|
1
|
Moretti M, Farina A, Angeloni A, Anastasi E. Emerging horizons on molecular and circulating biomarkers in pancreatic adenocarcinoma. Front Oncol 2024; 14:1483306. [PMID: 39575418 PMCID: PMC11578827 DOI: 10.3389/fonc.2024.1483306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 10/17/2024] [Indexed: 11/24/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer and is expected to soon become the second leading cause of cancer-associated death. The high mortality rate is due to the clinical features that allow asymptomatic progression to advanced stages, a period when current therapeutic treatments have limited efficacy. To address these challenges, researchers are focused on identifying new molecular and circulating markers for early PDAC detection and precision medicine. In this mini-review, we report the most well-known and recently identified molecular and circulating biomarkers. This study aimed to emphasize the need for continued innovative research to develop diagnostic algorithms and therapies to improve the management of patients with PDAC.
Collapse
Affiliation(s)
| | | | | | - Emanuela Anastasi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| |
Collapse
|
|
2
|
Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma. Int J Mol Sci 2021; 22:ijms221910219. [PMID: 34638560 PMCID: PMC8508406 DOI: 10.3390/ijms221910219] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 09/18/2021] [Accepted: 09/20/2021] [Indexed: 12/11/2022] Open
Abstract
The most frequent mutated oncogene family in the history of human cancer is the RAS gene family, including NRAS, HRAS, and, most importantly, KRAS. A hallmark of pancreatic cancer, recalcitrant cancer with a very low survival rate, is the prevalence of oncogenic mutations in the KRAS gene. Due to this fact, studying the function of KRAS and the impact of its mutations on the tumor microenvironment (TME) is a priority for understanding pancreatic cancer progression and designing novel therapeutic strategies for the treatment of the dismal disease. Despite some recent enlightening studies, there is still a wide gap in our knowledge regarding the impact of KRAS mutations on different components of the pancreatic TME. In this review, we will present an updated summary of mutant KRAS role in the initiation, progression, and modulation of the TME of pancreatic ductal adenocarcinoma (PDAC). This review will highlight the intriguing link between diabetes mellitus and PDAC, as well as vitamin D as an adjuvant effective therapy via TME modulation of PDAC. We will also discuss different ongoing clinical trials that use KRAS oncogene signaling network as therapeutic targets.
Collapse
|
|
3
|
Visani M, Acquaviva G, De Leo A, Sanza V, Merlo L, Maloberti T, Brandes AA, Franceschi E, Di Battista M, Masetti M, Jovine E, Fiorino S, Pession A, Tallini G, de Biase D. Molecular alterations in pancreatic tumors. World J Gastroenterol 2021; 27:2710-2726. [PMID: 34135550 PMCID: PMC8173386 DOI: 10.3748/wjg.v27.i21.2710] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2021] [Revised: 02/25/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Genetic alterations in pancreatic tumors can usually be classified in: (1) Mutational activation of oncogenes; (2) Inactivation of tumor suppressor genes; and (3) Inactivation of genome maintenance genes controlling the repair of DNA damage. Endoscopic ultrasound-guided fine-needle aspiration has improved pre-operative diagnosis, but the management of patients with a pancreatic lesion is still challenging. Molecular testing could help mainly in solving these “inconclusive” specimens. The introduction of multi-gene analysis approaches, such as next-generation sequencing, has provided a lot of useful information on the molecular characterization of pancreatic tumors. Different types of pancreatic tumors (e.g., pancreatic ductal adenocarcinomas, intraductal papillary mucinous neoplasms, solid pseudopapillary tumors) are characterized by specific molecular alterations. The aim of this review is to summarize the main molecular alterations found in pancreatic tumors.
Collapse
Affiliation(s)
- Michela Visani
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Giorgia Acquaviva
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Antonio De Leo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Viviana Sanza
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Lidia Merlo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Thais Maloberti
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
| | - Alba A Brandes
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Enrico Franceschi
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Monica Di Battista
- Medical Oncology Department, Azienda USL/IRCCS Istituto Delle Scienze Neurologiche di Bologna, Bologna 40139, Italy
| | - Michele Masetti
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Elio Jovine
- Division of Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40133, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Budrio Hospital Azienda USL, Bologna 40133, Italy
| | - Annalisa Pession
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
| | - Giovanni Tallini
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna–Molecular Diagnostic Unit, Azienda USL di Bologna, Bologna 40138, Italy
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
| | - Dario de Biase
- Division of Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna 40138, Italy
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna 40138, Italy
| |
Collapse
|
|
4
|
Haghighi M, Packey C, Gonda TA. Endoscopic Ultrasonography with Fine-needle Aspiration: New Techniques for Interpretation of Endoscopic Ultrasonography Cytology and Histology Specimens. Gastrointest Endosc Clin N Am 2017; 27:601-614. [PMID: 28918801 DOI: 10.1016/j.giec.2017.06.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Significant advances have been made in the last few years in the technologies for sampling pancreatic masses, and in the understanding of the biology of pancreatic cancer. Better and more targeted treatments are likely to become available. Because most pancreatic cancers are likely to remain unresectable at diagnosis, high-quality, high-cellularity specimens are essential. A tailored approach that considers indication, location, and treatment possibilities needs to be taken before embarking on a pancreatic biopsy. Because the demand from oncologists and patients for increasingly personalized therapy is likely to grow, optimal sampling beyond diagnostic accuracy is likely to become increasingly critical.
