|
1
|
Jia MH, Zhang SL, Liu TB, Jue YF, Liu XL, Liu JB. Systematic review and meta-analysis of relationship between p53 protein expression and lymph node metastasis, vascular invasion, and perineural invasion in pancreatic cancer. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:376-386. [DOI: 10.11569/wcjd.v32.i5.376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
|
|
2
|
Reshkin SJ, Cardone RA, Koltai T. Genetic Signature of Human Pancreatic Cancer and Personalized Targeting. Cells 2024; 13:602. [PMID: 38607041 PMCID: PMC11011857 DOI: 10.3390/cells13070602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/13/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease with a 5-year survival rate of around 11-12%. Surgery, being the treatment of choice, is only possible in 20% of symptomatic patients. The main reason is that when it becomes symptomatic, IT IS the tumor is usually locally advanced and/or has metastasized to distant organs; thus, early diagnosis is infrequent. The lack of specific early symptoms is an important cause of late diagnosis. Unfortunately, diagnostic tumor markers become positive at a late stage, and there is a lack of early-stage markers. Surgical and non-surgical cases are treated with neoadjuvant and/or adjuvant chemotherapy, and the results are usually poor. However, personalized targeted therapy directed against tumor drivers may improve this situation. Until recently, many pancreatic tumor driver genes/proteins were considered untargetable. Chemical and physical characteristics of mutated KRAS are a formidable challenge to overcome. This situation is slowly changing. For the first time, there are candidate drugs that can target the main driver gene of pancreatic cancer: KRAS. Indeed, KRAS inhibition has been clinically achieved in lung cancer and, at the pre-clinical level, in pancreatic cancer as well. This will probably change the very poor outlook for this disease. This paper reviews the genetic characteristics of sporadic and hereditary predisposition to pancreatic cancer and the possibilities of a personalized treatment according to the genetic signature.
Collapse
Affiliation(s)
- Stephan J. Reshkin
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Rosa Angela Cardone
- Department of Biosciences, Biotechnologies and Environment, University of Bari “Aldo Moro”, 70125 Bari, Italy;
| | - Tomas Koltai
- Oncomed, Via Pier Capponi 6, 50132 Florence, Italy
| |
Collapse
|
|
3
|
Tewari M, Swain JR, Mishra RR, Dixit VK, Shukla HS. Expression Profile of KRAS and p16 in Periampullary Cancer. Indian J Surg Oncol 2024; 15:25-34. [PMID: 38511045 PMCID: PMC10948726 DOI: 10.1007/s13193-023-01819-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/06/2023] [Indexed: 03/22/2024] Open
Abstract
Activating point mutations in codons 12, 13, and 61 of the KRAS gene and loss of p16 expression, a tumor suppressor gene, are common genetic alterations in periampullary cancer (PAC). The present study explores expression profile of KRAS and p16 genes in PAC and its prognostic relevance. A total of 50 patients with PAC who underwent potentially curative pancreaticoduodenectomy were included in the study. Formalin-fixed, paraffin-embedded tissue samples were analyzed for point mutations in codons 12 and 13 of KRAS and codon 9 of p16 using polymerase chain reaction. KRAS mutation in codon 12/13 was found in 32 (64%) and loss of p16 expression in 36 (72%) cases. KRAS mutation was significantly associated with higher grade, higher pathological tumor (pT) stage, lymphovascular invasion (LVI), perineural invasion (PNI), and pathological lymph nodes (pN) involvement on univariate analysis. On multivariate analysis, significant association of KRAS remained with higher grade (p = 0.031), pT stage (p = 0.09), and LVI (p = 0.028). On univariate analysis, loss of p16 expression was significantly associated with higher grade, pN involvement, LVI, PNI, and pT stage whereas on multivariate analysis, statistical significant association of p16 was found with higher grade of tumor only (p = 0.04). Patients with KRAS mutation had significantly (p = 0.018) worse disease-free survival (DFS) whereas no significant association was found in overall survival (OS). Loss of p16 expression had no association with either DFS or OS. The presence of p16 and KRAS alterations in patients with PAC suggests aggressive tumor biology. KRAS mutations confer a significantly poor DFS in PAC.
Collapse
Affiliation(s)
- Mallika Tewari
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P. 221005 India
| | - Jyoti R. Swain
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P. 221005 India
| | - Raghvendra R. Mishra
- Medical Lab Technology, DDU Kaushal Kendra, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P. 221005 India
| | - Vinod K. Dixit
- Department Gastroenterology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P. 221005 India
| | - H. S. Shukla
- Department of Surgical Oncology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, U.P. 221005 India
| |
Collapse
|
|
4
|
Ayasun R, Saridogan T, Gaber O, Sahin IH. Systemic Therapy for Patients With Pancreatic Cancer: Current Approaches and Opportunities for Novel Avenues Toward Precision Medicine. Clin Colorectal Cancer 2023; 22:2-11. [PMID: 36418197 PMCID: PMC11219281 DOI: 10.1016/j.clcc.2022.11.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 10/01/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis with a 5-year overall survival of 11%. The disease is usually diagnosed at advanced stages, and systemic chemotherapy is the standard-of-care treatment for the majority of patients with PDAC. Although novel treatment options, such as targeted therapy and immunotherapy, have achieved substantial progress leading to practice-changing results, with FDA approvals for several solid tumors so far, the progress achieved for PDAC is relatively limited. Recent studies uncovered potential therapeutic targets for patients with PDAC, and potential therapeutic opportunities are currently being further examined. Herein, we review recent advances in systemic therapy regimens, including cytotoxic agents, targeted therapies, immunotherapy, and novel therapeutic options for managing patients with PDAC. We also elaborate on molecular profiling to guide treatment and existing therapeutic opportunities that may further advance the clinical care of patients with this devastating disease.
