWCI
- 7.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01ca121113-15)
- Japan Society for the Promotion of Science (23390326, 24659612)
- National Cancer Institute (CA-101955, P20CA101955, R01CA140599, P50CA101955, R01-CA121113, CA-121113, CA140599, P50CA062924, 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
- Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
- Keywords
- pancreatic cancer, driver gene alterations, KRAS, CDKN2A, TP53, SMAD4, long-term survival, disease-free survival, metastatic burden, prognostic factors, autopsy tissue
- MeSH terms
- Aged, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Pancreatic Neoplasms, Proto-Oncogene Proteins, Risk Factors, Proportional Hazards Models, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Survivors, Disease-Free Survival, ras Proteins, Cyclin-Dependent Kinase Inhibitor p16, Carcinoma, Pancreatic Ductal, Tumor Burden, Smad4 Protein, Kaplan-Meier Estimate
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