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Khan AA, Liu X, Yan X, Tahir M, Ali S, Huang H. An overview of genetic mutations and epigenetic signatures in the course of pancreatic cancer progression. Cancer Metastasis Rev 2021; 40:245-272. [PMID: 33423164 DOI: 10.1007/s10555-020-09952-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/23/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer (PC) is assumed to be an intimidating and deadly malignancy due to being the leading cause of cancer-led mortality, predominantly affecting males of older age. The overall (5 years) survival rate of PC is less than 9% and is anticipated to be aggravated in the future due to the lack of molecular acquaintance and diagnostic tools for its early detection. Multiple factors are involved in the course of PC development, including genetics, cigarette smoking, alcohol, family history, and aberrant epigenetic signatures of the epigenome. In this review, we will mainly focus on the genetic mutations and epigenetic signature of PC. Multiple tumor suppressor and oncogene mutations are involved in PC initiation, including K-RAS, p53, CDKN2A, and SMAD4. The mutational frequency of these genes ranges from 50 to 98% in PC. The nature of mutation diagnosis is mostly homozygous deletion, point mutation, and aberrant methylation. In addition to genetic modification, epigenetic alterations particularly aberrant hypermethylation and hypomethylation also predispose patients to PC. Hypermethylation is mostly involved in the downregulation of tumor suppressor genes and leads to PC, while multiple genes also represent a hypomethylation status in PC. Several renewable drugs and detection tools have been developed to cope with this aggressive malady, but all are futile, and surgical resection remains the only choice for prolonged survival if diagnosed before metastasis. However, the available therapeutic development is insufficient to cure PC. Therefore, novel approaches are a prerequisite to elucidating the genetic and epigenetic mechanisms underlying PC progression for healthier lifelong survival.
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Affiliation(s)
- Aamir Ali Khan
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China
| | - Xinhui Liu
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China
| | - Xinlong Yan
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China.
| | - Muhammad Tahir
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China
| | - Sakhawat Ali
- College of Life Science, Beijing Institute of Technology, 5 South Zhongguancun Street, Haidian District, Beijing, 100081, China
| | - Hua Huang
- College of Life Science and Bioengineering, Beijing University of Technology, 100 Ping Le Yuan, Chaoyang, Beijing, 100124, China.
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Natale F, Vivo M, Falco G, Angrisano T. Deciphering DNA methylation signatures of pancreatic cancer and pancreatitis. Clin Epigenetics 2019; 11:132. [PMID: 31492175 PMCID: PMC6729090 DOI: 10.1186/s13148-019-0728-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 08/16/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Chronic pancreatitis presents a high risk of inflammation-related progression to pancreatic cancer. Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The high mortality rate is directly related to the difficulty in promptly diagnosing the disease, which often presents as overt and advanced. Hence, early diagnosis for pancreatic cancer becomes crucial, propelling research into the molecular and epigenetic landscape of the disease. MAIN BODY Recent studies have shown that cell-free DNA methylation profiles from inflammatory diseases or cancer can vary, thus opening a new venue for the development of biomarkers for early diagnosis. In particular, cell-free DNA methylation could be employed in the identification of pre-neoplastic signatures in individuals with suspected pancreatic conditions, representing a specific and non-invasive method of early diagnosis of pancreatic cancer. In this review, we describe the molecular determinants of pancreatic cancer and how these are related to chronic pancreatitis. We will then present an overview of differential methylated genes in the two conditions, highlighting their diagnostic or prognostic potential. CONCLUSION Exploiting the relation between abnormally methylated cell-free DNA and pre-neoplastic lesions or chronic pancreatitis may become a game-changing approach for the development of tools for the early diagnosis of pancreatic cancer.
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Affiliation(s)
- Francesco Natale
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
| | - Maria Vivo
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.,Biogem Scarl, Istituto di Ricerche Genetiche "Gaetano Salvatore", 83031, Ariano Irpino, Italy
| | - Tiziana Angrisano
- Department of Biology, University of Naples Federico II, 80126, Naples, Italy.