Collapse
Affiliation(s)
| | | | - Ola Gaber
- Department of Gastrointestinal Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ibrahim Halil Sahin
- Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| |
Collapse
|
|
5
|
Szymoński K, Milian-Ciesielska K, Lipiec E, Adamek D. Current Pathology Model of Pancreatic Cancer. Cancers (Basel) 2022; 14:2321. [PMID: 35565450 PMCID: PMC9105915 DOI: 10.3390/cancers14092321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.
Collapse
Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
- Department of Pathomorphology, University Hospital, 30-688 Cracow, Poland;
| | | | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, 30-348 Cracow, Poland;
| | - Dariusz Adamek
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
| |
Collapse
|
|
6
|
Pekarek L, Fraile-Martinez O, Garcia-Montero C, Saez MA, Barquero-Pozanco I, Del Hierro-Marlasca L, de Castro Martinez P, Romero-Bazán A, Alvarez-Mon MA, Monserrat J, García-Honduvilla N, Buján J, Alvarez-Mon M, Guijarro LG, Ortega MA. Clinical Applications of Classical and Novel Biological Markers of Pancreatic Cancer. Cancers (Basel) 2022; 14:1866. [PMID: 35454771 PMCID: PMC9029823 DOI: 10.3390/cancers14081866] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 04/02/2022] [Accepted: 04/06/2022] [Indexed: 01/27/2023] Open
Abstract
The incidence and prevalence of pancreatic adenocarcinoma have increased in recent years. Pancreatic cancer is the seventh leading cause of cancer death, but it is projected to become the second leading cause of cancer-related mortality by 2040. Most patients are diagnosed in an advanced stage of the disease, with very limited 5-year survival. The discovery of different tissue markers has elucidated the underlying pathophysiology of pancreatic adenocarcinoma and allowed stratification of patient risk at different stages and assessment of tumour recurrence. Due to the invasive capacity of this tumour and the absence of screening markers, new immunohistochemical and serological markers may be used as prognostic markers for recurrence and in the study of possible new therapeutic targets because the survival of these patients is low in most cases. The present article reviews the currently used main histopathological and serological markers and discusses the main characteristics of markers under development.
Collapse
Affiliation(s)
- Leonel Pekarek
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Oncology Service, Guadalajara University Hospital, 19002 Guadalajara, Spain
| | - Oscar Fraile-Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Cielo Garcia-Montero
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Miguel A Saez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Pathological Anatomy Service, Central University Hospital of Defence-UAH Madrid, 28801 Alcala de Henares, Spain
| | - Ines Barquero-Pozanco
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Laura Del Hierro-Marlasca
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Patricia de Castro Martinez
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Adoración Romero-Bazán
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Jorge Monserrat
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Natalio García-Honduvilla
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Julia Buján
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
| | - Melchor Alvarez-Mon
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service an Internal Medicine (CIBEREHD), University Hospital Príncipe de Asturias, 28806 Alcala de Henares, Spain
| | - Luis G Guijarro
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Unit of Biochemistry and Molecular Biology, Department of System Biology (CIBEREHD), University of Alcalá, 28801 Alcala de Henares, Spain
| | - Miguel A Ortega
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcala de Henares, Spain
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain
- Cancer Registry and Pathology Department, Principe de Asturias University Hospital, 28806 Alcala de Henares, Spain
| |
Collapse
|
|
7
|
Digiacomo G, Volta F, Garajova I, Balsano R, Cavazzoni A. Biological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC. Life (Basel) 2021; 11:life11080843. [PMID: 34440587 PMCID: PMC8400856 DOI: 10.3390/life11080843] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/04/2021] [Accepted: 08/13/2021] [Indexed: 12/27/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest solid tumors and is estimated to become a leading cause of cancer-related death in coming years. Despite advances in surgical approaches and the emergence of new chemotherapy options, its poor prognosis has not improved in the last decades. The current treatment for PDAC is the combination of cytotoxic chemotherapy agents. However, PDAC shows resistance to many antineoplastic therapies with rapid progression. Although PDAC represents a heterogeneous disease, there are common alterations including oncogenic mutations of KRAS, and the frequent inactivation of different cell cycle regulators including the CDKN2A tumor suppressor gene. An emerging field of investigation focuses on inhibiting the function of proteins that suppress the immune checkpoint PD-1/PD-L1, with activation of the endogenous immune response. To date, all conventional immunotherapies have been less successful in patients with PDAC compared to other tumors. The need for new targets, associated with an extended molecular analysis of tumor samples could give new pharmacological options for the treatment of PDAC. It is, therefore, important to push for a broader molecular approach in PDAC research. Here, we provide a selected summary of emerging strategy options for targeting PDAC using CDK4/6 inhibitors, RAS inhibitors, and new drug combinations with immune checkpoint agents.
Collapse
Affiliation(s)
- Graziana Digiacomo
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
- Correspondence: ; Tel.: +39-0521-903965
| | - Francesco Volta
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy; (I.G.); (R.B.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy; (I.G.); (R.B.)
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
| |
Collapse
|
|
8
|
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.
Collapse
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
| |
Collapse
|
|
9
|
Sun H, Zhang B, Li H. The Roles of Frequently Mutated Genes of Pancreatic Cancer in Regulation of Tumor Microenvironment. Technol Cancer Res Treat 2020; 19:1533033820920969. [PMID: 32372692 PMCID: PMC7225789 DOI: 10.1177/1533033820920969] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Pancreatic ductal adenocarcinoma has extremely high malignancy and patients with pancreatic ductal adenocarcinoma have dismal prognosis. The failure of pancreatic ductal adenocarcinoma treatment is largely due to the tumor microenvironment, which is featured by ample stromal cells and complicated extracellular matrix. Recent genomic analysis revealed that pancreatic ductal adenocarcinoma harbors frequently mutated genes including KRAS, TP53, CDKN2A, and SMAD4, which can widely alter cellular processes and behaviors. As shown by accumulating studies, these mutant genes may also change tumor microenvironment, which in turn affects pancreatic ductal adenocarcinoma progression. In this review, we summarize the role of such genetic mutations in tumor microenvironment regulation and potential mechanisms.
