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Tanaka T, Masuda A, Inoue J, Hamada T, Ikegawa T, Toyama H, Sofue K, Shiomi H, Sakai A, Kobayashi T, Tanaka S, Nakano R, Yamada Y, Ashina S, Tsujimae M, Yamakawa K, Abe S, Gonda M, Masuda S, Inomata N, Uemura H, Kohashi S, Nagao K, Kanzawa M, Itoh T, Ueda Y, Fukumoto T, Kodama Y. Integrated analysis of tertiary lymphoid structures in relation to tumor-infiltrating lymphocytes and patient survival in pancreatic ductal adenocarcinoma. J Gastroenterol 2023; 58:277-291. [PMID: 36705749 DOI: 10.1007/s00535-022-01939-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 12/04/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND Tertiary lymphoid structure (TLS) reflects an intense immune response against cancer, which correlates with favorable patient survival. However, the association of TLS with tumor-infiltrating lymphocytes (TILs) and clinical outcomes has not been investigated comprehensively in pancreatic ductal adenocarcinoma (PDAC). METHODS We utilized an integrative molecular pathological epidemiology database on 162 cases with resected PDAC, and examined TLS in relation to levels of TILs, patient survival, and treatment response. In whole-section slides, we assessed the formation of TLS and conducted immunohistochemistry for tumor-infiltrating T cells (CD4, CD8, CD45RO, and FOXP3). As confounding factors, we assessed alterations of four main driver genes (KRAS, TP53, CDKN2A [p16], and SMAD4) using next-generation sequencing and immunohistochemistry, and tumor CD274 (PD-L1) expression assessed by immunohistochemistry. RESULTS TLSs were found in 112 patients with PDAC (69.1%). TLS was associated with high levels of CD4+ TILs (multivariable odds ratio [OR], 3.50; 95% confidence interval [CI] 1.65-7.80; P = 0.0002), CD8+ TILs (multivariable OR, 11.0; 95% CI 4.57-29.7, P < 0.0001) and CD45RO+ TILs (multivariable OR, 2.65; 95% CI 1.25-5.80, P = 0.01), but not with levels of FOXP3+ TILs. TLS was associated with longer pancreatic cancer-specific survival (multivariable hazard ratio, 0.37; 95% CI 0.25-0.56, P < 0.0001) and favorable outcomes of adjuvant S-1-treatment. TLS was not associated with driver gene alterations but tumor CD274 negative expression. CONCLUSIONS Our comprehensive data supports the surrogacy of TLS for vigorous anti-tumor immune response characterized by high levels of helper and cytotoxic T cells and their prognostic role.
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Affiliation(s)
- Takeshi Tanaka
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Atsuhiro Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan.
| | - Jun Inoue
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-5-1 Kusunoki-Cho, Chuo-Ku, Tokyo, 113-8655, Japan
| | - Takuya Ikegawa
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Hirochika Toyama
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Keitaro Sofue
- Department of Radiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Hideyuki Shiomi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Arata Sakai
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Takashi Kobayashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Shunta Tanaka
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Ryota Nakano
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Yasutaka Yamada
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Shigeto Ashina
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Masahiro Tsujimae
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Kohei Yamakawa
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Shohei Abe
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Masanori Gonda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Shigeto Masuda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Noriko Inomata
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Hisahiro Uemura
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Shinya Kohashi
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Kae Nagao
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Maki Kanzawa
- Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Tomoo Itoh
- Division of Diagnostic Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Yoshihide Ueda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Takumi Fukumoto
- Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-Cho, Chuo-Ku, Kobe, Hyogo, 650-0017, Japan
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Gu Y, Ji Y, Jiang H, Qiu G. Clinical Effect of Driver Mutations of KRAS, CDKN2A/P16, TP53, and SMAD4 in Pancreatic Cancer: A Meta-Analysis. Genet Test Mol Biomarkers 2021; 24:777-788. [PMID: 33347393 DOI: 10.1089/gtmb.2020.0078] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Objective: To evaluate the prognostic value of driver mutations in the KRAS, CDKN2A/P16, TP53, and SMAD4 genes in pancreatic cancer to aid in the design of therapeutic strategies. Search Strategy: A systematic search was conducted using PubMed, MEDLINE, Springer, and Cochrane library to identify eligible studies published between January 1990 and June 2018 that reported an association between driver mutations in these genes and survival data. Inclusion Criteria: Articles which passed the primary screen were further scrutinized for the presence of all the following items: (1) cohort studies or case-control studies, evaluating the relationship between driver mutations and cancer; (2) cancer diagnoses clearly proved; and (3) hazard ratios (HR) and 95% confidence intervals (CIs) were characterized by sufficient information. Data Extraction and Analysis: Selection of included articles, data extraction, and methodological quality assessments were, respectively, conducted by two authors. Results: The meta-analysis was composed of 17 studies on the P53, 8 on SMAD4, 7 on CDKN2A/P16, and 2 on KRAS, containing 3373 samples. Our pooled results demonstrated that the patients with overexpression of the P53 (HR = 1.249, 95% CI = 1.003-1.554, p = 0.047), SMAD4 (HR = 1.397, 95% CI = 1.015-1.922, p = 0.040), CDKN2A/P16 (HR = 0.916, 95% CI = 0.583-1.439, p = 0.704), and KRAS (HR = 1.68, 95% CI = 1.27-2.22, p < 0.001) mutations all had poorer overall survival. Conclusion: This systematic review and meta-analysis supports the use of driver mutations in the P53, SMAD4, and KRAS genes as prognostic markers for pancreatic cancer.
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Affiliation(s)
- Yujun Gu
- Department of Ultrasound Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou City, China
| | - Yayun Ji
- Department of Interventional Ultrasound, Xianyang Central Hospital, Xianyang City, China
| | - Hui Jiang
- Medical Imaging Department, Zhaoqing Medical College, Zhaoqing City, China
| | - Ganbin Qiu
- Medical Imaging Department, Zhaoqing Medical College, Zhaoqing City, China
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Visani M, Acquaviva G, De Leo A, Sanza V, Merlo L, Maloberti T, Brandes AA, Franceschi E, Di Battista M, Masetti M, Jovine E, Fiorino S, Pession A, Tallini G, de Biase D. Molecular alterations in pancreatic tumors. World J Gastroenterol 2021; 27:2710-2726. [PMID: 34135550 PMCID: PMC8173386 DOI: 10.3748/wjg.v27.i21.2710] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/25/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these "inconclusive" specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.
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Affiliation(s)
- Michela Visani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Viviana Sanza
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Lidia Merlo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Thais Maloberti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Alba A Brandes
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Enrico Franceschi
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Monica Di Battista
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Michele Masetti
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Elio Jovine
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital Azienda USL, Bologna 40133, Italy
| | - Annalisa Pession
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
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Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Endo I, Katz MHG, Takabe K. High G2M Pathway Score Pancreatic Cancer is Associated with Worse Survival, Particularly after Margin-Positive (R1 or R2) Resection. Cancers (Basel) 2020; 12:E2871. [PMID: 33036243 PMCID: PMC7599494 DOI: 10.3390/cancers12102871] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 10/01/2020] [Accepted: 10/04/2020] [Indexed: 12/21/2022] Open
Abstract
Pancreatic cancer is highly mortal due to uncontrolled cell proliferation. The G2M checkpoint pathway is an essential part of the cell cycle. We hypothesized that a high G2M pathway score is associated with cell proliferation and worse survival in pancreatic cancer patients. Gene set variation analysis using the Hallmark G2M checkpoint gene set was used as a score to analyze a total of 390 human pancreatic cancer patients from 3 cohorts (TCGA, GSE62452, GSE57495). High G2M score tumors enriched other cell proliferation genes sets as well as MKI67 expression, pathological grade, and proliferation score. Independent of other prognostic factors, G2M score was predictive of disease-specific survival in pancreatic cancer. High G2M tumor was associated with high mutation rate of KRAS and TP53 and significantly enriched these pathway gene sets, as well as high infiltration of Th2 cells. High G2M score consistently associated with worse overall survival in 3 cohorts, particularly in R1/2 resection, but not in R0. High G2M tumor in R1/2 highly enriched metabolic and cellular components' gene sets compared to R0. To our knowledge, this is the first study to use gene set variation analysis as a score to examine the clinical relevancy of the G2M pathway in pancreatic cancer.