Collapse
Affiliation(s)
- Mehrvash Haghighi
- Department of Pathology, Columbia University Medical Center, 161, Fort Washington Avenue, New York, NY 10023, USA
| | - Christopher Packey
- Department of Medicine, Columbia University Medical Center, 161, Fort Washington Avenue, New York, NY 10023, USA
| | - Tamas A Gonda
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University, 161, Fort Washington Avenue, New York, NY 10023, USA.
| |
Collapse
|
|
5
|
Fabbri C, Gibiino G, Fornelli A, Cennamo V, Grifoni D, Visani M, Acquaviva G, Fassan M, Fiorino S, Giovanelli S, Bassi M, Ghersi S, Tallini G, Jovine E, Gasbarrini A, de Biase D. Team work and cytopathology molecular diagnosis of solid pancreatic lesions. Dig Endosc 2017; 29:657-666. [PMID: 28190274 DOI: 10.1111/den.12845] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/08/2017] [Indexed: 02/05/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second leading cause of cancer-associated death in the next decade or so. It is widely accepted that tumorigenesis is linked to specific alterations in key genes and pancreatic neoplasms are some of the best characterized at the genomic level. Recent whole-exome and whole-genome sequencing analyses confirmed that PDAC is frequently characterized by mutations in a set of four genes among others: KRAS, TP53, CDKN2A/p16, and SMAD4. Sequencing, for example, is the preferable technique available for detecting KRAS mutations, whereas in situ immunochemistry is the main approach for detecting TP53 gene alteration. Nevertheless, the diagnosis of PDAC is still a clinical challenge, involving adequate acquisition of endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) and specific pathological assessment from tissue architecture to specific biomolecular tests. The aim of the present review is to provide a complete overview of the current knowledge of the biology of pancreatic cancer as detected by the latest biomolecular techniques and, moreover, to propose a paradigm for strict teamwork collaboration in order to improve the correct use of diagnostic sources.
Collapse
Affiliation(s)
- Carlo Fabbri
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Giulia Gibiino
- Medical Pathology, Department of Internal Medicine, Gastroenterology Division, Policlinico Universitario A. Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Adele Fornelli
- Anatomic Pathology Unit, AUSL of Bologna, Maggiore Hospital, Italy
| | - Vincenzo Cennamo
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Daniela Grifoni
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy
| | - Michela Visani
- Department of Medicine (DIMES), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Italy
| | - Giorgia Acquaviva
- Department of Medicine (DIMES), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Italy
| | - Matteo Fassan
- Department of Medicine, Anatomic Pathology, University of Padua, Padova, Italy
| | - Sirio Fiorino
- Internal Medicine Unit, Maggiore Hospital, Bologna, Italy
| | - Silvia Giovanelli
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Marco Bassi
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Stefania Ghersi
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Giovanni Tallini
- Department of Medicine (DIMES), Molecular Diagnostic Unit AUSL of Bologna, University of Bologna School of Medicine, Italy
| | - Elio Jovine
- Unit of Gastroenterology and Digestive Endoscopy, AUSL Bologna Bellaria-Maggiore Hospital, Italy
| | - Antonio Gasbarrini
- Medical Pathology, Department of Internal Medicine, Gastroenterology Division, Policlinico Universitario A. Gemelli, Catholic University of Sacred Heart, Rome, Italy
| | - Dario de Biase
- Department of Pharmacy and Biotechnology (FaBiT), University of Bologna, Italy
| |
Collapse
|
|
6
|
Strzelczyk JK, Gołąbek K, Cuber P, Krakowczyk Ł, Owczarek AJ, Fronczek M, Choręża P, Hudziec E, Ostrowska Z. Comparison of Selected Protein Levels in Tumour and Surgical Margin in a Group of Patients with Oral Cavity Cancer. Biochem Genet 2017; 55:322-334. [DOI: 10.1007/s10528-017-9799-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 04/03/2017] [Indexed: 12/20/2022]
|
|
7
|
Loss of CDKN2A Promoter Methylation Coincides With the Epigenetic Transdifferentiation of Uterine Myosarcomatous Cells. Int J Gynecol Pathol 2016; 35:309-15. [DOI: 10.1097/pgp.0000000000000181] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
|
|
8
|
Tumor Suppressor Inactivation in the Pathogenesis of Adult T-Cell Leukemia. JOURNAL OF ONCOLOGY 2015; 2015:183590. [PMID: 26170835 PMCID: PMC4478360 DOI: 10.1155/2015/183590] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Accepted: 05/24/2015] [Indexed: 12/12/2022]
Abstract
Tumor suppressor functions are essential to control cellular proliferation, to activate the apoptosis or senescence pathway to eliminate unwanted cells, to link DNA damage signals to cell cycle arrest checkpoints, to activate appropriate DNA repair pathways, and to prevent the loss of adhesion to inhibit initiation of metastases. Therefore, tumor suppressor genes are indispensable to maintaining genetic and genomic integrity. Consequently, inactivation of tumor suppressors by somatic mutations or epigenetic mechanisms is frequently associated with tumor initiation and development. In contrast, reactivation of tumor suppressor functions can effectively reverse the transformed phenotype and lead to cell cycle arrest or death of cancerous cells and be used as a therapeutic strategy. Adult T-cell leukemia/lymphoma (ATLL) is an aggressive lymphoproliferative disease associated with infection of CD4 T cells by the Human T-cell Leukemia Virus Type 1 (HTLV-I). HTLV-I-associated T-cell transformation is the result of a multistep oncogenic process in which the virus initially induces chronic T-cell proliferation and alters cellular pathways resulting in the accumulation of genetic defects and the deregulated growth of virally infected cells. This review will focus on the current knowledge of the genetic and epigenetic mechanisms regulating the inactivation of tumor suppressors in the pathogenesis of HTLV-I.