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Martinelli P, Real FX. Animal Modeling of Pancreatitis-to-Cancer Progression. PANCREATIC CANCER 2018:313-347. [DOI: 10.1007/978-1-4939-7193-0_66] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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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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Rebours V, Gaujoux S, d'Assignies G, Sauvanet A, Ruszniewski P, Lévy P, Paradis V, Bedossa P, Couvelard A. Obesity and Fatty Pancreatic Infiltration Are Risk Factors for Pancreatic Precancerous Lesions (PanIN). Clin Cancer Res 2015; 21:3522-8. [PMID: 25700304 DOI: 10.1158/1078-0432.ccr-14-2385] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 01/21/2015] [Indexed: 12/14/2022]
Abstract
PURPOSE The roles of intravisceral and subcutaneous fat are unknown, and the prevalence of precancerous lesions in obese patients was never evaluated. This study aims to assess the frequency and severity of pancreatic intraepithelial neoplasia (PanIN) and to correlate pathologic findings with metabolic abnormalities, type of fat, and fatty pancreatic infiltration. EXPERIMENTAL DESIGN Normal pancreatic tissue from surgical specimens was analyzed. Fatty infiltration and fibrosis in intra- and extralobular locations and PanIN lesions were assessed. General characteristics were collected: body mass index (BMI), diabetes, and tobacco intake. Liver steatosis and subcutaneous and intravisceral fat were assessed by CT scan (ImageJ software). RESULTS Of note, 110 patients were included [median age, 53.8 (17-85) years]. Arterial hypertension, diabetes, and tobacco intake were found in 19%, 9%, and 23%, respectively. Median BMI was 24 (16-37; BMI < 25: 45%, 25 ≤ 30: 24%, ≥30: 11%). Overall, PanIN lesions were found in 65% (type I, II, and III PanIN in 62%, 38%, and 1%, respectively). Fibrosis and fatty pancreas (intra- and extralobular locations) were found in 1% and 24% and in 30% and 51%, respectively. A correlation was observed between PanIN lesions and fatty pancreas [extralobular (0.01) and intralobular (<0.0001)], intralobular fibrosis (0.003), high BMI (P = 0.02), and subcutaneous (P = 0.02) and intravisceral fat (P = 0.02). The number of PanIN lesions was correlated with intravisceral fat (r = 0.22, P = 0.04), but not with subcutaneous fat (r = 0.14, P = 0.22). In multivariate analysis, PanIN lesions were associated with intralobular fibrosis [OR, 5.61; 95% confidence interval (CI), 1.18-42.99] and intralobular fat (OR, 17.86; 95% CI, 4.935-88.12). CONCLUSIONS Obesity (especially android obesity) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions.
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Affiliation(s)
- Vinciane Rebours
- Pancreatology Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France. Inserm U773-CRB3, DHU Unity, Paris-Diderot University, Paris, France.
| | - Sébastien Gaujoux
- Inserm U773-CRB3, DHU Unity, Paris-Diderot University, Paris, France. Pancreatic Surgery Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France
| | - Gaspard d'Assignies
- Radiology Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France
| | - Alain Sauvanet
- Pancreatic Surgery Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France
| | - Philippe Ruszniewski
- Pancreatology Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France. Inserm U773-CRB3, DHU Unity, Paris-Diderot University, Paris, France
| | - Philippe Lévy
- Pancreatology Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France
| | - Valérie Paradis
- Inserm U773-CRB3, DHU Unity, Paris-Diderot University, Paris, France. Pathology Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France
| | - Pierre Bedossa
- Inserm U773-CRB3, DHU Unity, Paris-Diderot University, Paris, France. Pathology Department, Beaujon Hospital, DHU Unity, AP-HP, Clichy, Paris-Diderot University, Paris, France
| | - Anne Couvelard
- Inserm U773-CRB3, DHU Unity, Paris-Diderot University, Paris, France. Pathology Department, Bichat Hospital, DHU Unity, AP-HP, Paris-Diderot University, Paris, France
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Herreros-Villanueva M, Gironella M, Castells A, Bujanda L. Molecular markers in pancreatic cancer diagnosis. Clin Chim Acta 2013; 418:22-29. [PMID: 23305796 DOI: 10.1016/j.cca.2012.12.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Revised: 12/11/2012] [Accepted: 12/17/2012] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) represents a fatal neoplasia with a high mortality rate. Effective early detection methods are needed since this is the best way to cure this disease. During the last several years, many investigations focused on determining relevant biomarkers that may be present during early stages of pancreatic tumor development. Although several biomarkers have been proposed for pancreatic cancer detection, the clinical applicability has been confusing. Currently, although CA19-9 is one test used, the sensitivity and specificity for the disease are less than optimal. Here, we review several new potential serum, plasma and stool markers that are currently under evaluation. Although these have not been sufficiently validated for routine clinical use, these markers could prove valuable with further investigations. We keep the hope that a combination of some of these novel biomarkers can be a useful tool for early PDAC diagnosis before image techniques and/or patient's symptoms reveal disease in an incurable state.