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Affiliation(s)
- Masanori Oshi
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
| | - Stephanie Newman
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
| | - Yoshihisa Tokumaru
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
| | - Matthew H. G. Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Kazuaki Takabe
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; (M.O.); (R.M.); (I.E.)
- Breast Surgery, Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; (S.N.); (Y.T.)
- Department of Surgery, Jacobs School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY 14263, USA
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8520, Japan
- Department of Breast Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 160-8402, Japan
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Huang BZ, Binder AM, Sugar CA, Chao CR, Setiawan VW, Zhang ZF. Methylation of immune-regulatory cytokine genes and pancreatic cancer outcomes. Epigenomics 2020; 12:1273-1285. [PMID: 32867538 DOI: 10.2217/epi-2019-0335] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: Given the immunosuppressive nature of pancreatic cancer, we investigated the relationship between epigenetic modification of immune-regulatory cytokine genes and pancreatic cancer outcomes. Materials & methods: We evaluated DNA methylation of 184 pancreatic tumor samples from The Cancer Genome Atlas for 111 CpG loci in seven cytokine genes: IL10, IL6, IL8, TGFβ1, TGFβ2, TGFβ3 and TNF. We used Cox regression to evaluate the associations between methylation and overall survival, disease-specific survival and disease progression (α = 0.05). Results: Poorer survival was associated with increased methylation in fifteen CpG probes in TGFβ1, TGFβ2, TGFβ3 and TNF. We also detected improved outcomes for three loci in IL10, IL8 and IL6. Conclusion: Epigenetic regulation of cytokine-related gene expression may be associated with pancreatic cancer outcomes.
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Affiliation(s)
- Brian Z Huang
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.,Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA.,Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Alexandra M Binder
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.,Department of Cancer Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Catherine A Sugar
- Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Chun R Chao
- Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA
| | - Veronica Wendy Setiawan
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.,Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Zuo-Feng Zhang
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA
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Iwatate Y, Hoshino I, Ishige F, Itami M, Chiba S, Arimitsu H, Yanagibashi H, Nagase H, Yokota H, Takayama W. Prognostic significance of p16 protein in pancreatic ductal adenocarcinoma. Mol Clin Oncol 2020; 13:83-91. [PMID: 32499915 DOI: 10.3892/mco.2020.2047] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 04/30/2020] [Indexed: 12/30/2022] Open
Abstract
The p16 gene, which is also known as CDKN2A, INK4A, or CDK4I, and its products that are known to be cell cycle inhibitors and tumor suppressors have been reported to be altered in various human tumor types. Altered p16 has been indicated to be correlated with negative p16 expression using immunohistochemistry (IHC). However, its association with the prognosis remains controversial because the findings of previous studies are inconsistent. The current study evaluated the relationship between the expression levels of p16 and the clinicopathological features associated with prognosis in patients with primary pancreatic ductal adenocarcinomas (PDACs). From January 2013 to December 2017, tissues of 103 PDAC patients who had undergone elective pancreatic resection were obtained and assessed for p16 expression by IHC. No correlation was observed between p16 status and clinicopathological factors (P>0.05). Notably, negative p16 expression on IHC was not significantly associated with poor prognosis using the Kaplan-Meier method.
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Affiliation(s)
- Yosuke Iwatate
- Division of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Isamu Hoshino
- Division of Gastroenterological Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Fumitaka Ishige
- Division of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Makiko Itami
- Division of Clinical Pathology, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Satoshi Chiba
- Division of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Hidehito Arimitsu
- Division of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Hiroo Yanagibashi
- Division of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Hiroki Nagase
- Laboratory of Cancer Genetics, Chiba Cancer Center Research Institute, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
| | - Hajime Yokota
- Department of Radiology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba 260-8670, Japan
| | - Wataru Takayama
- Division of Hepato-Biliary-Pancreatic Surgery, Chiba Cancer Center, Chuo-ku, Chiba 260-8717, Japan
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Singh N, Rashid S, Rashid S, Dash NR, Gupta S, Saraya A. Clinical significance of promoter methylation status of tumor suppressor genes in circulating DNA of pancreatic cancer patients. J Cancer Res Clin Oncol 2020; 146:897-907. [PMID: 32146565 DOI: 10.1007/s00432-020-03169-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2019] [Accepted: 02/27/2020] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive cancer. There are various sub-cellular events (both genetic and epigenetic) that get dysregulated leading to tumorigenesis. Methylation in promoters of tumor suppressor genes is one of these epigenetic phenomena contributing to the pathogenesis of cancer. Genes analyzed for promoter methylation status in this study namely SPARC (Secreted Protein Acidic and Rich in Cysteine, UCHL1 (ubiquitin carboxy-terminal hydrolase L1), NPTX2 (neuronal pentraxin 2), PENK (proenkephalin) had been studied in pancreatic cancer, but there is a need to check methylation in these genes as circulatory non-invasive markers. This study analyzed the absolute quantification of methylation levels of SPARC, UCHL1, PENK, and NPTX2 genes promoters in PDAC patients as well as in chronic pancreatitis (CP) patients and healthy subjects (HC) and evaluated its clinical significance in PDAC. MATERIALS AND METHODS The study included 65 PDAC patients, 25 CP patients, and 25 healthy controls. DNA was extracted from their plasma samples and subsequently given bisulfite treatment. Absolute quantization of methylated and unmethylated copies of gene promoters of all the four genes was performed using real-time PCR (SYBR green) by the standard curve method. Methylation levels were expressed as methylation index (MI) for each gene in each patient. MI was calculated from absolute copy numbers as follows: MI-methylated copy number/methylated copy number + unmethylated copy number). These indices were used to compare gene methylation levels within different groups and to correlate with clinicopathological features and survival of pancreatic cancer patients. An appropriate statistical analysis was applied. RESULTS Methylation indices for all the four genes in PDAC cases were found to be significantly higher as compared to that in healthy individuals. SPARC MI values were found to differentiate early-stage PDAC patients from CP patients. PDAC patients with the metastasized disease and stage IV disease were found to have high MI for the SPARC gene as well as for the NPTX2 gene, while a higher UCHL1 methylation index was found to correlate with an advanced stage of the disease. Higher MI values for SPARC and NPTX2 genes were found to associate with poor survival in patients with PDAC. CONCLUSION Methylation load in the form of MI for each of the four genes assessed in plasma may emerge as a non-invasive biomarker to differentiate pancreatic cancer from healthy individuals. But only SPARC and NPTX2 hypermethylation were able to distinguish pancreatic cancer from chronic pancreatitis. Association of aberrant methylation in SPARC and NPTX2 gene with metastasis and poor survival of patients suggest the role of methylation in these genes as prognostic markers.