Collapse
|
|
9
|
Smith JP, Whitcomb DC, Matters GL, Brand RE, Liao J, Huang YJ, Frazier ML. Distribution of cholecystokinin-B receptor genotype between patients with pancreatic cancer and controls and its impact on survival. Pancreas 2015; 44:236-42. [PMID: 25469546 PMCID: PMC4326549 DOI: 10.1097/mpa.0000000000000263] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Cholecystokinin (CCK) and gastrin stimulate growth of pancreatic cancer through the CCK-B receptor (CCK-BR). A splice variant of the CCK-BR that results from a single nucleotide polymorphism (SNP) has been identified. Because the splice variant receptor has an extended third intracellular loop, an area involved in cell signaling and growth, we hypothesized that this genetic variant could contribute to the poor prognosis and short survival of this malignancy. METHODS DNA from 931 patients with pancreatic cancer was evaluated for the SNP (C > A; rs1800843) in the CCK-BR gene. For statistical analysis, the Fisher exact test was used to compare the genotype and allele frequency between the cancer cohort and normal controls and the dependence of genotype on factors, such as stage of disease and age, was analyzed using Cox proportional hazards models. RESULTS Compared to the normal cohort, the frequency of the A-allele in pancreatic cancer subjects was increased (P = 0.01123; odds ratio, 2.283). Even after adjustment for stage of disease, survival of subjects with the minor allele was significantly shorter than those with the wild-genotype (hazard ratio, 1.83; P = 3.11 × 10(-11)). CONCLUSIONS The CCK-BR SNP predicts survival and should be studied as a candidate genetic biomarker for those at risk of pancreatic cancer.
Collapse
Affiliation(s)
- Jill P. Smith
- Dept. of Medicine, Georgetown University, Washington, DC, USA
- Dept. of Medicine, Pennsylvania State University, College of Medicine, Hershey, PA
| | - David C. Whitcomb
- Department of Medicine, University of Pittsburgh & UPMC, Pittsburgh, PA
| | - Gail L. Matters
- Dept. of Biochemistry & Molecular Biology, Pennsylvania State University, College of Medicine, Hershey, PA
| | - Randall E. Brand
- Department of Medicine, University of Pittsburgh & UPMC, Pittsburgh, PA
| | - Jiangang Liao
- Public Health Sciences, Pennsylvania State University, College of Medicine, Hershey, PA
| | - Yu-Jing Huang
- Department of Epidemiology, University of Texas at MD Anderson Cancer Center, Houston, TX, USA
| | - Marsha L. Frazier
- Department of Epidemiology, University of Texas at MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
10
|
Abstract
It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.
Collapse
|
|
11
|
Molecular Biologic Approach to the Diagnosis of Pancreatic Carcinoma Using Specimens Obtained by EUS-Guided Fine Needle Aspiration. Gastroenterol Res Pract 2012. [PMID: 23197977 PMCID: PMC3503278 DOI: 10.1155/2012/243524] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
We review the utility of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), a rapid, safe, cost-effective, and accurate diagnostic modality for evaluating pancreatic tumors. EUS-FNA is currently used for the diagnosis and staging of pancreatic tumors. The sensitivity of EUS-FNA for pancreatic malignancy ranges from 75% to 94%, and its specificity approaches 100% in most studies. However, EUS-FNA has some limitations in the diagnosis of well-differentiated or early-stage cancers. Recent evidence suggests that molecular biological analysis using specimens obtained by EUS-FNA improves diagnostic sensitivity and specificity, especially in borderline cytological cases. It was also reported that additional information regarding patient response to chemotherapy, surgical resectability, time to metastasis, and overall survival was acquired from the genetic analysis of specimens obtained by EUS-FNA. Other studies have revealed that the analysis of KRAS, MUC, p53, p16, S100P, SMAD4, and microRNAs is helpful in making the diagnosis of pancreatic carcinoma. In this paper, we describe the present state of genetic diagnostic techniques for use with EUS-FNA samples in pancreatic diseases. We also discuss the role of molecular biological analyses for the diagnosis of pancreatic carcinoma.