Collapse
Affiliation(s)
- Hongzhi Sun
- Department of General Surgery, Shenzhen Luohu People's Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Bo Zhang
- Department of General Surgery, Shenzhen Luohu People's Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Haijun Li
- Department of General Surgery, Shenzhen Luohu People's Hospital, The Third Affiliated Hospital of Shenzhen University, Shenzhen, China
| |
Collapse
|
|
10
|
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.
Collapse
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
| |
Collapse
|
|
11
|
Xu JZ, Wang WQ, Zhang WH, Xu HX, Gao HL, Zhang SR, Wu CT, Li S, Li H, Xu J, Yu XJ, Liu L. The Loss of SMAD4/DPC4 Expression Associated with a Strongly Activated Hedgehog Signaling Pathway Predicts Poor Prognosis in Resected Pancreatic Cancer. J Cancer 2019; 10:4123-4131. [PMID: 31417657 PMCID: PMC6692626 DOI: 10.7150/jca.30883] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 05/19/2019] [Indexed: 12/14/2022] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) progression is mediated by mutations in driver genes and a complex stroma that is mainly dependent on the Sonic hedgehog (Shh) signaling pathway. However, the association between driver genes and Shh-pathway proteins and their potential prognostic significance remain unclear. Methods: We analyzed protein expressions of the KRAS, TP53, SMAD4, and CDKN2A/P16 driver genes and the Shh-pathway molecules, including Shh, glioma-associated oncogene (Gli) 1, Gli2, and smoothened (SMO) by immunohistochemistry using tissue microarrays in 237 patients with resectable PDAC and statistically determined their prognostic significance. Results: SMAD4 lost mutation was associated with shorter survival outcomes [overall survival (OS): Hazard ratio (HR) 1.887, p < 0.001]; recurrence-free survival (RFS): HR 1.886, p < 0.001) and abnormal p53 immunolabeling was associated with poor OS (HR 1.436, p = 0.011) in patients with PDAC. The mutational status of p16 had no effect on patient survival. High levels of SMO and Gli1 expression were associated with poor survival outcomes in both univariate and multivariate analyses. Pearson's χ2 test showed a medium correlation between the SMAD4 lost mutation and Shh (R = 0.343) and Gli1 (R = 0.505) expression levels (p < 0.001). Patients with the SMAD4 lost mutation and high levels of Shh and Gli1 expression showed the poorest survival outcomes (RFS: HR 2.976; OS: HR 3.598; p < 0.001 for both) compared with other patients in the study. Conclusion: Loss of SMAD4 associated with a strongly activated Shh pathway resulted in poor survival outcomes in patients with resected PDAC.
Collapse
Affiliation(s)
- Jin-Zhi Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shi-Rong Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| |
Collapse
|
|
12
|
Lu L, Zeng J. Evaluation of K-ras and p53 expression in pancreatic adenocarcinoma using the cancer genome atlas. PLoS One 2017; 12:e0181532. [PMID: 28742845 PMCID: PMC5526503 DOI: 10.1371/journal.pone.0181532] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 07/05/2017] [Indexed: 12/12/2022] Open
Abstract
Genetic alterations in K-ras and p53 are thought to be critical in pancreatic cancer development and progression. However, K-ras and p53 expression in pancreatic adenocarcinoma have not been systematically examined in The Cancer Genome Atlas (TCGA) Data Portal. Information regarding K-ras and p53 alterations, mRNA expression data, and protein/protein phosphorylation abundance was retrieved from The Cancer Genome Atlas (TCGA) databases, and analyses were performed by the cBioPortal for Cancer Genomics. The mutual exclusivity analysis showed that events in K-ras and p53 were likely to co-occur in pancreatic adenocarcinoma (Log odds ratio = 1.599, P = 0.006). The graphical summary of the mutations showed that there were hotspots for protein activation. In the network analysis, no solid association between K-ras and p53 was observed in pancreatic adenocarcinoma. In the survival analysis, neither K-ras nor p53 were associated with both survival events. As in the data mining study in the TCGA databases, our study provides a new perspective to understand the genetic features of K-ras and p53 in pancreatic adenocarcinoma.
Collapse
Affiliation(s)
- Liming Lu
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China
| | - Jingchun Zeng
- The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| |
Collapse
|
|
13
|
Feng CM, Gao YL, Liu JX, Zheng CH, Yu J. PCA Based on Graph Laplacian Regularization and P-Norm for Gene Selection and Clustering. IEEE Trans Nanobioscience 2017; 16:257-265. [PMID: 28371780 DOI: 10.1109/tnb.2017.2690365] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
In modern molecular biology, the hotspots and difficulties of this field are identifying characteristic genes from gene expression data. Traditional reconstruction-error-minimization model principal component analysis (PCA) as a matrix decomposition method uses quadratic error function, which is known sensitive to outliers and noise. Hence, it is necessary to learn a good PCA method when outliers and noise exist. In this paper, we develop a novel PCA method enforcing P-norm on error function and graph-Laplacian regularization term for matrix decomposition problem, which is called as PgLPCA. The heart of the method designing for reducing outliers and noise is a new error function based on non-convex proximal P-norm. Besides, Laplacian regularization term is used to find the internal geometric structure in the data representation. To solve the minimization problem, we develop an efficient optimization algorithm based on the augmented Lagrange multiplier method. This method is used to select characteristic genes and cluster the samples from explosive biological data, which has higher accuracy than compared methods.