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Affiliation(s)
- Nidhi Singh
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sumaira Rashid
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Safoora Rashid
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Gupta
- Department of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India
| | - Anoop Saraya
- Department of Gastroenterology and Human Nutrition Unit, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Kim DJ, Park JM, Kim JH, Nam K, Kang CD, Lee SJ, Lee K, Jeon YH. Pancreatic Metastasis from Adenocarcinoma of the Uterine Cervix. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 73:182-185. [PMID: 31013562 DOI: 10.4166/kjg.2019.73.3.182] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Revised: 07/16/2018] [Accepted: 08/09/2018] [Indexed: 11/03/2022]
Abstract
Pancreatic metastasis from cervical cancer is extremely rare. We report a case of metastatic adenocarcinoma of the pancreas from uterine cervical cancer. A 70-year-old woman was referred because of a pancreatic mass detected by CT. She had been diagnosed with uterine cervical adenocarcinoma 20 months previously. After concurrent chemoradiotherapy, CT showed no evidence of the cervical mass, and follow-up showed no evidence of recurrence. Endoscopic ultrasound-guided fine needle aspiration biopsy of the pancreatic mass resulted in a diagnosis of metastatic adenocarcinoma from uterine cervix.
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Affiliation(s)
- Do Jun Kim
- Departments of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Jin Myung Park
- Departments of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Ji Hyun Kim
- Departments of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Kilwoo Nam
- Departments of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Chang Don Kang
- Departments of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Sung Joon Lee
- Departments of Internal Medicine, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Kyoungyul Lee
- Department of Anatomic Pathology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Yong Hwan Jeon
- Department of Radiology, Kangwon National University Hospital, Kangwon National University School of Medicine, Chuncheon, Korea
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9
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Henriksen SD, Madsen PH, Larsen AC, Johansen MB, Pedersen IS, Krarup H, Thorlacius-Ussing O. Cell-free DNA promoter hypermethylation in plasma as a predictive marker for survival of patients with pancreatic adenocarcinoma. Oncotarget 2017; 8:93942-93956. [PMID: 29212200 PMCID: PMC5706846 DOI: 10.18632/oncotarget.21397] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 09/13/2017] [Indexed: 12/11/2022] Open
Abstract
Introduction Few prognostic biomarkers are available for pancreatic cancer. The aim of this study is to examine the correlation between the survival of pancreatic adenocarcinoma patients and hypermethylated genes in plasma-derived cell-free DNA. Methods Consecutive patients with pancreatic adenocarcinoma were prospectively included and staged according to the TNM classification. Methylation-specific PCR of 28 genes was conducted. A survival prediction model independent of cancer stage and stage-specific survival prediction models were developed by multivariable Cox regression analysis using backward stepwise selection. Results Ninety-five patients with pancreatic adenocarcinoma were included. Patients with more than 10 hypermethylated genes had a HR of 2.03 (95% CI; 1.15-3.57) compared to patients with fewer hypermethylated genes. Three survival prediction models were developed: Total group; (American Society of Anesthesiologists score (ASA)=3, GSTP1, SFRP2, BNC1, SFRP1, TFPI2, and WNT5A) Risk groups 2, 3 and 4 had a HR of 2.65 (95% CI; 1.24-5.66), 4.34 (95% CI; 1.98-9.51) and 21.19 (95% CI; 8.61-52.15), respectively, compared to risk group 1. Stage I-II; (ASA=3, SFRP2, and MESTv2) Risk groups 2, 3 and 4 had a HR of 4.83 (95% CI; 2.01-11.57), 9.12 (95% CI; 2.18-38.25) and 70.90 (95% CI; 12.63-397.96), respectively, compared to risk group 1. Stage IV; (BMP3, NPTX2, SFRP1, and MGMT) Risk group 2 had a HR of 5.23 (95% CI; 2.13-12.82) compared to risk group 1. Conclusion Prediction models based on cell-free DNA hypermethylation stratified pancreatic adenocarcinoma patients into risk groups according to survival. The models have the potential to work as prognostic biomarkers. However, further validation of the results is required to substantiate the findings.
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Affiliation(s)
- Stine Dam Henriksen
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark.,Department of General Surgery, Hospital of Vendsyssel, Hjørring, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - Poul Henning Madsen
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | | | - Martin Berg Johansen
- Unit of Clinical Biostatistics and Bioinformatics, Aalborg University Hospital, Aalborg, Denmark
| | - Inge Søkilde Pedersen
- Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Henrik Krarup
- Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.,Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
| | - Ole Thorlacius-Ussing
- Department of Gastrointestinal Surgery, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
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10
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Abstract
Pancreatic neoplasms have a wide range of histologic types with distinct clinical outcomes. Recent advances in high-throughput sequencing technologies have greatly deepened our understanding of pancreatic neoplasms. Now, the exomes of major histologic types of pancreatic neoplasms have been sequenced, and their genetic landscapes have been revealed. This article reviews the molecular changes underlying pancreatic neoplasms, with a special focus on the genetic changes that characterize the histologic types of pancreatic neoplasms. Emphasis is also made on the molecular features of key genes that have the potential for therapeutic targets.
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11
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Can Molecular Biomarkers Change the Paradigm of Pancreatic Cancer Prognosis? BIOMED RESEARCH INTERNATIONAL 2016; 2016:4873089. [PMID: 27689078 PMCID: PMC5023838 DOI: 10.1155/2016/4873089] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/28/2016] [Accepted: 08/03/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal types of tumour, and its incidence is rising worldwide. Although survival can be improved when these tumours are detected at an early stage, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. The only prognostic biomarker approved by the FDA to date is carbohydrate antigen 19-9 (CA19-9); however, the specificity of this biomarker has been called into question, and diagnosis is usually based on clinical parameters. Tumour size, degree of differentiation, lymph node status, presence of distant metastasis at diagnosis, protein levels of KI-67 or C-reactive protein, and mutational status of P53, KRAS, or BRCA2 are the most useful biomarkers in clinical practice. In addition to these, recent translational research has provided evidence of new biomarkers based on different molecules involved in endoplasmic reticulum stress, epithelial-to-mesenchymal transition, and noncoding RNA panels, especially microRNAs and long noncoding RNAs. These new prospects open new paths to tumour detection using minimally or noninvasive techniques such as liquid biopsies. To find sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
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12
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Striefler JK, Sinn M, Pelzer U, Jühling A, Wislocka L, Bahra M, Sinn BV, Denkert C, Dörken B, Oettle H, Riess H, Bläker H, Lohneis P. P53 overexpression and Ki67-index are associated with outcome in ductal pancreatic adenocarcinoma with adjuvant gemcitabine treatment. Pathol Res Pract 2016; 212:726-34. [DOI: 10.1016/j.prp.2016.06.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Revised: 03/28/2016] [Accepted: 06/08/2016] [Indexed: 02/06/2023]
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13
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Le N, Sund M, Vinci A. Prognostic and predictive markers in pancreatic adenocarcinoma. Dig Liver Dis 2016; 48:223-30. [PMID: 26769569 DOI: 10.1016/j.dld.2015.11.001] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Revised: 10/27/2015] [Accepted: 11/01/2015] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma is characterized by a poor prognosis and a low median survival, despite improvements observed for many other solid tumours. Intensive research efforts have been undertaken during the last decades to discover new prognostic and treatment predictive biomarkers for pancreatic ductal adenocarcinoma. The mainstay of medical treatment for the disease has been the well-tolerated nucleoside analogue, gemcitabine. The only targeted agent currently used in pancreatic ductal adenocarcinoma patients is the epithelial growth factor receptor inhibitor erlotinib in combination with gemcitabine. Recently, treatment regimens such as a combination of fluorouracil-leucovorin-irinotecan-oxaliplatin (FOLFIRINOX) and the combination of nab-paclitaxel with gemcitabine have been introduced for metastatic pancreatic ductal adenocarcinoma. Although these treatment regimens significantly improve survival of patients, there are no good predictive biomarkers available that can be used to identify who would benefit most from them. Therefore, the search for predictive biomarkers that would facilitate personalization of chemotherapy is highly relevant.