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Affiliation(s)
- Marta Herreros-Villanueva
- Department of Gastroenterology, Hospital Donostia/Instituto Biodonostia, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco UPV/EHU, San Sebastián, Spain
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Park JW, Baek IH, Kim YT. Preliminary study analyzing the methylated genes in the plasma of patients with pancreatic cancer. Scand J Surg 2012; 101:38-44. [PMID: 22414467 DOI: 10.1177/145749691210100108] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND AIMS CpG islands of the promoter region of some genes are methylated in pancreatic cancer tissue and the detection of this methylation has been suggested to be useful in the diagnosis of various cancers. The aim of this study was to investigate whether the detection of methylated CpG islands in plasma can be used in the diagnosis of pancreatic cancer. MATERIAL AND METHODS Plasma DNA was collected from patients with pancreatic cancer, chronic pancreatitis, and healthy controls. The methylation status of six genes, UCHL1, NPTX2, SARP2, ppENK, p16, and RASSF1A, was checked by methylation-specific PCR and was subsequently confirmed by direct sequencing after bisulfite treatment. RESULTS CpG island methylation was detectable in 13 of 16 patients (81.3%) with pancreatic cancer, 1 of 29 healthy controls (3.5%), and 8 of 13 patients with chronic pancreatitis (61.5%). The mean number of genes with CpG island methylation was 1.6±1.2 in pancreatic cancer, 0.04±0.19 in healthy controls, and 1.2±1.1 in chronic pancreatitis. Among six genes, p16 was more specifically methylated in pancreatic cancer compared with chronic pancreatitis (p=0.016). The methylation status was not correlated with smoking history, tumor size, or cancer stage. CONCLUSIONS The detection of methylated genes in the plasma may have a role in differentiating between pancreatic cancers and healthy controls but not between pancreatic cancer and chronic pancreatitis.
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Affiliation(s)
- J W Park
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Anyang, Korea
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Rebours V, Lévy P, Ruszniewski P. An overview of hereditary pancreatitis. Dig Liver Dis 2012; 44:8-15. [PMID: 21907651 DOI: 10.1016/j.dld.2011.08.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2011] [Accepted: 08/05/2011] [Indexed: 12/11/2022]
Abstract
Hereditary pancreatitis is a rare cause of chronic pancreatitis. The prevalence was evaluated to 0.3/100000 in Western Countries. Genetic disorders are due to mutations of the PRSS1 gene on the long arm of the chromosome 7, encoding for the cationic trypsinogen. The inheritance pattern is autosomal dominant with an incomplete penetrance (80%). Since 1996, more than 30 mutations were found. The three more common mutations are R122H, N29I and A16V. First symptoms begin since childhood, mainly before 10 years old. Main symptoms are pancreatic pain and acute pancreatitis (>70%). CP morphological changes as pancreatic calcifications are diagnosed at a median age of 22-25 years. Exocrine and endocrine pancreatic insufficiency occurred in 34% and 26% at a median age of 29 and 38 years. No clinical differences exist according to the mutation type. No excess of mortality in hereditary pancreatitis population compared to general population was found, despite a real risk of cancer. The cumulative risks of pancreatic cancer at 50, 60 and, 75 years are 10%, 18.7% and, 53.5%, respectively. The relative risk of cancer increases in smokers and is evaluated to 8.55. Hereditary pancreatitis diagnosis permits to propose an adapted management in expert centres.