Collapse
|
|
14
|
Kameta E, Sugimori K, Kaneko T, Ishii T, Miwa H, Sato T, Ishii Y, Sue S, Sasaki T, Yamashita Y, Shibata W, Matsumoto N, Maeda S. Diagnosis of pancreatic lesions collected by endoscopic ultrasound-guided fine-needle aspiration using next-generation sequencing. Oncol Lett 2016; 12:3875-3881. [PMID: 27895743 PMCID: PMC5104195 DOI: 10.3892/ol.2016.5168] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Accepted: 08/10/2016] [Indexed: 12/25/2022] Open
Abstract
Endoscopic ultrasound-guided fine-needle aspiration (EUF-FNA) has improved the diagnosis of pancreatic lesions. Next-generation sequencing (NGS) facilitates the production of millions of sequences concurrently. Therefore, in the current study, to improve the detectability of oncogenic mutations in pancreatic lesions, an NGS system was used to diagnose EUS-FNA samples. A total of 38 patients with clinically diagnosed EUS-FNA specimens were analyzed; 27 patients had pancreatic ductal adenocarcinoma (PDAC) and 11 had non-PDAC lesions. DNA samples were isolated and sequenced by NGS using an Ion Personal Genome Machine system. The Cancer Hotspot Panel v2, which includes 50 cancer-related genes and 2,790 COSMIC mutations, was used. A >2% mutation frequency was defined as positive. KRAS mutations were detected in 26 of 27 PDAC aspirates (96%) and 0 of 11 non-PDAC lesions (0%). The G12, G13, and Q61 KRAS mutations were found in 25, 0, and 1 of the 27 PDAC samples, respectively. Mutations were confirmed by TaqMan® polymerase chain reaction analysis. TP53 mutations were detected in 12 of 27 PDAC aspirates (44%). SMAD4 was observed in 3 PDAC lesions and cyclin-dependent kinase inhibitor 2A in 4 PDAC lesions. Therefore, the current study was successfully able to develop an NGS assay with high clinical sensitivity for EUS-FNA samples.
Collapse
Affiliation(s)
- Eri Kameta
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Kazuya Sugimori
- Gastroenterological Centre, Yokohama City University Medical Centre, Yokohama 232-0024, Japan
| | - Takashi Kaneko
- Gastroenterological Centre, Yokohama City University Medical Centre, Yokohama 232-0024, Japan
| | - Tomohiro Ishii
- Gastroenterological Centre, Yokohama City University Medical Centre, Yokohama 232-0024, Japan
| | - Haruo Miwa
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Takeshi Sato
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Yasuaki Ishii
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Soichiro Sue
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Tomohiko Sasaki
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Yuki Yamashita
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Wataru Shibata
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
- Advanced Medical Research Center, Yokohama City University, Yokohama 236-0004, Japan
| | - Naomichi Matsumoto
- Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan
| |
Collapse
|
|
15
|
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.
Collapse
|
|
16
|
Mukherjee I, Powell B, Parianos M, Downs D, Ross SB. Available technologies and clinical applications of targeted chemotherapy in pancreatic cancer. Cancer Genet 2016; 209:582-591. [PMID: 27613576 DOI: 10.1016/j.cancergen.2016.08.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 08/01/2016] [Indexed: 02/08/2023]
Abstract
The incidence of pancreatic cancer, the fourth leading cause of cancer death in United States, is increasing worldwide. Even though the cure rate has doubled in 40 years, it is abysmally poor at 6-7%. As surgical resection remains the only curative treatment and less than 20% of the newly diagnosed cancers are resectable, the major burden of disease management lies in early diagnosis, good prognostication, and proper neo-adjuvant and/or adjuvant therapy. With advancing technologies and their ease of availability, researchers have better tools to understand pancreatic cancer. In the post-genetic era, proteomic, phosphoproteomic, metabolomic, and more have brought us to a multi-omics era. These newer avenues bring promises of better screening modalities, less invasive diagnostics and monitoring, subtyping of pancreatic cancer, and fine tuning the treatment modalities not only to the right stage of tumor but also to the right tumor biology. As the multitudes of technologies are generating extensive amounts of incongruous data, they are giving clinicians a lot of non-actionable information. In this paper, we wish to encompass the newer technologies, sub-classifications, and future treatment modalities in personalized care of patients with pancreatic cancer.
Collapse
Affiliation(s)
- Indraneil Mukherjee
- Southeastern Center for Digestive Disorders and Pancreatic Cancer, Florida Hospital Tampa, Tampa, FL, USA.
| | - Brett Powell
- Southeastern Center for Digestive Disorders and Pancreatic Cancer, Florida Hospital Tampa, Tampa, FL, USA
| | - Mary Parianos
- Southeastern Center for Digestive Disorders and Pancreatic Cancer, Florida Hospital Tampa, Tampa, FL, USA
| | - Darrell Downs
- Southeastern Center for Digestive Disorders and Pancreatic Cancer, Florida Hospital Tampa, Tampa, FL, USA
| | - Sharona B Ross
- Southeastern Center for Digestive Disorders and Pancreatic Cancer, Florida Hospital Tampa, Tampa, FL, USA
| |
Collapse
|
|
17
|
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]
|
|
18
|
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.