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Affiliation(s)
- Nha Le
- Semmelweis University, Second Internal Medicine Department, Gastroenterology Division, Budapest, Hungary
| | - Malin Sund
- University of Umeå, Department of Surgical and Perioperative Sciences, Umeå, Sweden.
| | - Alessio Vinci
- University of Pavia, Department of Surgery, IRCCS S. Matteo University Hospital Foundation, Pavia, Italy
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14
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Clinicopathological Significance of CDKN2A Promoter Hypermethylation Frequency with Pancreatic Cancer. Sci Rep 2015; 5:13563. [PMID: 26338139 PMCID: PMC4642558 DOI: 10.1038/srep13563] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 04/07/2015] [Indexed: 12/23/2022] Open
Abstract
The prognosis of pancreatic cancer patients is very poor, with a 5-year survival of less than 6%. Previous studies demonstrated that the loss of function of CDKN2A is mainly caused by the hypermethylation of CDKN2A gene promoter; however, whether or not it is associated with the incidence of pancreatic cancer still remains unclear. In this study, we systematically reviewed the association between CDKN2A promoter methylation and pancreatic cancer using meta-analysis methods. The pooled data were analyzed by Review Manager 5.2. Fourteen studies eligible studies, including 418 pancreatic cancer, 155 pancreatic intraepithelial neoplasia (PanINs) and 45 chronic pancreatitis (CP) patients were analyzed. We observed that the frequency of CDKN2A methylation was significantly higher in pancreatic cancer patients than in normal healthy controls, the pooled OR = 17.19, 95% CI = 8.72–33.86, P < 0.00001. The frequency of CDKN2A methylation was also significantly higher in PanINs patients than that in normal individual controls, OR = 12.35, 95% CI = 1.70–89.89, P = 0.01. In addition, CDKN2A methylation was associated with worse survival in pancreatic cancer, HR = 4.46, 95% CI = 1.37–14.53, P = 0.01. The results strongly suggest that CDKN2A methylation is correlated with an increased risk of pancreatic cancer. CDKN2A methylation plays a critical role in pancreatic carcinogenesis and may serve as a prognostic marker.
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15
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Zhu Z, Liu T, Han F, Zhan SD, Wang CY. Mutations in the p16 gene in DMBA-induced pancreatic intraepithelial neoplasia and pancreatic cancer in rats. Hepatobiliary Pancreat Dis Int 2015; 14:208-14. [PMID: 25865695 DOI: 10.1016/s1499-3872(15)60331-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND 7, 12-dimethylbenzanthracene (DMBA)-induced pancreatic intraepithelial neoplasia (PanIN) and pancreatic cancer in rats provide a classic model for uncovering the molecular mechanisms underlying pancreatic cancer. However, this model has not been characterized genetically, and in particular, the major genetic alterations in the p16 gene are unknown. METHODS Lesions of PanIN and pancreatic cancer were induced with DMBA implantation in 40 rats, and control pancreatic tissue was obtained from 10 age-matched rats without exposure to DMBA. Pancreatic tissue was harvested three months after DMBA implantation and DNA was extracted. Homozygous deletions and point mutations of the p16 (exons 1 and 2) gene were detected by PCR amplification and direct sequencing. RESULTS DMBA implantation in the 40 rats induced 26 PanINs and 9 carcinomas. The overall frequency of p16 alterations in the pancreatic tissue of these rats was 42.86% (15/35), and the changes were point mutations, not homozygous deletions. p16 mutations were present in 30.77% (8/26) of the rats with PanIN and 77.78% (7/9) of the rats with carcinoma (P<0.05). The increasing incidence of p16 alterations was detected in 20.00% (1/5) of PanIN-1, 28.57% (2/7) of PanIN-2 and 35.71% (5/14) of PanIN-3 lesions. CONCLUSION Our findings indicated that p16 alteration is a common event in the carcinogenesis of this model and that the mutation pattern is analogous to that of human lesions.
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Affiliation(s)
- Zhu Zhu
- Department of Pancreatic Surgery, Union Hospital, Huazhong University of Science and Technology, Wuhan 430022, China.
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16
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Georgiadou D, Sergentanis TN, Sakellariou S, Filippakis GM, Zagouri F, Vlachodimitropoulos D, Psaltopoulou T, Lazaris AC, Patsouris E, Zografos GC. Cyclin D1, p16(INK) (4A) and p27(Kip1) in pancreatic adenocarcinoma: assessing prognostic implications through quantitative image analysis. APMIS 2014; 122:1230-9. [PMID: 25053516 DOI: 10.1111/apm.12289] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 04/08/2014] [Indexed: 12/17/2022]
Abstract
The prognostic significance of cyclin D1, p16(INK) (4A) and p27(Kip1) expression has been documented in several human malignancies; however, their prognostic potential in pancreatic adenocarcinoma is still unclear. This study aimed to assess the correlation of the aforementioned molecules with clinicopathological parameters and prognosis. Sixty patients with pancreatic ductal adenocarcinoma underwent surgical resection at a single institution; immunohistochemical staining of the studied markers was quantified by Ιmage analysis system. Cyclin D1 overexpression was positively associated with grade, neural infiltration and vascular invasion, whereas p27 positively correlated with age. Higher cyclin D1 expression indicated poorer survival (adjusted HR = 9.75, 95%CI: 1.48-64.31, p = 0.018, increment: one unit in H-score), whereas a marginal trend toward an association between p16 positivity and improved survival was observed (adjusted HR = 0.58, 95%CI: 0.32-1.05, p = 0.072 regarding positive vs negative cases). No significant association with overall survival was noted regarding p27. In conclusion, cyclin D1 overexpression and possibly p16 loss of expression in pancreatic adenocarcinoma seem to be adverse prognostic factors, whereas p27 expression did not seem to possess such prognostic properties. Further validation of the present findings in studies encompassing larger samples seems to be needed.
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Affiliation(s)
- Despoina Georgiadou
- 3rd Surgical Clinic of George Gennimatas General Hospital, Mesogeion Ave 154, Athens, 156 69, Greece
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17
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Abstract
The neuronal pentraxin II (NPTX2) gene is methylated in over 90% primary pancreatic cancer tissues but rarely in normal pancreatic ductal epithelia. Here, the authors investigated the utility of methylated NPTX2 as a diagnostic marker for pancreatic cancer in pure pancreatic juice samples of patients with benign and malignant pancreatic diseases, including pancreatic cancer, intraductal papillary mucinous neoplasm or chronic pancreatitis using methylation-specific polymerase chain reaction (MSP) and quantitative MSP. MSP assays revealed that the incidence of aberrant NPTX methylation in pure pancreatic juice samples was 64.5% (20 of 31) in patients with pancreatic cancer, 70.0% (7 of 10) in patients with malignant intraductal papillary mucinous neoplasm, 33.3% (2 of 6) in patients with benign intraductal papillary mucinous neoplasm and 21.7% (5 of 23) in patients with chronic pancreatitis. NPTX2 hypermethylation in patients with chronic pancreatitis was significantly lower than that of pancreatic cancer (P < 0.01) or patients with intraductal papillary mucinous neoplasm (P < 0.05). At a cutoff value of 1.39 for quantitative MSP, the incidence of aberrant NPTX2 methylation was 61.3% (19 of 31) in patients with pancreatic cancer, 50.0% (5 of 10) in patients with malignant intraductal papillary mucinous neoplasm, 0% in patients with benign intraductal papillary mucinous neoplasm and 8.7% (2 of 23) in patients with chronic pancreatitis. There was a significant difference in NPTX2 methylation between pancreatic cancer and chronic pancreatitis (P < 0.01). Our findings indicate that detection of aberrant methylation of NPTX2 in pure pancreatic juice samples could be useful as a molecular marker to discriminate between patients with malignant and benign disease of the pancreas.