Collapse
|
|
12
|
Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One 2012; 7:e43192. [PMID: 23071490 PMCID: PMC3468610 DOI: 10.1371/journal.pone.0043192] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2012] [Accepted: 07/19/2012] [Indexed: 12/24/2022] Open
Abstract
Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.
Collapse
Affiliation(s)
- Winnie S. Liang
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - David W. Craig
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - John Carpten
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | | | - Michael J. Demeure
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
| | - Glen J. Weiss
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
| | - Tyler Izatt
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Shripad Sinari
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Alexis Christoforides
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Jessica Aldrich
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Ahmet Kurdoglu
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Michael Barrett
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Lori Phillips
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Hollie Benson
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Waibhav Tembe
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | | | - Jeffrey A. Kiefer
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Christophe Legendre
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Richard Posner
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Galen H. Hostetter
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Angela Baker
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Jan B. Egan
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Mayo Clinic, Scottsdale, Arizona, United States of America
| | - Haiyong Han
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Douglas Lake
- Arizona State University, Tempe, Arizona, United States of America
| | - Edward C. Stites
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | - Ramesh K. Ramanathan
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
| | - Rafael Fonseca
- Mayo Clinic, Scottsdale, Arizona, United States of America
| | | | - Daniel Von Hoff
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
- Mayo Clinic, Scottsdale, Arizona, United States of America
- Virginia G. Piper Cancer Center Clinical Trials, Scottsdale Healthcare, Scottsdale, Arizona, United States of America
- * E-mail:
| |
Collapse
|
|
13
|
Liang WS, Craig DW, Carpten J, Borad MJ, Demeure MJ, Weiss GJ, Izatt T, Sinari S, Christoforides A, Aldrich J, Kurdoglu A, Barrett M, Phillips L, Benson H, Tembe W, Braggio E, Kiefer JA, Legendre C, Posner R, Hostetter GH, Baker A, Egan JB, Han H, Lake D, Stites EC, Ramanathan RK, Fonseca R, Stewart AK, Von Hoff D. Genome-wide characterization of pancreatic adenocarcinoma patients using next generation sequencing. PLoS One 2012. [PMID: 23071490 DOI: 10.137/journal.pone.0043192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Pancreatic adenocarcinoma (PAC) is among the most lethal malignancies. While research has implicated multiple genes in disease pathogenesis, identification of therapeutic leads has been difficult and the majority of currently available therapies provide only marginal benefit. To address this issue, our goal was to genomically characterize individual PAC patients to understand the range of aberrations that are occurring in each tumor. Because our understanding of PAC tumorigenesis is limited, evaluation of separate cases may reveal aberrations, that are less common but may provide relevant information on the disease, or that may represent viable therapeutic targets for the patient. We used next generation sequencing to assess global somatic events across 3 PAC patients to characterize each patient and to identify potential targets. This study is the first to report whole genome sequencing (WGS) findings in paired tumor/normal samples collected from 3 separate PAC patients. We generated on average 132 billion mappable bases across all patients using WGS, and identified 142 somatic coding events including point mutations, insertion/deletions, and chromosomal copy number variants. We did not identify any significant somatic translocation events. We also performed RNA sequencing on 2 of these patients' tumors for which tumor RNA was available to evaluate expression changes that may be associated with somatic events, and generated over 100 million mapped reads for each patient. We further performed pathway analysis of all sequencing data to identify processes that may be the most heavily impacted from somatic and expression alterations. As expected, the KRAS signaling pathway was the most heavily impacted pathway (P<0.05), along with tumor-stroma interactions and tumor suppressive pathways. While sequencing of more patients is needed, the high resolution genomic and transcriptomic information we have acquired here provides valuable information on the molecular composition of PAC and helps to establish a foundation for improved therapeutic selection.