Collapse
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
| | | |
Collapse
|
|
19
|
Knösel T, Altendorf-Hofmann A, Lindner L, Issels R, Hermeking H, Schuebbe G, Gibis S, Siemens H, Kampmann E, Kirchner T. Loss of p16(INK4a) is associated with reduced patient survival in soft tissue tumours, and indicates a senescence barrier. J Clin Pathol 2014; 67:592-8. [DOI: 10.1136/jclinpath-2013-202106] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
|
|
20
|
Giovinazzo F, Turri G, Zanini S, Butturini G, Scarpa A, Bassi C. Clinical implications of biological markers in Pancreatic Ductal Adenocarcinoma. Surg Oncol 2012; 21:e171-82. [PMID: 22981281 DOI: 10.1016/j.suronc.2012.07.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2012] [Revised: 07/17/2012] [Accepted: 07/26/2012] [Indexed: 12/29/2022]
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a malignant neoplasm and is the fourth leading cause of cancer-related deaths in US with a 5-year survival rate less than 5%. Surgery is the only potentially curative treatment even though the result is a palliation in the majority of cases and the majority of lesions are lately diagnosed. Progression from normal pancreatic epithelium to metastatic disease is now a well-characterized sequence of events. Research has shown that pancreatic cancer is fundamentally a genetic disease with several biological pathway implied in apoptosis, cell proliferation and self-sufficiency in growth signaling, but how those findings could be applied in daily clinical practice remain unknown. Several studies tried to characterize diagnostic and prognostic biomarkers in PDAC to make it possible an earlier diagnosis, guarantee a more effective treatment and reach a better prognosis even though the results remain contrasting. The main limit of the published researches is the small number of patients studied, but even the heterogeneity of the used methods of analysis. Examining critically the research of the last years future trials may be addressed toward a translational models integrating "the bench and the bed" with the clinical experience and drive the basic research toward the clinical applications.
Collapse
Affiliation(s)
- Francesco Giovinazzo
- Laboratory of Translational Surgery, University Laboratories of Medical Research (LURM), G.B. Rossi Hospital, University of Verona, Piazzale L.A. Scuro 10, Verona 37134, Italy
| | | | | | | | | | | |
Collapse
|
|
21
|
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.
Collapse
Affiliation(s)
- Yanli Luo
- Experimental Research Center, First People's Hospital, Shanghai Jiaotong University, 85 Wujin Road, Shanghai 200080, China
| | | | | | | | | | | |
Collapse
|
|
22
|
Bhat K, Wang F, Ma Q, Li Q, Mallik S, Hsieh TC, Wu E. Advances in biomarker research for pancreatic cancer. Curr Pharm Des 2012; 18:2439-51. [PMID: 22372502 PMCID: PMC3408036 DOI: 10.2174/13816128112092439] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Accepted: 01/18/2012] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related deaths in United States. The lack of early symptoms results in latestage detection and a high mortality rate. Currently, the only potentially curative approach for PC is surgical resection, which is often unsuccessful because the invasive and metastatic nature of the tumor masses makes their complete removal difficult. Consequently, patients suffer relapses from remaining cancer stem cells or drug resistance that eventually lead to death. To improve the survival rate, the early detection of PC is critical. Current biomarker research in PC indicates that a serum carbohydrate antigen, CA 19-9, is the only available biomarker with approximately 90% specificity to PC. However, the efficacy of CA 19-9 for assessing prognosis and monitoring patients with PC remains contentious. Thus, advances in technology and the detection of new biomarkers with high specificity to PC are needed to reduce the mortality rate of pancreatic cancer.
Collapse
Affiliation(s)
- Kruttika Bhat
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Fengfei Wang
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
| | - Qinyu Li
- Department of Surgery, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200025, China
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| | - Tze-chen Hsieh
- Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA
| | - Erxi Wu
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA
| |
Collapse
|
|
23
|
Up and downregulation of p16(Ink4a) expression in BRAF-mutated polyps/adenomas indicates a senescence barrier in the serrated route to colon cancer. Mod Pathol 2011; 24:1015-22. [PMID: 21423154 DOI: 10.1038/modpathol.2011.43] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
P16(Ink4a) is an important factor in carcinogenesis and its expression can be linked to oncogene-induced senescence. Oncogene-induced senescence is characterized by growth arrest and occurs as a consequence of oncogene activation due to KRAS or BRAF mutation. It has been shown that the induction of p16(Ink4a) in premalignant lesions and its loss during malignant transformation is an important mechanism in the carcinogenesis of several tumours. Loss of p16(Ink4a) is often caused by CDKN2A promoter hypermethylation. This mechanism of gene silencing is associated with the CpG island methylator phenotype (CIMP) in colorectal carcinomas, which is characterized by widespread promoter methylation. In particular, colorectal carcinomas with BRAF mutations have been shown to be strongly associated with CIMP. Also, BRAF mutations are strongly correlated with the serrated route to colorectal cancer. In this study, we investigated p16(Ink4a) expression and promoter methylation in BRAF-mutated serrated lesions of the colon. P16(Ink4a) expression was found to be upregulated in premalignant lesions and was lost in invasive serrated carcinomas. P16(Ink4a) expression and Ki67 expression were mutually exclusive, indicating that p16(Ink4a) acts as cell cycle inhibitor. Additionally, progression of malignant transformation in serrated lesions was accompanied by increasing methylation of the CDKN2A promoter. Therefore, our data provide evidence for oncogene-induced senescence in the serrated route to colorectal cancer with BRAF mutation and upregulation of p16(Ink4a) expression appears to be a useful indicator of induction of senescence. Loss of p16(Ink4a) expression occurs during malignant transformation and is caused mainly by aberrant methylation of the CDKN2A promoter.
Collapse
|
|
24
|
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.