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Affiliation(s)
- Vinciane Rebours
- Pôle des Maladies de l'Appareil Digestif, Service de Gastroentérologie - Pancréatologie, Hôpital Beaujon, AP-HP, Université Denis Diderot-Paris VII, Clichy, France.
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Farris AB, Basturk O, Adsay NV. Pancreatitis, Other Inflammatory Lesions, and Pancreatic Pseudotumors. Surg Pathol Clin 2011; 4:625-650. [PMID: 26837491 DOI: 10.1016/j.path.2011.03.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
The pancreas is versatile in the diversity of disorders that it can exhibit. In this article, characteristics of disorders such as chronic, autoimmune, eosinophilic, hereditary, and infectious pancreatitis are described. With regard to autoimmune pancreatitis, the role of clinical evaluation, histologic examination, and IgG4 immunohistochemistry is discussed. The role of pancreatitis in the pathogenesis of diabetes is also mentioned. Some implications of pancreatitis are highlighted, including the neoplastic predisposition caused by inflammatory lesions of the pancreas. The goal of this article is to convey an appreciation of these disorders because their recognition can benefit patients tremendously, as inflammatory lesions of the pancreas can be mass-forming, giving rise to pseudotumors, and leading to surgical resection that may otherwise be unnecessary.
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Affiliation(s)
- Alton B Farris
- Department of Pathology and Laboratory Medicine, Emory University Hospital, Emory University, 1364 Clifton Road Northeast, Room H-188, Atlanta, GA 30322, USA.
| | - Olca Basturk
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - N Volkan Adsay
- Department of Pathology and Laboratory Medicine, Emory University, 1364 Clifton Road NE, Room H-180B, Atlanta, GA 30322, USA
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Genomic instability at both the base pair level and the chromosomal level is detectable in earliest PanIN lesions in tissues of chronic pancreatitis. Pancreas 2010; 39:1093-103. [PMID: 20531246 DOI: 10.1097/mpa.0b013e3181dc62f6] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE Chronic pancreatitis (CP) is a predisposing disease for pancreatic carcinoma (PC), however, precise molecular mechanisms of cancer development in the background of CP are ill defined. METHODS A total of 443 laser-microdissected pancreatic intraepithelial neoplasias (PanINs), acinar-ductal metaplasia (ADM), and normal ducts from 21 patients with CP were analyzed for loss of heterozygosity (LOH) and immunohistochemical protein expression of p53, p16, and DPC4. Pancreatic intraepithelial neoplasias were analyzed for mutations in p53, p16, and Ki-ras genes by ABI sequencing. Aneuploidy was determined by fluorescence in situ hybridization with probes for chromosomes 3, 7, 8, and 17. RESULTS Loss of heterozygosity rate in PanIN-1 and ADM was between 1.7% (p53) and 5.8% (p16). In PanIN-3, p53 protein overexpression and loss of expression for p16 and DPC4 protein were seen. Heterozygous mutations of p53 and p16 without LOH were found in PanIN-1A and ADM, whereas homozygous mutations were found in PanIN-3. Aneuploidy increased from PanIN-1A to PanIN-3. Ki-ras mutations were discovered first in PanIN-1. CONCLUSIONS Heterozygous mutations of p53- and p16 genes together with chromosomal instability occur early in CP and are clonally expanded, but final inactivation mostly by LOH happens later in pancreatic carcinogenesis. Determination of aneuploidy in pancreatic juice may be of value for early detection and risk assessment in patients with long-standing CP.