Collapse
Affiliation(s)
- Winnie S Liang
- Translational Genomics Research Institute (TGen), Phoenix, Arizona, United States of America
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Fonseca AL, Kugelberg J, Starker LF, Scholl U, Choi M, Hellman P, Åkerström G, Westin G, Lifton RP, Björklund P, Carling T. Comprehensive DNA methylation analysis of benign and malignant adrenocortical tumors. Genes Chromosomes Cancer 2012; 51:949-60. [PMID: 22733721 DOI: 10.1002/gcc.21978] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2011] [Accepted: 05/10/2012] [Indexed: 12/20/2022] Open
Abstract
The molecular pathogenesis of benign and malignant adrenocortical tumors (ACT) is incompletely clarified. The role of DNA methylation in adrenocortical tumorigenesis has not been analyzed in an unbiased, systematic fashion. Using the Infinium HumanMethylation27 BeadChip, the DNA methylation levels of 27,578 CpG sites were investigated in bisulfite-modified DNA from 6 normal adrenocortical tissue samples, 27 adrenocortical adenomas (ACA), and 15 adrenocortical carcinomas (ACC). Genes involved in cell cycle regulation, apoptosis, and transcriptional regulation of known or putative importance in the development of adrenal tumors showed significant and frequent hypermethylation. Such genes included CDKN2A, GATA4, BCL2, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. Comparing benign versus malignant ACT, a total of 212 CpG islands were identified as significantly hypermethylated in ACC. Gene expression studies of selected hypermethylated genes (CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, SCGB3A1/HIN1) in 6 normal and 16 neoplastic adrenocortical tissues (10 ACA and 6 ACC), displayed reduced gene expression in benign and malignant ACT versus normal adrenocortical tissue. Treatment with 5-aza-2'-deoxycytidine of adrenocortical cancer H-295R cells increased expression of the hypermethylated genes CDKN2A, GATA4, DLEC1, HDAC10, PYCARD, and SCGB3A1/HIN1. In conclusion, the current study represents the first unbiased, quantitative, genome-wide study of adrenocortical tumor DNA methylation. Genes with altered DNA methylation patterns were identified of putative importance to benign and malignant adrenocortical tumor development.
Collapse
Affiliation(s)
- Annabelle L Fonseca
- Department of Surgery, Yale University School of Medicine, New Haven, CT 06520, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
15
|
Sheikh R, Walsh N, Clynes M, O'Connor R, McDermott R. Challenges of drug resistance in the management of pancreatic cancer. Expert Rev Anticancer Ther 2011; 10:1647-61. [PMID: 20942635 DOI: 10.1586/era.10.148] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The current treatment of choice for metastatic pancreatic cancer involves single-agent gemcitabine or a combination of gemcitabine with capecitabine or erlotinib (a tyrosine kinase inhibitor). Only 25–30% of patients respond to this treatment and patients who do respond initially ultimately exhibit disease progression. Median survival for pancreatic cancer patients has reached a plateau due to inherent and acquired resistance to these agents. Key molecular factors implicated in this resistance include: deficiencies in drug uptake, alteration of drug targets, activation of DNA repair pathways, resistance to apoptosis and the contribution of the tumor microenvironment. Moreover, for newer agents including tyrosine kinase inhibitors, overexpression of signaling proteins, mutations in kinase domains, activation of alternative pathways, mutations of genes downstream of the target and/or amplification of the target represent key challenges for treatment efficacy. Here we will review the contribution of known mechanisms and markers of resistance to key pancreatic cancer drug treatments.
Collapse
Affiliation(s)
- Rizwan Sheikh
- Adelaide and Meath Hospital incorporating The National Children's Hospital, Tallaght, Dublin 24, Ireland.
| | | | | | | | | |
Collapse
|
|
16
|
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]
|
|
17
|
Iwasa A, Oda Y, Kurihara S, Ohishi Y, Yasunaga M, Nishimura I, Takagi E, Kobayashi H, Wake N, Tsuneyoshi M. Malignant transformation of mature cystic teratoma to squamous cell carcinoma involves altered expression of p53- and p16/Rb-dependent cell cycle regulator proteins. Pathol Int 2008; 58:757-64. [DOI: 10.1111/j.1440-1827.2008.02307.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
|
|
18
|
Abstract
The diagnosis of pancreatic cancer is devastating for patients and their relatives as the incidence rate is approximately the same as mortality rate. Only a small percentage, which ranges from 0.4% to 4% of patients who have been given this diagnosis, will be alive at five years. At the time of diagnosis, 80% of pancreatic cancer patients have unresectable or metastatic disease. Moreover, the therapeutic alternatives offered by chemotherapy or radiotherapy are few, if not zero. For all these reasons, there is an imperative need of analyzing and understanding the primitive lesions that lead to invasive pancreatic adenocarcinoma. Molecular pathology of these lesions is the key of our understanding of the mechanisms underlying the development of this cancer and will probably help us in earlier diagnosis and better therapeutic results. This review focuses on medical research on pancreatic cancer models and the underlying genetic alterations.