Collapse
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
| |
Collapse
|
|
25
|
LOZANO-LEON ANTONIO, PEREZ-QUINTELA BEGONAVIEITES, IGLESIAS-GARCÍA JULIO, LARIÑO-NOIA JOSE, VARO EVARISTO, FORTEZA JERONIMO, DOMÍNGUEZ-MUÑOZ JENRIQUE. Ductal adenocarcinoma of the pancreas: Expression of growth factor receptors, oncogenes and suppressor genes, and their relationship to pathological features, staging and survival. Oncol Lett 2011; 2:161-166. [PMID: 22870146 PMCID: PMC3412479 DOI: 10.3892/ol.2010.206] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2010] [Accepted: 11/10/2010] [Indexed: 11/06/2022] Open
Abstract
Pancreatic ductal adenocarcinoma results in high short-term mortality despite recent advances in diagnostics, surgery and chemotherapy. Modern chemotherapeutic agents directed to specific tumor receptors have higher therapeutic efficacy and lower adverse effects. However, few studies exist that evaluate the clinical impact in pancreatic cancer. The expression of tumor growth factor receptors, oncogenes and tumor suppressor oncogenes in surgical pancreatic cancer specimens as related to pathological characteristics, staging and prognosis was evaluated. Data were recorded for 50 patients who underwent a pancreatic cancer resection and were suitable for immunohistochemical evaluation (32 male, mean age 61 years, range 44-78) with regard to pTN, tumor size and location, histological differentiation grade, vascular and perineural invasion, adjuvant chemotherapy and survival time. Tumor specimens and normal pancreatic tissue were deparaffinized and the expression of vascular epidermal growth factor (VEGF) receptors (R)-1 and -2, epidermal growth factor receptor (EGFR), Her-2/neu, COX-2, p16, p21 and p53 was immunohistochemically evaluated using tissue microarrays. Associations between molecular marker expression and clinicopathological tumor characteristics were evaluated using the Chi-square test (SPSS) and the survival time was defined. The Kaplan-Meier method was utilized to analyze survival curves, verified by the log-rank test. No molecular markers evaluated were expressed in normal tissue. Tumor expression data included VEGF-R1 (74%), EGFR (52%), Her-2/neu (7.84%), COX-2 (21.5%), p16 (29.4%), p21 (21.7%) and p53 (50%). Tumors expressing VEGF-R1, EGFR and/or p53 were larger (p<0.02), frequently poorly differentiated (p<0.05) and more frequently associated with perineural and lymph node invasion (p<0.05). Marker expression did not correlate with pathological tumor characteristics. The median post-surgery survival was 15 months; 60 and 27% patients survived to 12 and 24 months, respectively, with a longer survival time in patients receiving adjuvant chemotherapy (n=20) (median 36 vs. 15 months, p<0.02). Growth factor receptors, oncogenes and tumor suppressor genes were frequently expressed in pancreatic cancer tissue. VEGF-R1, EGFR and p53 expression were associated with poor tissue differentiation and perineural and lymph node infiltration. Only VEGF-R1 expression was associated with a longer survival time and a more favorable response to adjuvant chemotherapy.
Collapse
Affiliation(s)
- ANTONIO LOZANO-LEON
- Department of Gastroenterology and Foundation for Research in Digestive Diseases, University Hospital Santiago de Compostela, c/Choupana s/n. Santiago de Compostela, Spain
| | | | - JULIO IGLESIAS-GARCÍA
- Department of Gastroenterology and Foundation for Research in Digestive Diseases, University Hospital Santiago de Compostela, c/Choupana s/n. Santiago de Compostela, Spain
| | - JOSE LARIÑO-NOIA
- Department of Gastroenterology and Foundation for Research in Digestive Diseases, University Hospital Santiago de Compostela, c/Choupana s/n. Santiago de Compostela, Spain
| | - EVARISTO VARO
- Department of General Surgery, University Hospital Santiago de Compostela, c/Choupana s/n. Santiago de Compostela, Spain
| | - JERONIMO FORTEZA
- Department of Pathology, University Hospital Santiago de Compostela, c/Choupana s/n. Santiago de Compostela, Spain
| | - J. ENRIQUE DOMÍNGUEZ-MUÑOZ
- Department of Gastroenterology and Foundation for Research in Digestive Diseases, University Hospital Santiago de Compostela, c/Choupana s/n. Santiago de Compostela, Spain
| |
Collapse
|
|
26
|
Chang DT, Chapman CH, Norton JA, Visser B, Fisher GA, Kunz P, Ford JM, Koong AC, Pai RK. Expression of p16INK4A but not hypoxia markers or poly adenosine diphosphate-ribose polymerase is associated with improved survival in patients with pancreatic adenocarcinoma. Cancer 2010; 116:5179-87. [DOI: 10.1002/cncr.25481] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
|
|
27
|
Blackford A, Serrano OK, Wolfgang C, Parmigiani G, Jones S, Zhang X, Parsons DW, Lin JCH, Leary RJ, Eshleman JR, Goggins M, Jaffee EM, Iacobuzio-Donahue CA, Maitra A, Cameron JL, Olino K, Schulick R, Winter J, Herman JM, Laheru D, Vogelstein B, Kinzler KW, Velculescu VE, Hruban RH. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res 2009; 15:4674-9. [PMID: 19584151 PMCID: PMC2819274 DOI: 10.1158/1078-0432.ccr-09-0227] [Citation(s) in RCA: 288] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE Recently, the majority of protein coding genes were sequenced in a collection of pancreatic cancers, providing an unprecedented opportunity to identify genetic markers of prognosis for patients with adenocarcinoma of the pancreas. EXPERIMENTAL DESIGN We previously sequenced more than 750 million base pairs of DNA from 23,219 transcripts in a series of 24 adenocarcinomas of the pancreas. In addition, 39 genes that were mutated in more than one of these 24 cancers were sequenced in a separate panel of 90 well-characterized adenocarcinomas of the pancreas. Of these 114 patients, 89 underwent pancreaticoduodenectomy, and the somatic mutations in these cancers were correlated with patient outcome. RESULTS When adjusted for age, lymph node status, margin status, and tumor size, SMAD4 gene inactivation was significantly associated with shorter overall survival (hazard ratio, 1.92; 95% confidence interval, 1.20-3.05; P = 0.006). Patients with SMAD4 gene inactivation survived a median of 11.5 months, compared with 14.2 months for patients without SMAD4 inactivation. By contrast, mutations in CDKN2A or TP53 or the presence of multiple (> or =4) mutations or homozygous deletions among the 39 most frequently mutated genes were not associated with survival. CONCLUSIONS SMAD4 gene inactivation is associated with poorer prognosis in patients with surgically resected adenocarcinoma of the pancreas.