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Deer EL, González-Hernández J, Coursen JD, Shea JE, Ngatia J, Scaife CL, Firpo MA, Mulvihill SJ. Phenotype and genotype of pancreatic cancer cell lines. Pancreas 2010; 39:425-35. [PMID: 20418756 PMCID: PMC2860631 DOI: 10.1097/mpa.0b013e3181c15963] [Citation(s) in RCA: 720] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The dismal prognosis of pancreatic adenocarcinoma is due in part to a lack of molecular information regarding disease development. Established cell lines remain a useful tool for investigating these molecular events. Here we present a review of available information on commonly used pancreatic adenocarcinoma cell lines as a resource to help investigators select the cell lines most appropriate for their particular research needs. Information on clinical history; in vitro and in vivo growth characteristics; phenotypic characteristics, such as adhesion, invasion, migration, and tumorigenesis; and genotypic status of commonly altered genes (KRAS, p53, p16, and SMAD4) was evaluated. Identification of both consensus and discrepant information in the literature suggests careful evaluation before selection of cell lines and attention be given to cell line authentication.
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Affiliation(s)
- Emily L Deer
- Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
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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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Mu DQ, Peng YS, Xu QJ. Values of mutations of K-ras oncogene at codon 12 in detection of pancreatic cancer: 15-year experience. World J Gastroenterol 2004; 10:471-5. [PMID: 14966900 PMCID: PMC4716963 DOI: 10.3748/wjg.v10.i4.471] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [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 summarize progress in the study of K-ras gene studies in pancreatic cancer and its potential clinical significance in screening test for early detection of pancreatic cancer, and to differentiate pancreatic cancer from chronic pancreatitis in recent decade.
METHODS: Literature search (MEDLINE 1986-2003) was performed using the key words K-ras gene, pancreatic cancer, chronic pancreatitis, and diagnosis. Two kind of opposite points of view on the significance of K-ras gene in detection early pancreatic cancer and differentiation pancreatic cancer from chronic pancreatitis were investigated. The presence of a K-ras gene mutation at codon 12 has been seen in 75% - 100% of pancreatic cancers, and is not rare in patients with chronic pancreatitis, and represents an increased risk of developing pancreatic cancer. However, the significance of the detection of this mutation in specimens obtained by needle aspiration from pure pancreatic juice and from stools for its utilization for the detection of early pancreatic cancer, and differentiation pancreatic cancer from chronic pancreatitis remains controversial.
CONCLUSION: The value of K-ras gene mutation for the detection of early pancreatic cancer and differentiation pancreatic cancer from chronic pancreatitis remains uncertains in clinical pratice. Nevertheless, K-ras mutation screening may increase the sensitivity of FNA and ERP cytology and may be useful in identifying pancreatitis patients at high risk for developing cancer, and as a adjunct with cytology to differentiate pancreatic cancer from chronic pancreatitis.
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Affiliation(s)
- De-Qing Mu
- Department of Surgery of the Second Affiliated Hospital, Medical College of Zhejiang University, Hangzhou 310009, Zhejiang Province, China.
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House MG, Wistuba II, Argani P, Guo M, Schulick RD, Hruban RH, Herman JG, Maitra A. Progression of gene hypermethylation in gallstone disease leading to gallbladder cancer. Ann Surg Oncol 2004; 10:882-9. [PMID: 14527906 DOI: 10.1245/aso.2003.02.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
BACKGROUND Aberrant methylation of tumor-suppressor genes is associated with a loss of gene function that can afford selective growth advantages to sporadic neoplastic cells arising during gallbladder inflammation. METHODS Fifty-four gallbladder neoplasms were selected from tumor banks in the United States and Chile. Each of the neoplasms was subjected to methylation-specific polymerase chain reaction to detect promoter methylation associated with six candidate tumor-suppressor genes (p16, APC, methylguanine methyltransferase, hMLH1, retinoic acid receptor beta-2, and p73) implicated in multiple human cancer types. RESULTS Aberrant methylation of any of the six candidate tumor-suppressor genes was detected in 72% of the gallbladder neoplasms, 28% of the cases of chronic cholecystitis, and in only 1 of the 15 normal gallbladder controls. The four most commonly methylated genes in the gallbladder cancers were p16 (56%), p73 (28%), APC (27%), and hMLH1 (14%). Significant differences in gene methylation were discovered between US gallbladder cancers and those from Chile, where gallbladder cancer is one of the leading causes of cancer-related deaths. APC methylation was present in 42% of the US cases but in only 14% of the Chilean tumors (P =.028). p73 methylation was common among the Chilean cancers (40%) compared with those from the United States (13%; P =.034). CONCLUSIONS The acquisition of hypermethylation at multiple tumor-suppressor gene-promoter sites may contribute to tumor formation and progression within the chronically inflamed gallbladder. The apparent differences in methylation patterns among the Chilean and US gallbladder cases may indicate a unique biology associated with this cancer in different parts of the world.