Collapse
Affiliation(s)
- Muhammad Wasif Saif
- Yale University School of Medicine, Section of Medical Oncology, New Haven, CT 06520, USA.
| | | | | |
Collapse
|
|
19
|
Augello C, Gregorio V, Bazan V, Cammareri P, Agnese V, Cascio S, Corsale S, Calò V, Gullo A, Passantino R, Gargano G, Bruno L, Rinaldi G, Morello V, Gerbino A, Tomasino RM, Macaluso M, Surmacz E, Russo A. TP53 and p16INK4A, but not H-KI-Ras, are involved in tumorigenesis and progression of pleomorphic adenomas. J Cell Physiol 2006; 207:654-9. [PMID: 16447252 DOI: 10.1002/jcp.20601] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The putative role of TP53 and p16(INK4A) tumor suppressor genes and Ras oncogenes in the development and progression of salivary gland neoplasias was studied in 28 cases of pleomorphic adenomas (PA), 4 cases of cystic adenocarcinomas, and 1 case of carcinoma ex-PA. Genetic and epigenetic alterations in the above genes were analyzed by Polymerase Chain Reaction/Single Strand Conformational Polymorphism (PCR/SSCP) and sequencing and by Methylation Specific-PCR (MS-PCR). Mutations in TP53 were found in 14% (4/28) of PAs and in 60% (3/5) of carcinomas. Mutations in H-Ras and K-Ras were identified in 4% (1/28) and 7% (2/28) of PAs, respectively. Only 20% (1/5) of carcinomas screened displayed mutations in K-Ras. p16(INK4A) promoter hypermethylation was found in 14% (4/28) of PAs and 100% (5/5) carcinomas. All genetic and epigenetic alterations were detected exclusively in the epithelial and transitional tumor components, and were absent in the mesenchymal parts. Our analysis suggests that TP53 mutations and p16(INK4A) promoter methylation, but not alterations in the H-Ras and K-Ras genes, might be involved in the malignant progression of PA into carcinoma.
Collapse
Affiliation(s)
- Claudia Augello
- Department of Oncology, Università of Palermo, Palermo, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
20
|
Fendrich V, Slater EP, Heinmöller E, Ramaswamy A, Celik I, Nowak O, Chaloupka B, Gerdes B, Bartsch DK. Alterations of the tissue inhibitor of metalloproteinase-3 (TIMP3) gene in pancreatic adenocarcinomas. Pancreas 2005; 30:e40-5. [PMID: 15714128 DOI: 10.1097/01.mpa.0000153325.62192.8a] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES Tissue inhibitor of metalloproteinase-3 (TIMP3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastases. In the present study, the involvement of TIMP3 in the tumorigenesis of 34 pancreatic adenocarcinomas was evaluated. METHODS Immunohistochemistry, methylation-specific PCR, and RNA expression analysis (RT-PCR) of TIMP3 were performed in 34 resected and microdissected primary pancreatic adenocarcinomas. RESULTS Immunohistochemistry showed loss or strongly reduced protein expression in 17 of 34 pancreatic adenocarcinomas (50%) that corresponded to loss of TIMP3-RNA-expression. Promoter hypermethylation was identified in 2 of 34 tumors (6%). It was tumor specific and corresponded to a loss of TIMP3 protein expression. TIMP3 alterations did not correlate with any clinical feature such as tumor size or survival. CONCLUSION TIMP3 seems to play an important role in the tumorigenesis of primary pancreatic adenocarcinomas. In contrast to other tumors, hypermethylation seems not to be the key mechanism for the inactivation of TIMP3. Other methods of gene inactivation need to be identified.
Collapse
Affiliation(s)
- Volker Fendrich
- Department of Visceral-, Thoracic-, and Vascular Surgery, Philipps-University, Marburg, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Eisold S, Ryschich E, Linnebacher M, Giese T, Nauheimer D, Wild A, Bartsch DK, Büchler MW, Schmidt J. Characterization of FAMPAC, a newly identified human pancreatic carcinoma cell line with a hereditary background. Cancer 2004; 100:1978-86. [PMID: 15112280 DOI: 10.1002/cncr.20193] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND A novel pancreatic carcinoma cell line, FAMPAC, was identified from investigation of poorly differentiated pancreatic adenocarcinoma cells found in a patient with a familial predisposition to pancreatic carcinoma. A gene responsible for familial pancreatic carcinoma has not been identified to date. METHODS The FAMPAC cell line was characterized by its morphology, growth rate, tumorigenicity, and chromosomal analysis. Three known tumor suppressor genes, p16/CDKN2, BRCA2, and p53, all of which are important in the development of pancreatic carcinoma and frequently are involved in a variety of cancer syndromes, were analyzed. RESULTS FAMPAC cells grew as an adhering monolayer in culture medium supplemented with 10% fetal bovine serum and formed tumors rapidly in nude mice. The doubling time ranged from 24 to 48 hours. Karyotype analysis demonstrated the complexity of chromosomal deletions and rearrangements. The cells were negative for ductal differentiation markers such as cytokeratin 7 and MUC1, indicating poor differentiation. Analysis of FAMPAC cells revealed overexpression of the mutated p53 gene (exon 5, codon 175: CGC --> CAC), the presence of a homozygous deletion in the p16 gene, and the presence of wild-type BRCA2 in the tested hot spots. CONCLUSIONS To the authors' knowledge, FAMPAC is the first established human pancreatic carcinoma cell line associated with a familial background. FAMPAC is a tumorigenic cell line with a complex molecular pattern of mutations. These findings may be useful in understanding the mechanisms responsible for the development of sporadic or hereditary forms of pancreatic carcinoma.