Collapse
Affiliation(s)
- Amanda Blackford
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Oscar K. Serrano
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Christopher Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Giovanni Parmigiani
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Siân Jones
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Xiaosong Zhang
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - D. Williams Parsons
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Jimmy Cheng-Ho Lin
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Rebecca J. Leary
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - James R. Eshleman
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Michael Goggins
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Elizabeth M. Jaffee
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Christine A. Iacobuzio-Donahue
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Anirban Maitra
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - John L. Cameron
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Kelly Olino
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Richard Schulick
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Jordan Winter
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Joseph M. Herman
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Radiation Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Daniel Laheru
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Bert Vogelstein
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Kenneth W. Kinzler
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Victor E. Velculescu
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| | - Ralph H. Hruban
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD
| |
Collapse
|
|
28
|
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]
|
|
29
|
Abstract
PURPOSE Cell cycle progression is regulated by interactions of specific cyclins and cyclin dependent kinases (CDKs) at the G1-S and G2-M checkpoints and cell cycle deregulation plays a major role in carcinogenesis of human cancers. PATIENTS AND METHODS To investigate the role of cell cycle regulators in the pathogenesis and progression of human gastric cancers, 23 cases of gastric carcinomas were examined for the expression of cyclin B1, p34cdc2, p27(Kip1) and p53 by immunohistochemical methods, and gene expression was correlated with various clinicopathologic findings. RESULTS Out of 23 cases studied, cyclin B1 was diffusely expressed in 20 cases (87.0%), p34cdc2 in 14 cases (60.9%) and p53 in 12 cases (52.2%), whereas in normal gastric tissues, cyclin B1 and p34cdc2 were weakly expressed and p53 was not expressed. In contrast, p27(Kip1) was expressed in only 8.7% of gastric carcinomas compared with 78.3% of normal gastric tissues. There was correlation between the expression of cyclin B1 and expression of p34cdc2 (p=0.002), between the expression of cyclin B1 and loss of p27(Kip1) (p=0.025), and between the expression of p34cdc2 and loss of p27(Kip1) (p=0.065). In addition, expression of cyclin B1 was correlated with regional lymph node metastasis (p=0.032). CONCLUSION Our results indicate that cyclin B1 and p34cdc2 are involved in the genesis or progression of gastric cancers. Furthermore, overexpression of cyclin B1 may play an important role in lymph node metastatic potential of gastric cancer. Thus, abnormal expression of cyclin B1 and CDKs, overexpression of p53 and loss of p27(Kip1) expression may play important roles in human gastric carcinogenesis.
Collapse
Affiliation(s)
- Dong-Hoon Kim
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 108 Pyung-dong, Jongro-gu, Seoul 110-746, Korea.
| |
Collapse
|
|
30
|
Liu T, Gou SM, Wang CY, Wu HS, Xiong JX, Zhou F. Pancreas duodenal homeobox-1 expression and significance in pancreatic cancer. World J Gastroenterol 2007; 13:2615-8. [PMID: 17552012 PMCID: PMC4146825 DOI: 10.3748/wjg.v13.i18.2615] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To study the correlations of Pancreas duodenal homeobox-1 with pancreatic cancer characteristics, including pathological grading, TNM grading, tumor metastasis and tumor cell proliferation.
METHODS: Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to detect PDX-1 mRNA expression in pancreatic cancer tissue and normal pancreatic tissue. The expression of PDX-1 protein was measured by Western blot and immunohistochemistry. Immunohistochemistry was also used to detect proliferative cell nuclear antigen (PCNA). Correlations of PDX-1 with pancreatic cancer characteristics, including pathological grading, TNM grading, tumor metastasis and tumor cell proliferation, were analyzed by using χ2 test.
RESULTS: Immunohistochemistry showed that 41.1% of pancreatic cancers were positive for PDX-1 expression, but normal pancreatic tissue except islets showed no staining for PDX-1. In consistent with the result of imunohistochemistry, Western blot showed that 37.5% of pancreatic cancers were positive for PDX-1. RT-PCR showed that PDX-1 expression was significantly higher in pancreatic cancer tissues than normal pancreatic tissues (2-3.56 ± 0.35vs 2-8.76 ± 0.14, P < 0.01). Lymph node metastasis (P < 0.01), TNM grading (P < 0.05), pathological grading (P < 0.05) and tumor cell proliferation (P < 0.01) were significantly correlated with PDX-1 expression levels.
CONCLUSION: PDX-1 is re-expressed in pancreatic cancer, and PDX-1-positive pancreatic cancer cells show more malignant potential compared to PDX-1-negative cells. Therefore, PDX-1-positive cells may be tumor stem cells and PDX-1 may act as alternate surface marker of pancreatic cancer stem cells.