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Affiliation(s)
- Michael G House
- Department of Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231-1000, USA.
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Rosty C, Geradts J, Sato N, Wilentz RE, Roberts H, Sohn T, Cameron JL, Yeo CJ, Hruban RH, Goggins M. p16 Inactivation in pancreatic intraepithelial neoplasias (PanINs) arising in patients with chronic pancreatitis. Am J Surg Pathol 2004; 27:1495-501. [PMID: 14657708 DOI: 10.1097/00000478-200312000-00001] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Patients with long-standing chronic pancreatitis are thought to be at increased risk of developing pancreatic ductal adenocarcinoma, but the mechanism for this increased risk is unknown. Since increasing evidence supports the notion that infiltrating pancreatic ductal adenocarcinomas arise from pancreatic intraepithelial lesions (PanINs), we sought to determine if patients with chronic pancreatitis harbor PanINs with alterations in tumor suppressor genes that are associated with infiltrating pancreatic ductal adenocarcinoma. We identified 122 patients with a diagnosis of chronic pancreatitis and 29 patients with a well-differentiated pancreatic endocrine tumor that underwent pancreatic surgery at the Johns Hopkins Hospital from 1985 to 1999. PanINs from each resection specimen were identified, graded, counted, and correlated with smoking and alcohol history. The expression patterns of p16 and Smad4 were determined in a subset of PanINs by immunohistochemistry, and the pattern of labeling compared with that seen in PanINs associated with infiltrating adenocarcinoma of the pancreas as identified in prior studies, and to PanINs associated with pancreatic endocrine tumor. Duct lesions were present in 80 of the 122 pancreata with chronic pancreatitis (66%). Of 405 duct lesions identified in the chronic pancreatitis group, 7.6% were reactive changes, 65.5% were PanIN-1A, 18% were PanIN-1B, 7.4% were PanIN-2, and 1.5% were PanIN-3. Within the pancreatic endocrine tumor group, 22 PanINs were identified: 15 PanIN-1A, 4 PanIN-1B, and 3 PanIN-2. There were significantly fewer high-grade PanINs in the pancreata with chronic pancreatitis than in pancreata with pancreatic adenocarcinoma (P < 0.0001). Within the chronic pancreatitis group, the 80 patients with PanINs were significantly older than the 42 patients without PanINs (mean age 57.0 +/- 14.1 years vs. 50.9 +/- 14.7 years, P = 0.01). Smoking history was not associated with PanIN prevalence or grade, but patients who reported a history of excessive alcohol consumption had fewer PanINs (25 of 44 harbored PanINs, 57%) than those who did not (54 of 74, 73%, P = 0.07). In the chronic pancreatitis group, 0% of PanIN-1A, 11% of the PanIN-1B, 16% of the PanIN-2, and 40% of the PanIN-3 lesions showed loss of p16 expression, whereas all of the PanINs from patients with an pancreatic endocrine tumor retained p16 expression. All of the PanINs analyzed from patients with chronic pancreatitis retained normal Smad4 expression. We conclude that a significant minority of PanINs arising in patients with chronic pancreatitis show loss of p16 expression. This alteration, common to pancreatic cancer-associated PanINs, may contribute to the predisposition of patients with chronic pancreatitis to develop pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Christophe Rosty
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA
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Heinmöller E, Bockholt A, Werther M, Ziemer M, Müller A, Ghadimi BM, Rüschoff J. Laser microdissection of small tissue samples--application to chronic pancreatitis tissues. Pathol Res Pract 2003; 199:363-71. [PMID: 12924436 DOI: 10.1078/0344-0338-00432] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Laser microdissection is considered to be the gold standard of tissue sampling, especially if a defined small tissue area consisting of single or few cells within a heterogeneous tissue compartment is of interest. This sophisticated technique offers the opportunity of rapid and contamination-free tissue sampling for RNA- or DNA-based molecular genetic studies. We have applied laser microdissection to a molecular genetic study of