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18
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Abstract
MicroRNAs (miRNAs) are 18- to 22-nucleotide-long, single-stranded, noncoding RNAs that regulate important biological processes including differentiation, proliferation, and response to cellular stressors such as hypoxia, nutrient depletion, and traversion of the cell cycle by controlling protein expression within the cell. Many investigators have profiled cancer tissue and serum miRNAs to identify potential therapeutic targets, understand the pathways involved in tumorigenesis, and identify diagnostic tumor signatures. In the setting of pancreatic cancer, obtaining pancreatic tissue is invasive and impractical for early diagnosis. Several groups have profiled miRNAs that are present in the blood as a means to diagnose tumor progression and predict prognosis/survival or drug resistance. Several miRNA signatures found in pancreatic tissue and the peripheral blood, as well as the pathways that are associated with pancreatic cancer, are reviewed here in detail. Three miRNA biomarkers (miR-21, miR-155, and miR-200) have been repetitively identified in both pancreatic cancer tissue and patients' blood. Those miRNAs regulate and are regulated by the central genetic and epigenetic changes observed in pancreatic cancer including p53, transforming growth factor β, p16(INK4A), BRCA1/2, and Kras. These miRNAs are involved in DNA repair, cell cycle, and cell invasion and also play important roles in promoting metastases.
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19
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Zhao Y, Zhao H, Sun Y, Hao J, Qi X, Zhou X, Wu Z, Wang P, Kaech SM, Weaver CT, Flavell RA, Zhao L, Yao Z, Yin Z. IL-4 induces a suppressive IL-10-producing CD8+ T cell population via a Cdkn2a-dependent mechanism. J Leukoc Biol 2013; 94:1103-12. [PMID: 23772040 PMCID: PMC6607996 DOI: 10.1189/jlb.0213064] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
IL‐4 induced IL‐10‐producing CD8+ T cells possess suppressive function both in vitro and in vivo. CD8+ T cells play an important role in immune regulation and effective immune responses against tumor cells, viral infection, and intracellular pathogens. In this report, using tiger or 10BiT mice, we defined a population of IL‐10‐producing CD8+ T cells that were induced by IL‐4. These IL‐10+CD8+ T cells possessed a strong inhibitory effect on the CD4+ T cell proliferation in an IL‐10‐dependent and cell contact‐dependent fashion. In comparison with IL‐10−CD8+ T cells, IL‐10+CD8+ T cells expressed an array of Th2‐like cytokines (IL‐4, IL‐5), perforin, and granzymes, as well as the cell cycle regulatory protein Cdkn2a. Interestingly, knockdown of cdkn2a using siRNA reduced IL‐4‐induced IL‐10 production significantly. Furthermore, CD8+ T cells from Cdkn2a−/− mice produced a significantly lower amount of IL‐10, and the effect was limited to CD8+ T cells but not observed in CD4+ T cells and APCs. Finally, IL‐10+CD8+ T cells played a protective role in the TNBS‐induced murine colitis model, indicating a critical role of this population of CD8+ T cells in regulatory immune responses. Taken together, we have defined a population of IL‐10‐producing CD8+ Tregs induced by IL‐4 and mediated by Cdkn2a.
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Affiliation(s)
- Yapu Zhao
- 2.College of Life Sciences, Nankai University, Tianjin 300071, China. or
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RhoT1 and Smad4 are correlated with lymph node metastasis and overall survival in pancreatic cancer. PLoS One 2012; 7:e42234. [PMID: 22860091 PMCID: PMC3409151 DOI: 10.1371/journal.pone.0042234] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 07/05/2012] [Indexed: 12/22/2022] Open
Abstract
Cancer cell invasion and metastasis are the most important adverse prognostic factors for pancreatic cancer. Identification of biomarkers associated with outcome of pancreatic cancer may provide new approaches and targets for anticancer therapy. The aim of this study is to examine the relationship between the expression of RhoT1, Smad4 and p16 and metastasis and survival in patients with pancreatic cancer. The analysis showed that the high cytoplasmic expression levels of RhoT1, Smad4 and p16 in pancreatic cancer tissues had significantly negative correlation with lymph node metastasis (LNM) (P = 0.017, P = 0.032, P = 0.042, respectively). However, no significant association was observed between perineural invasion (PNI) and the expression of above three proteins (all P>0.05). Additionally, the survival analysis showed that the low expression levels of RhoT1 and Smad4 were significantly associated with worse survival (P = 0.034, P = 0.047, respectively). In conclusion, these results indicated that the low-expression levels of RhoT1 and Smad4 were significantly associated with LNM and shorter survival. RhoT1 may be considered as a potential novel marker for predicting the outcome in patients with pancreatic cancer.
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Luo Y, Tian L, Feng Y, Yi M, Chen X, Huang Q. The predictive role of p16 deletion, p53 deletion, and polysomy 9 and 17 in pancreatic ductal adenocarcinoma. Pathol Oncol Res 2012; 19:35-40. [PMID: 22782330 DOI: 10.1007/s12253-012-9555-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 06/26/2012] [Indexed: 12/22/2022]
Abstract
In this study, we investigated p53 and p16 deletions, and chromosome 9 and 17 amplifications in pancreatic ductal adenocarcinoma (PDAC), and further analyzed their associations with clinical characteristics and prognosis of PDAC. A total of 32 PDAC and 23 peritumoral tissues were collected. Molecular abnormalities of CEP9/p16 and CEP17/p53 were detected using Fluorescence in situ hybridization (FISH). Deletions of p16 and p53 were detected in 50 % and 65.7 % of PDAC, respectively. Polysomy 9 and 17 were identified in 75 % and 71.8 % of PDAC, respectively. No p16 and p53 deletion, polysomy 9 and 17 were identified in peritumoral tissues. We also observed significant correlations of p16 deletion, polysomy 9 and 17 with shorter survival of PDAC. P16 deletion, polysomy 9 and 17 are predictive markers for poor prognosis of PDAC patients, but p53 deletion is not associated with the clinical characteristics and prognosis of PDAC.
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Affiliation(s)
- Yanli Luo
- Experimental Research Center, First People's Hospital, Shanghai Jiaotong University, 85 Wujin Road, Shanghai 200080, China
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22
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Smith RA, Tang J, Tudur-Smith C, Neoptolemos JP, Ghaneh P. Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. Br J Cancer 2011; 104:1440-51. [PMID: 21448172 PMCID: PMC3101928 DOI: 10.1038/bjc.2011.110] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Revised: 03/02/2011] [Accepted: 03/08/2011] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log(e) hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ(2) test for heterogeneity and its impact on the meta-analysis was assessed by the I(2) statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining. RESULTS Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups. CONCLUSION These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.
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Affiliation(s)
- R A Smith
- Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK
| | - J Tang
- Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK
| | - C Tudur-Smith
- Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK
| | - J P Neoptolemos
- Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK
| | - P Ghaneh
- Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK
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Voidonikolas G, Kreml SS, Chen C, Fisher WE, Brunicardi FC, Gibbs RA, Gingras MC. Basic principles and technologies for deciphering the genetic map of cancer. World J Surg 2009; 33:615-29. [PMID: 19115029 PMCID: PMC2924149 DOI: 10.1007/s00268-008-9851-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The progress achieved in the field of genomics in recent years is leading medicine to adopt a personalized model in which the knowledge of individual DNA alterations will allow a targeted approach to cancer. Using pancreatic cancer as a model, we discuss herein the fundamentals that need to be considered for the high throughput and global identification of mutations. These include patient-related issues, sample collection, DNA isolation, gene selection, primer design, and sequencing techniques. We also describe the possible applications of the discovery of DNA changes to the approach of this disease and cite preliminary efforts where the knowledge has been translated into the clinical or preclinical setting.