Collapse
Affiliation(s)
- Tao Liu
- Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | | | | | | | | | | |
Collapse
|
|
31
|
Miranda E, Destro A, Malesci A, Balladore E, Bianchi P, Baryshnikova E, Franchi G, Morenghi E, Laghi L, Gennari L, Roncalli M. Genetic and epigenetic changes in primary metastatic and nonmetastatic colorectal cancer. Br J Cancer 2006; 95:1101-7. [PMID: 16969349 PMCID: PMC2360724 DOI: 10.1038/sj.bjc.6603337] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Colorectal cancer (CRC) develops as multistep process, which involves genetic and epigenetic alterations. K-Ras, p53 and B-Raf mutations and RASSF1A, E-Cadherin and p16INK4A promoter methylation were investigated in 202 CRCs with and without lymph node and/or liver metastasis, to assess whether gene abnormalities are related to a metastogenic phenotype. K-Ras, B-Raf and p53 mutations were detected in 27, 3 and 32% of the cases, with K-Ras mutations significantly associated with metastatic tumour (P=0.019). RASSF1A, E-Cadherin and p16INK4A methylation was documented in 20, 44 and 33% of the cases with p16INK4A significantly associated with metastatic tumours (P=0.001). Overall, out of 202 tumours, 34 (17%) did not show any molecular change, 125 (62%) had one or two and 43 (21%) three or more. Primary but yet metastatic CRCs were prevalent in the latter group (P=0.023) where the most frequent combination was one genetic (K-Ras in particular) and two epigenetic alterations. In conclusion, this analysis provided to detect some molecular differences between primary metastatic and nonmetastatic CRCs, with K-Ras and p16INK4A statistically altered in metastatic tumours; particular gene combinations, such as coincidental K-Ras mutation with two methylated genes are associated to a metastogenic phenotype.
Collapse
Affiliation(s)
- E Miranda
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - A Destro
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - A Malesci
- Departement of Gastroenterology, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - E Balladore
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - P Bianchi
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - E Baryshnikova
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - G Franchi
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - E Morenghi
- Clinical Trial Office, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - L Laghi
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
- Departement of Gastroenterology, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - L Gennari
- Departement of Surgery, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
| | - M Roncalli
- Molecular Genetics Laboratory, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
- Departement of Pathology, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy
- Departement of Pathology, Istituto Clinico Humanitas, University of Milan, Via Manzoni 56, Rozzano, Milano 20089, Italy; E-mail:
| |
Collapse
|
|
32
|
Li Q, Gao SL, Cui LJ, Li MQ. Expression of COX-2 and P16 protein and their correlations in various types of gastric polyps and gastric cancer cell. Shijie Huaren Xiaohua Zazhi 2005; 13:2506-2509. [DOI: 10.11569/wcjd.v13.i20.2506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the expression of COX-2 and P16 in various types of gastric polyps and gastric cancer cell, and to investigate the relationship between COX-2 and P16 protein in the process of gastric cancer.
METHODS: The expression of COX-2 and P16 proteins were detected in normal gastric mucosa (n = 10), non-tumor gastric polyps (n = 30, inflammatory polyps and hyperplastic polyps), tumor gastric polyps (n = 20, adenomatous polyps), and gastric cancer (n = 40) by S-P immunohistochemical staining.
RESULTS: In the normal gastric mucosa, non-tumor gastric polyps, tumor gastric polyps, and gastric cancer cell, the expression rate of the COX-2 was 10%, 13.33%, 45%, and 75%, respectively; and the rate of P16 protein expression in those tissues was 90%, 86.67%, 60%, and 32.5%, respectively. The positive rates of COX-2 and P16 protein were both significantly different between gastric cancer and other tissues (P <0.05). The expression of COX-2 and P16 were associated with the differentiation degree of gastric cancer and lymph node metastasis. COX-2 expression was negatively related to P16 expression in gastric cancer (P <0.05).
CONCLUSION: COX-2 and P16 protein play key roles in the development of gastric cancer, and can be used as important indexes in the research of the biological behavior of gastric cancer.
Collapse
|
|
33
|
Goldbach-Mansky R, Suson S, Wesley R, Hack CE, El-Gabalawy HS, Tak PP. Raised granzyme B levels are associated with erosions in patients with early rheumatoid factor positive rheumatoid arthritis. Ann Rheum Dis 2005; 64:715-21. [PMID: 15471892 PMCID: PMC1755472 DOI: 10.1136/ard.2003.007039] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Raised granzyme B in serum and synovium of patients with rheumatoid arthritis suggests a role for cytotoxic T cells and natural killer cells in the pathogenesis of this disease. OBJECTIVE To evaluate serum granzyme B in patients with early arthritis and correlate it with specific diagnosis and clinical indices of disease severity. METHODS 257 patients with inflammatory arthritis for less than one year (46% rheumatoid arthritis, 17% spondyloarthropathy, 37% undifferentiated arthritis) had a prospective clinical, serological, and radiographic evaluation. Granzyme B was measured in initial sera by ELISA. Patients were HLA typed for DR alleles using sequence specific primers. A logistic regression model was used to evaluate the potential prognostic value of serum granzyme B in predicting radiographic erosions after one year of follow up. RESULTS Granzyme B values were similar in rheumatoid arthritis, spondyloarthropathy, and undifferentiated arthritis. Concentrations were higher in rheumatoid factor (RF) positive patients than in RF negative patients (mean (SD): 3.15 (0.92) v 2.89 (0.71) pg/ml; p<0.05). After one year, erosions were present in 30% of patients in the overall cohort, and in 44% of patients with rheumatoid arthritis. In the entire cohort, serum granzyme B did not predict erosions independently. However, high granzyme B was an independent predictor of early erosions in patients with RF positive rheumatoid arthritis (odds ratio = 4.83 (95% confidence interval, 1.13 to 20.59)) (p<0.05). CONCLUSIONS Granzyme B may be a useful prognostic marker in early rheumatoid arthritis and may provide important clues to the pathogenesis of this disease.
Collapse
Affiliation(s)
- R Goldbach-Mansky
- Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeltal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | | | | | | | | | | |
Collapse
|