pancreatic intraductal lesions (PanINs) in tissues of chronic pancreatitis, where an exact microdissection of small ducts within a dense fibrous tissue is of paramount importance for following analysis. From nine patients suffering from chronic pancreatitis, formalin-fixed, paraffin-embedded tissue specimens were laser microdissected, and a total of 202 normal ducts and PanINs of grade PanIN-1A to grade PanIN-2 were harvested. After whole genome amplification by improved primer extension and preamplification PCR (I-PEP-PCR), microsatellite-PCR based loss of heterozygosity analysis (LOH) of the tumor suppressor gene loci TP53, p16INK4, and DPC4 was performed. One of 85 informative duct lesions (1.2%) had LOH of TP53, 1 of 76 duct lesions (1.3%) had LOH of DPC4, and 2/29 duct lesions (6.9%) showed LOH of p16INK4. Microsatellite instability (MSI) was seen in 2 of 178 duct lesions (1.1%). Immunohistochemical staining of p53 protein and DPC4 protein revealed no aberrant expression. These preliminary data indicate that LOH of tumor suppressor genes, important in pancreatic cancer genesis or MSI, can be found in chronic pancreatitis tissues, but their incidence is low.
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Pancreatitis as a risk for pancreatic cancer. Hematol Oncol Clin North Am 2003. [DOI: 10.1016/s0889-8588(03)00017-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
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18
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Wong T, Howes N, Threadgold J, Smart HL, Lombard MG, Gilmore I, Sutton R, Greenhalf W, Ellis I, Neoptolemos JP. Molecular diagnosis of early pancreatic ductal adenocarcinoma in high-risk patients. Pancreatology 2002; 1:486-509. [PMID: 12120229 DOI: 10.1159/000055852] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The prevalence of pancreatic cancer in the general population is too low--even in high-prevalence areas such as Northern Europe and North America (8-12 per 10(5) population)--relative to the diagnostic accuracy of present detection methods to permit primary screening in the asymptomatic adult population. The recognition that the lifetime risk of developing pancreatic cancer for patients with hereditary pancreatitis (HP) is extremely high (20% by the age of 60 years and 40% by the age of 70 years) poses considerable challenges and opportunities for secondary screening in those patients without any clinical features of pancreatic cancer. Even for secondary screening, the detection of cancer at a biological stage that would be amenable to cure by surgery (total pancreatectomy) still requires diagnostic modalities with a very high sensitivity and specificity. Conventional radiological imaging methods such as endoluminal ultrasound and endoscopic retrograde pancreatography, which have proved to be valuable in the early detection of early neoplastic lesions in patients with familial pancreatic cancer, may well be applicable to patients with HP but only in those without gross morphological features of chronic pancreatitis (other than parenchymal atrophy). Unfortunately, most cases of HP also have associated gross features of chronic pancreatitis that are likely to seriously undermine the diagnostic value of these conventional imaging modalities. Pre-malignant molecular changes can be detected in the pancreatic juice of patients. Thus, the application of molecular screening in patients with HP is potentially the most powerful method of detection of early pancreatic cancer. Although mutant (mt) K-ras can be detected in the pancreatic juice of most patients with pancreatic cancer, it is also present in patients with non-inherited chronic pancreatitis who do not progress to pancreatic cancer (at least in the short to medium term), as well as increasingly in the older population without pancreatic disease. Nevertheless, the presence of mt-K-ras may identify a genuinely higher-risk group, enabling additional diagnostic imaging and molecular resources to be focussed on such a group. What is clear is that prospective multi-centre studies, such as that being pursued by the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), are essential for the development of an effective secondary screening programme for these patients.