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Affiliation(s)
- Georgios Voidonikolas
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Stephanie S. Kreml
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Changyi Chen
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - William E. Fisher
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
- The Elkins Pancreas Center, Baylor College of Medicine, Houston, Texas, USA
| | - F. Charles Brunicardi
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
| | - Richard A. Gibbs
- Human Genome Sequencing Center; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
| | - Marie-Claude Gingras
- Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA
- Human Genome Sequencing Center; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
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24
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Molecular markers of pancreatic cancer: development and clinical relevance. Langenbecks Arch Surg 2008; 393:883-90. [PMID: 18266003 DOI: 10.1007/s00423-007-0276-0] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2007] [Accepted: 12/11/2007] [Indexed: 02/06/2023]
Abstract
BACKGROUND The prognosis of pancreatic cancer remains poor, mainly because of its aggressive biological behaviour and late clinical diagnosis, which precludes the application of appropriate curative therapies. Therefore, one of the major goals in clinical pancreatology is to find molecular markers, specific and sensitive enough to make an early and correct diagnosis of pancreatic cancer, before it has disseminated and become untreatable. OBJECTIVE This overview article explores the potential utility of current molecular markers for the diagnosis of pancreatic cancer. RESULTS There is a wide array of serum-based and tissue-based markers for pancreatic cancer. Serum-based molecular markers include CA 19-9, CA 125, M2-PK and secreted proteins. A tissue can be used to test genetic mutations such as K-ras, inactivation of tumour suppressor genes (e.g. p16, p53), mucins, telomerase activity, growth factors, DNA methylation, and global gene expression of cDNA microarrays, mitochondrial mutations and proteomics. None of these markers is currently useful for the detection of early pancreatic cancer. In clinical practice, the most commonly accepted use of CA 19-9 is to assess the prognosis and monitor the response to therapy. CONCLUSIONS Many molecular markers have been proposed for the early diagnosis of PC, but most are not ready to be included as part of the routine diagnostic algorithm because they still lack sensitivity, specificity or reproducibility. CA 19-9 remains the most useful molecular marker for the diagnosis and follow-up of clinically and radiological evident pancreatic cancer.
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25
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Tonini G, Pantano F, Vincenzi B, Gabbrielli A, Coppola R, Santini D. Molecular prognostic factors in patients with pancreatic cancer. Expert Opin Ther Targets 2007; 11:1553-69. [DOI: 10.1517/14728222.11.12.1553] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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26
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Liu YS, Yu CH, Li L, Zhang BF, Fang J, Zhou Q, Hu Y, Li YM, Jun Gao H. Expression of p53, p16 and cyclooxygenase-2 in esophageal cancer with tissue microarray. J Dig Dis 2007; 8:133-138. [PMID: 17650224 DOI: 10.1111/j.1443-9573.2007.00299.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to obtain a comprehensive survey on the expression of p53, p16 and cyclooxygenase-2 (COX-2) in esophageal cancer progression and their clinical significance. METHODS A tissue microarray containing 86 specimens from esophageal cancer and 40 specimens from adjacent non-cancer tissue was constructed to survey the expression of p53, p16 and COX-2 by immunohistochemistry. The influence of each biomarker on the histotype of esophageal lesion was assessed by logistic regression analysis. RESULTS The expression of p53 and COX-2 was significantly higher in tumorous tissue than in non-tumorous tissue. As to p16, no significant difference was detected between tumorous and non-tumorous tissue. A significant correlation was observed among p53, COX-2 and p16 expression. Logistic regression analysis revealed that the risk factors of a tumorous histotype were the positive expression of p53 (odds ratio [OR] = 18.214) or COX-2 (OR = 42.703), and no reciprocal relationship to neoplastic progression was recognized with p53, p16 and COX-2. CONCLUSIONS p53 and COX-2 were independent predictors in esophageal carcinogenesis. Esophageal tissue with a positive expression of p53 or COX-2 was more likely to develop esophageal cancer.
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Affiliation(s)
- You Shi Liu
- Department of Gastroenterology, First Affiliated Hospital, Medical College, Zhejiang University, Hangzhou, China
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27
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Abe K, Suda K, Arakawa A, Yamasaki S, Sonoue H, Mitani K, Nobukawa B. Different patterns of p16INK4A and p53 protein expressions in intraductal papillary-mucinous neoplasms and pancreatic intraepithelial neoplasia. Pancreas 2007; 34:85-91. [PMID: 17198188 DOI: 10.1097/01.mpa.0000240608.56806.0a] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVES To examine aberrations and differences of cell cycle regulatory proteins between intraductal papillary-mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasias (PanINs). METHODS In total, 47 IPMN lesions and 42 PanIN lesions were obtained from 26 patients with IPMN and 16 patients who underwent pancreatic surgery for invasive pancreatic ductal cancer or other diseases. They were subjected to conventional hematoxylin-eosin staining and immunostaining for p16INK4A and p53. The percentages of immunohistochemical positivity or negativity were compared between IPMN and PanIN, in accordance with the same histological grade of atypia. The Ki-67 labeling index was also counted in each lesion. RESULTS Either the loss of p16INK4A expression or the overexpression of p53 was much more frequently observed among PanIN-3 than among carcinoma in situ in IPMN (P = 0.046 and 0.008, respectively). The Ki-67 labeling index was correlated with the histological grades of both PanINs and IPMNs (P = 0.0001 and P = 0.0001, respectively). CONCLUSIONS There are different immunohistochemical expression patterns of p16INK4A and p53 between IPMNs and PanINs. These may substantiate their different genetic progressions to invasive carcinoma.
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Affiliation(s)
- Keiko Abe
- Department of Pathology I, Juntendo University School of Medicine, Tokyo, Japan.
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28
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Jiang P, Watanabe H, Okada G, Ohtsubo K, Mouri H, Tsuchiyama T, Yao F, Sawabu N. Diagnostic utility of aberrant methylation of tissue factor pathway inhibitor 2 in pure pancreatic juice for pancreatic carcinoma. Cancer Sci 2006; 97:1267-73. [PMID: 16965396 PMCID: PMC11158502 DOI: 10.1111/j.1349-7006.2006.00308.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
The tissue factor pathway inhibitor 2 (TFPI-2) is a Kunitz-type serine proteinase inhibitor. Recently, the aberrant methylation of TFPI-2 was detected frequently in pancreatic carcinoma (PCa) tissues but not in normal pancreatic tissues. We analyzed the aberrant methylation of TFPI-2 in the pure pancreatic juice (PPJ) aspirated endoscopically from patients with various pancreatic diseases. Using the highly sensitive methylation-specific polymerase chain reaction (MSP) and quantitative MSP (Q-MSP) assay, we investigated the aberrant methylation of TFPI-2 in nine human PCa cell lines and in the PPJ from patients with PCa, intraductal papillary mucinous neoplasms (IPMN) and chronic pancreatitis (CP). The incidence of aberrant TFPI-2 methylation was seven (77.8%) of nine PCa cell lines by Q-MSP. In cell lines, the expression of TFPI-2 mRNA by quantitative reverse transcription-polymerase chain reaction showed an inverse correlation to the aberrant methylation of TFPI-2. The incidence of aberrant TFPI-2 methylation in the PPJ was 21 (58.3%) of 36 PCa patients, three (17.6%) of 17 IPMN and one (4.8%) of 21 CP by MSP assay. Using a suitable cut-off value of 2.5 according to the receiver operating characteristic curve, the incidence of aberrant TFPI-2 methylation in the PPJ by real-time MSP was 18 (62.1%) of 29 PCa patients, one (5.1%) of 17 IPMN and three (14.3%) of 21 CP, respectively. The incidence of quantitative TFPI-2 hypermethylation in the PPJ with PCa was significantly higher than that with IPMN (P < 0.001) or CP (P < 0.001). Moreover, the aberrant methylation rate of TFPI-2 in the PPJ was 100%, as observed (6/6) in the PCa patients with liver metastasis, and 86.7% (26/30) in stages IVa + IVb of PCa by Q-MSP assay. These results suggest that promoter methylation of TFPI-2 in the PPJ may be a useful marker in the diagnosis and progression of PCa using an endoscopically feasible approach.