Collapse
Affiliation(s)
- Sven Eisold
- Department of General Surgery, Ruprecht-Karls University, Heidelberg, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
22
|
Abstract
Pancreatic cancer is an almost universally fatal disease, with a five-year survival rate of 5%. Research into both sporadic and inherited forms of pancreatic cancer has yielded tremendous advances in the understanding of this disease at the molecular level. Elucidating genetic alterations in pancreatic cancer has identified various abnormalities ranging from gross chromosomal abnormalities to point mutations, many of which influence the development and progression of pancreatic cancer. Identifying precursor lesions within pancreatic ducts has led to the formulation of a progression model of pancreatic cancer and subsequent identification of early- and late-stage changes leading to invasive cancer. Ultimately, understanding the genetic events underlying the development of pancreatic cancer may serve as a useful adjunct in the screening and treatment of patients suffering from, or at risk for, pancreatic cancer.
Collapse
Affiliation(s)
- Donna E Hansel
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
| | | | | |
Collapse
|
|
23
|
Yin D, Xie D, Hofmann WK, Miller CW, Black KL, Koeffler HP. Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors. Oncogene 2002; 21:8372-8. [PMID: 12447702 DOI: 10.1038/sj.onc.1206031] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2002] [Revised: 08/30/2002] [Accepted: 09/04/2002] [Indexed: 12/19/2022]
Abstract
Methylation status of the p15(INK4B), p16(INK4A), p14(ARF) and retinoblastoma (RB) genes was studied using methylation specific polymerase chain reaction (MSP) in 85 human brain tumors of various subtypes and four normal brain samples. These genes play an important role in the control of the cell cycle. Twenty-four out of 85 cases (28%) had at least one of these genes methylated. The frequency of p14(ARF) methylation was 15 out of 85 (18%) cases, and the expression of p14(ARF) in methylated gliomas was significantly lower than in unmethylated gliomas. The incidence of methylation of p15(INK4B), p16(INK4A) and RB gene was 4%, 7%, and 4%, respectively. Samples with p14(ARF) methylation did not have p16(INK4A) methylation even though both genes physically overlap. None of the target genes was methylated in the normal brain samples. In addition, the p53 gene was mutated in 19 out of 85 (22%) samples as determined by single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Thirty out of 85 (35%) brain tumors had either a p53 mutation or methylation of p14(ARF). Also, the p14(ARF) expression in p53 wild-type gliomas was lower than levels in p53 mutated gliomas. This finding is consistent with wild-type p53 being able to autoregulate its levels by down-regulating expression of p14(ARF). In summary, inactivation of the apoptosis pathway that included the p14(ARF) and p53 genes by hypermethylation and mutation, respectively, occurred frequently in human brain tumors. Down-regulation of p14(ARF) in gliomas was associated with hypermethylation of its promoter and the presence of a wild-type p53 in these samples.
Collapse
Affiliation(s)
- Dong Yin
- Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California, CA 90048, USA.
| | | | | | | | | | | |
Collapse
|
|
24
|
Bazan V, Zanna I, Migliavacca M, Sanz-Casla MT, Maestro ML, Corsale S, Macaluso M, Dardanoni G, Restivo S, Quintela PL, Bernaldez R, Salerno S, Morello V, Tomasino RM, Gebbia N, Russo A. Prognostic significance of p16INK4a alterations and 9p21 loss of heterozygosity in locally advanced laryngeal squamous cell carcinoma. J Cell Physiol 2002; 192:286-93. [PMID: 12124774 DOI: 10.1002/jcp.10138] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The p16INK4a gene, localized within chromosome 9p21, has been identified as a cyclin-dependent kinase inhibitor and may negatively regulate the cell cycle acting as a tumor suppressor. Genetic alterations involving the 9p21 region are common in human cancers. A consecutive series of 64 untreated patients (median of follow up 53 months) undergoing surgical resection for locally advanced laryngeal squamous-cell carcinomas (LSCCs) has been studied prospectively. Our purpose was to investigate p16 alterations (9p21 allelic loss, hypermethylation and point mutations) and their possible association with clinico-pathological data and flow cytometric variables (DNA-ploidy and S-phase fraction (SPF)), and to determine the possible prognostic role of this gene in these tumors. PCR-based techniques were used for investigating 9p21 loss of heterozygosity (LOH) and methylation promoter status of the p16 gene. p16 mutations were detected by PCR-SSCP (single strand conformation polymorphism) and sequencing. 9p21 LOH was detected in 16/62 (26%) informative tumors, point mutations in 5% (3/64) and hypermethylation in 9% (6/64) of the cases. p16 alterations were significantly associated with high SPF and DNA-aneuploidy. By univariate analysis, poor histologic differentiation, stage IV, DNA-aneuploidy and p16 point mutations proved to be significantly related to quicker relapse, whereas these same factors, and in addition high SPF, 9p21 LOH and any p16 alterations were significantly related to shorter overall survival. By Cox proportional hazards analysis only histologic grade (G3) and p16 point mutations were independently related to both disease relapse and death. Our study has identified p16 point mutations as important biomolecular indicators in LSCCs.