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MESH Headings
- Biomarkers, Tumor
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/diagnostic imaging
- Carcinoma, Ductal, Breast/etiology
- Carcinoma, Ductal, Breast/genetics
- DNA, Neoplasm/genetics
- Europe
- Genetic Testing
- Humans
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/diagnostic imaging
- Pancreatic Neoplasms/etiology
- Pancreatic Neoplasms/genetics
- Radiography
- Risk Factors
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Affiliation(s)
- T Wong
- Department of Surgery, University of Liverpool, UK
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Abstract
Chronic pancreatitis clearly predisposes to pancreatic cancer, with early onset-long duration chronic pancreatitis from cystic fibrosis, TP, and HP conferring the highest risk. Chronic pancreatitis is not a critical step, however, but rather one of several conditions that accelerate the accumulation of critical genetic mutations and chromosomal losses necessary for carcinogenesis. Indeed, other germline mutations, environmental factors such as tobacco smoking and alcohol consumption, or dietary factors may also accelerate the pathway to carcinogenesis, and may be synergistic with the conditions created by chronic pancreatitis. Because patients with chronic pancreatitis are at high risk of pancreatic cancer, the physician is faced with decisions on how to manage this risk. Discontinuing smoking and alcohol consumption, and perhaps dietary modification are obvious recommendations for risk reduction. If, however, the patient is older and already in a very high-risk category (e.g., long-standing HP), then screening for cancers must be considered. Inclusion in multicenter trials is recommended, and information on ongoing studies can be obtained through the office of Dr. Whitcomb, or as posted on www.pancreas.org.
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Affiliation(s)
- David C Whitcomb
- Department of Medicine, University of Pittsburgh, UPMC Presbyterian, Mezzanine Level, C Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA.
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Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 160:1573-81. [PMID: 12000709 PMCID: PMC1850889 DOI: 10.1016/s0002-9440(10)61104-2] [Citation(s) in RCA: 167] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3, 15 invasive ductal adenocarcinomas, and 6 miscellaneous pancreatic neoplasms) were microdissected from 29 formalin-fixed paraffin-embedded surgically resected pancreata, and were analyzed by methylation-specific polymerase chain reaction. Fourteen of 15 (93.3%) invasive pancreatic ductal adenocarcinomas showed methylation of the ppENK gene and 4 of 15 (26.7%) showed methylation of the p16 gene. Nonneoplastic pancreatic epithelia did not harbor methylation of either gene. The prevalence of methylation of the ppENK gene increased significantly with increasing PanIN grade. A similar nonsignificant trend was noted for p16 methylation. Aberrant methylation of the ppENK gene was found in 7.7% of PanIN-1A, 7.3% of PanIN-1B, 22.7% of PanIN-2, and 46.2% of PanIN-3. Aberrant methylation of the p16 gene was found in 12% of PanIN-1A, 2.6% of PanIN-1B, 4.5% of PanIN-2, and 21.4% of PanIN-3. All but one of the PanINs from the 14 pancreata without pancreatic carcinoma was unmethylated with respect to either the p16 or ppENK gene. Our results suggest that methylation-related inactivation of the ppENK and p16 genes is an intermediate or late event during pancreatic carcinogenesis. Because aberrant methylation of ppENK or p16 was more often detected in similar grade PanINs from patients with pancreatic carcinoma than in those with other pancreatic diseases, it may be a useful indicator of the potential malignancy of epithelial cells of the pancreas.
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Affiliation(s)
- Noriyoshi Fukushima
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA
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