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MESH Headings
- Adenocarcinoma, Mucinous/diagnosis
- Adenocarcinoma, Mucinous/genetics
- Aged
- Antimetabolites, Antineoplastic/pharmacology
- Azacitidine/pharmacology
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Papillary/diagnosis
- Carcinoma, Papillary/genetics
- Cell Line, Tumor
- DNA Methylation
- DNA, Neoplasm/genetics
- DNA, Neoplasm/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Glycoproteins/genetics
- Humans
- Male
- Middle Aged
- Pancreatic Juice/metabolism
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/genetics
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/pathology
- Polymerase Chain Reaction
- Promoter Regions, Genetic
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
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Affiliation(s)
- PeiHong Jiang
- Department of Internal Medicine and Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan
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29
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McDonald R, Scott Winters R, Ankuda CK, Murphy JA, Rogers AE, Pereira F, Greenblatt MS, White PS. An automated procedure to identify biomedical articles that contain cancer-associated gene variants. Hum Mutat 2006; 27:957-64. [PMID: 16865690 DOI: 10.1002/humu.20363] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
The proliferation of biomedical literature makes it increasingly difficult for researchers to find and manage relevant information. However, identifying research articles containing mutation data, a requisite first step in integrating large and complex mutation data sets, is currently tedious, time-consuming and imprecise. More effective mechanisms for identifying articles containing mutation information would be beneficial both for the curation of mutation databases and for individual researchers. We developed an automated method that uses information extraction, classifier, and relevance ranking techniques to determine the likelihood of MEDLINE abstracts containing information regarding genomic variation data suitable for inclusion in mutation databases. We targeted the CDKN2A (p16) gene and the procedure for document identification currently used by CDKN2A Database curators as a measure of feasibility. A set of abstracts was manually identified from a MEDLINE search as potentially containing specific CDKN2A mutation events. A subset of these abstracts was used as a training set for a maximum entropy classifier to identify text features distinguishing "relevant" from "not relevant" abstracts. Each document was represented as a set of indicative word, word pair, and entity tagger-derived genomic variation features. When applied to a test set of 200 candidate abstracts, the classifier predicted 88 articles as being relevant; of these, 29 of 32 manuscripts in which manual curation found CDKN2A sequence variants were positively predicted. Thus, the set of potentially useful articles that a manual curator would have to review was reduced by 56%, maintaining 91% recall (sensitivity) and more than doubling precision (positive predictive value). Subsequent expansion of the training set to 494 articles yielded similar precision and recall rates, and comparison of the original and expanded trials demonstrated that the average precision improved with the larger data set. Our results show that automated systems can effectively identify article subsets relevant to a given task and may prove to be powerful tools for the broader research community. This procedure can be readily adapted to any or all genes, organisms, or sets of documents.
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Affiliation(s)
- Ryan McDonald
- Department of Computer and Information Science, University of Pennsylvania, Philadelphia, USA
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30
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Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H, Kuwano M. Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res 2006; 66:6233-42. [PMID: 16778198 DOI: 10.1158/0008-5472.can-06-0183] [Citation(s) in RCA: 133] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Cap43 has been identified as a nickel- and calcium-induced gene, and is also known as N-myc downstream-regulated gene 1 (NDRG1), Drg-1 and rit42. It is also reported that overexpression of Cap43 suppresses metastasis of some malignancies, but its precise role remains unclear. In this study, we asked how Cap43 could modulate the tumor growth of pancreatic cancer. Stable Cap43 cDNA transfectants of pancreatic cancer cells with Cap43 overexpression showed similar growth rates in culture as their control counterparts with low Cap43 protein level. By contrast, Cap43 overexpression showed a marked decrease in tumor growth rates in vivo. Moreover, a marked reduction in tumor-induced angiogenesis was observed. Gelatinolytic activity by matrix metalloproteinase-9 and invasive ability in Matrigel invasion activity were markedly decreased in pancreatic cancer cell lines with high Cap43 expression. Cellular expression of matrix metalloproteinase-9 and two major angiogenic factors, vascular endothelial growth factor and interleukin-8, were also significantly decreased in cell lines with Cap43 overexpression as compared with their parental counterparts. Immunohistochemical analysis of specimens from 65 patients with pancreatic ductal adenocarcinoma showed a significant association between Cap43 expression and tumor microvascular density (P = 0.0001) as well as depth of invasion (P = 0.0003), histopathologic grading (P = 0.0244), and overall survival rates for patients with pancreatic cancer (P = 0.0062). Thus, Cap43 could play a key role in the angiogenic on- or off-switch of tumor stroma in pancreatic ductal adenocarcinoma.
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MESH Headings
- Animals
- Carcinoma, Pancreatic Ductal/blood supply
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Cycle Proteins
- Cell Growth Processes/genetics
- Cell Line, Tumor
- Disease Progression
- Genes, Tumor Suppressor
- Humans
- Interleukin-8/biosynthesis
- Intracellular Signaling Peptides and Proteins
- Male
- Matrix Metalloproteinase 9/biosynthesis
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Pancreatic Neoplasms/blood supply
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Prognosis
- Proteins/genetics
- Proteins/metabolism
- Vascular Endothelial Growth Factor A/biosynthesis
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Affiliation(s)
- Yuichiro Maruyama
- Department of Surgery, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume, Japan
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31
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Ohtsubo K, Watanabe H, Yao F, Okada G, Mouri H, Yamaguchi Y, Sawabu N. Preproenkephalin hypermethylation in the pure pancreatic juice compared with p53 mutation in the diagnosis of pancreatic carcinoma. J Gastroenterol 2006; 41:791-7. [PMID: 16988769 DOI: 10.1007/s00535-006-1857-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2006] [Accepted: 05/22/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Aberrant methylation of CpG islands is a common mechanism for the dysregulation of tumor suppressor genes in a variety of human malignancies. Preproenkephalin ppENK) hypermethylation is recognized in 90% of pancreatic carcinoma (PCa) tissues, but not in normal pancreas. We analyzed ppENK hypermethylation in pure pancreatic juice (PPJ) in patients with PCa, intraductal papillary mucinous neoplasms (IPMN), and chronic pancreatitis (CP), and elucidated its usefulness as a marker in the diagnosis of PCa compared with p53 mutation. METHODS PPJ was collected endoscopically from 28 patients with PCa, 15 patients with IPMN, and 20 patients with CP. DNA was extracted from the supernatant and the sediment of PPJ. Methylation-specific polymerase chain reaction was performed for hypermethylation analysis of ppENK. In addition, single-strand conformation polymorphism and direct sequencing were performed simultaneously to identify p53 mutations. RESULTS The incidence of ppENK hypermethylation in the supernatant and/or the sediment of PPJ was 50% (14 of 28) in patients with PCa. In contrast, the incidence of ppENK hypermethylation was 26.7% (4 of 15) in patients with IPMN, and 5% (1 of 20) in patients with CP (P < 0.002). The incidence of p53 mutations in the PPJ was 42.9% (12 of 28) in patients with PCa and 0% (0 of 20) in patients with CP. Furthermore, the incidence of ppENK hypermethylation and/or p53 mutations in the PPJ was enhanced to 67.9% (19 of 28) in patients with PCa in the combination assay. CONCLUSIONS These results suggest that ppENK hypermethylation in PPJ is specific for cancer, and the combination assay with p53 enhances the genetic diagnosis of PCa.
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Affiliation(s)
- Koushiro Ohtsubo
- Department of Internal Medicine and Medical Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan
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32
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Garcea G, Neal CP, Pattenden CJ, Steward WP, Berry DP. Molecular prognostic markers in pancreatic cancer: a systematic review. Eur J Cancer 2005; 41:2213-36. [PMID: 16146690 DOI: 10.1016/j.ejca.2005.04.044] [Citation(s) in RCA: 186] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2005] [Accepted: 04/08/2005] [Indexed: 12/30/2022]
Abstract
Pancreatic cancer is one of the most lethal tumours of the gastrointestinal tract. The ability to predict which patients would benefit most from surgical intervention and/or chemotherapy would be a great clinical asset. Considerable research has focused on identifying molecular events in pancreatic carcinogenesis, and their correlation with clinicopathological variables of pancreatic tumours and survival. This systematic review examined evidence from published manuscripts looking at molecular markers in pancreatic cancer and their correlation with tumour stage and grade, response to chemotherapy and long-term survival. A literature search was undertaken using PubMed and MEDLINE search engines, using the keywords p53, p21, p16, p27, SMAD4, K-ras, cyclin D1, Bax, Bcl-2, EGFR, EGF, c-erbB2, HB-EGF, TGFbeta, FGF, MMP, uPA, cathepsin, heparanase, E-cadherin, laminins, integrins, TMSF, CD44, cytokines, angiogenesis, VEGF, IL-8, beta-catenin, DNA microarray, and gene profiling. A bewildering number of biomarkers are currently under evaluation. For the most part, the evidence regarding their application as prognostic indicators is conflicting. The advent of gene microarray and mass spectrometric protein profiling offers the potential to examine many different biomarkers simultaneously. This 'protein/gene signature' could revolutionise work in this field and allow researchers to develop accurate and reproducible predictions of survival based on protein or gene profiles.
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Affiliation(s)
- G Garcea
- Cancer Studies and Molecular Medicine, The Robert Kilpatrick Clinical Sciences Building, University of Leicester, The Leicester Royal Infirmary, Leicester LE2 7LX, UK.
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Attri J, Srinivasan R, Majumdar S, Radotra BD, Wig J. Alterations of tumor suppressor gene p16INK4a in pancreatic ductal carcinoma. BMC Gastroenterol 2005; 5:22. [PMID: 15985168 PMCID: PMC1185532 DOI: 10.1186/1471-230x-5-22] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2004] [Accepted: 06/28/2005] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Cell cycle inhibitor and tumor suppressor gene p16/MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations. METHODS We investigated the status of p16 gene by polymerase chain reaction (PCR), nonradioisotopic single strand conformation polymorphism (SSCP), DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC) using a monoclonal antibody clone (MS-887-PO). RESULTS Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25). Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25) cases, followed by coding sequence mutations in 16% (4/25) cases and presumably homozygous deletion in 12% (3/25) cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%). CONCLUSION These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type.
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Affiliation(s)
- Jyotika Attri
- Department of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Radhika Srinivasan
- Department of Cytology and Gynaec Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Siddhartha Majumdar
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Bishan Dass Radotra
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jaidev Wig
- Department of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Ren YX, Xu GM, Li ZS, Song YG. Detection of point mutation in K-ras oncogene at codon 12 in pancreatic diseases. World J Gastroenterol 2004; 10:881-4. [PMID: 15040037 PMCID: PMC4727022 DOI: 10.3748/wjg.v10.i6.881] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To investigate frequency and clinical significance of K-ras mutations in pancreatic diseases and to identify its diagnostic values in pancreatic carcinoma.
METHODS: 117 ductal lesions were identified in the available sections from pancreatic resection specimens of pancreatic ductal adenocarcinoma, comprising 24 pancreatic ductal adenocarcinoma, 19 peritumoral ductal atypical hyperplasia, 58 peritumoral ductal hyperplasia and 19 normal duct at the tumor free resection margin. 24 ductal lesions were got from 24 chronic pancreatitis. DNA was extracted. Codon 12 K-ras mutations were examined using the two-step polymerase chain reaction (PCR) combined with restriction enzyme digestion, followed by nonradioisotopic single-strand conformation polymorphism (SSCP) analysis and by means of automated DNA sequencing.
RESULTS: K-ras mutation rate of the pancreatic carcinoma was 79%(19/24) which was significantly higher than that in the chronic pancreatitis 33%(8/24) (P < 0.01). It was also found that K-ras mutation rate was progressively increased from normal duct at the tumor free resection margin, peritumoral ductal hyperplasia, peritumoral ductal atypical hyperplasia to pancreatic ductal adenocarcinoma. The mutation pattern of K-ras 12 codon of chronic pancreatitis was GGT→GAT, GGT and CGT, which is identical to that in pancreatic carcinoma.
CONCLUSION: K-ras mutation may play a role in the malignant transformation of pancreatic ductal cell. K-ras mutation was not specific enough to diagnose pancreatic carcinoma.
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Affiliation(s)
- Yue-Xin Ren
- Department of Gastroenterology, Nanfang Hospital, First Military Medical University, Guangzhou 510515, China.
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35
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Ren YX, Xu GM, Li ZS, Liu F. Aberrant expression and mutations of K-ras gene in pancreatic adenocarcinoma and chronic pancreatitis. Shijie Huaren Xiaohua Zazhi 2004; 12:664-668. [DOI: 10.11569/wcjd.v12.i3.664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate frequency and clinical significance of P21ras expression and K-ras mutations in pancreatic diseases and to identify their diagnostic values in pancreatic carcinoma.
METHODS: A total of 117 ductal lesions were identified in the available sections from pancreatic resection specimens of patients with pancreatic diseases, comprising 24 pancreatic ductal adenocarcinoma, 19 peritumoral ductal atypical hyperplasia, 58 peritumoral ductal hyperplasia and 19 normal duct at the tumor free resection margin. 24 ductal lesions were gotten from 24 chronic panctratitis. The expression of P21ras was examined by immunohistochemical method. DNA was extracted. Codon 12 K-ras mutations were examined using the two-step polymerase chain reaction (PCR) combined with restriction enzyme digestion, followed by nonradioisotopic single-strand conformation polymorphism (SSCP) analysis by means of automated DNA sequencing.
RESULTS: The expression level of P21ras in pancreatic carcinoma and chronic pancreatitis was higher than that of normal pancreatic tissue, but the expression of P21ras in ductal hyperplasia neighboring pancreatic carcinoma was similar to that in ductal hyperplasia of chronic pancretitis. P21ras showed a gradual stepwise increase in the frequency of expression ranged from normal pancreatic duct (0%), to hyperplasia duct (36.6%) and to atypical hyperplasia duct (78.9%). The expression level of P21ras of atypical hyperplasia duct was higher than that of hyperplasia duct (P < 0.01). K-ras mutation rate of the pancreatic carcinoma was 79%, which was significantly higher than that in the chronic pancreatitis (33%) (P < 0.01). It was also found that K-ras mutation rate was gradually increased from normal duct at the tumor free resection margin, peritumoral ductal hyperplasia, peritumoral ductal atypical hyperplasia to pancreatic ductal adenocarcinoma. The mutation pattern of K-ras 12 codon of chronic pancreatitis was GGT→GAT, GGT and CGT, which was identical to that in pancreatic carcinoma.
CONCLUSION: Overexpression of P21ras and K-ras mutation may play roles in the malignant transformation of pancreatic ductal cell. K-ras mutation only is not specific enough to diagnose pancreatic carcinoma.
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