Collapse
Affiliation(s)
- Viviana Bazan
- Section of Molecular Oncology, University of Palermo, Italy
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Gerdes B, Ramaswamy A, Ziegler A, Lang SA, Kersting M, Baumann R, Wild A, Moll R, Rothmund M, Bartsch DK. p16INK4a is a prognostic marker in resected ductal pancreatic cancer: an analysis of p16INK4a, p53, MDM2, an Rb. Ann Surg 2002; 235:51-9. [PMID: 11753042 PMCID: PMC1422395 DOI: 10.1097/00000658-200201000-00007] [Citation(s) in RCA: 72] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To identify the prognostic relevance of the G1/S cell cycle regulator genes p16INK4a, p53, MDM2, and Rb in patients with resected ductal pancreatic cancer (PC). SUMMARY BACKGROUND DATA The tumor suppressor genes p16INK4a, p53, and Rb are altered in PC in 27% to 95%, 40% to 70%, and 5%, respectively. The role of MDM2 is not clearly defined in PC. The prognostic value of these cell cycle regulators has not been clarified. METHODS Sixty-two patients with PC with complete follow-up who underwent potentially curative resections were included in the study. An extreme group analysis was performed including the 20 patients with the shortest survival and the 20 patients with the longest survival. Protein expression of p16, p53, MDM2, and Rb was investigated, and mutation analysis of p16INK4a and p53 was performed. p16INK4a promoter hypermethylation was examined by methylation-specific polymerase chain reaction. RESULTS Significantly more tumors in the shortest-surviving patients had p16INK4a alterations compared with tumors of the longest-surviving patients. In contrast, the frequency of p53 alterations was not significantly higher in the shortest-surviving versus the longest-surviving groups. Stabilization of MDM2 and loss of Rb expression were identified in a minority of tumors, independent of survival length. CONCLUSIONS The presence of p16INK4a alterations in resected tumors of patients with PC is connected with a worse prognosis, indicating patients that might benefit from adjuvant therapy regimens. p53 alterations, MDM2 overexpression, and loss of Rb expression could not be identified as prognostic markers from this study, but a larger study with greater statistical power might show a different result with regard to p53.
Collapse
Affiliation(s)
- Berthold Gerdes
- Department of Visceral-, Thoracic-, and Vascular Surgery, Philipps University of Marburg, Marburg, Germany.
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Wild A, Langer P, Ramaswamy A, Chaloupka B, Bartsch DK. A novel insulinoma tumor suppressor gene locus on chromosome 22q with potential prognostic implications. J Clin Endocrinol Metab 2001; 86:5782-7. [PMID: 11739439 DOI: 10.1210/jcem.86.12.8089] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The molecular mechanisms contributing to the tumorigenesis of insulinomas are still poorly understood. As moderate to high rates of LOH have been found on chromosome 22q in gastrinomas, we performed a finer deletion mapping study of chromosome 22q with 8 microsatellite markers in 15 insulinomas (4 malignant and 11 benign). Fourteen of 15 (93%) insulinomas revealed LOH on chromosome 22q, whereas the shortest region of overlap implicated a deletion of approximately 700 kb at 22q12.1-q12.2 with an LOH rate of up to 57% (8 of 14). Although the expressed sequence tag marker A006E25 that is localized in the hSNF5/INI1 gene on 22q11.2 revealed LOH in 50% of informative cases (7 of 14), no alterations in this gene could be identified by single strand conformational polymorphism analysis, direct DNA sequencing, or RNA expression analysis. Remarkably, the four malignant tumors showed a common deleted region between markers D22S345 and D22S1144 compared with none of the 11 benign insulinomas. The observed high frequency of chromosome 22q12 deletions in insulinomas is suggestive for a region compatible with harboring a tumor suppressor gene. The hSNF5/INI1 gene is most likely not the candidate gene, because no alterations could be identified. The distinct pattern of allelic loss identified in this chromosomal region appears to be an attractive candidate marker for further evaluation with regard to the discrimination between benign and malignant insulinomas.
Collapse
Affiliation(s)
- A Wild
- Department of General Surgery, Philipps University of Marburg, D-35043 Marburg, Germany
| | | | | | | | | |
Collapse
|
|
27
|
Mayr B, Grüneis C, Brem G, Reifinger M, Schaffner G, Hochsteiner W. Lack of sequence variation in sporadic bovine leucosis in regions of tumour suppressor genes p53 and p16. JOURNAL OF VETERINARY MEDICINE. A, PHYSIOLOGY, PATHOLOGY, CLINICAL MEDICINE 2001; 48:365-71. [PMID: 11554494 DOI: 10.1046/j.1439-0442.2001.00371.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Regions of the promoter and exons 5-8 of the tumour suppressor gene p53 were analysed in 25 cases of sporadic bovine leucosis. The study included 17 cases of juvenile leucosis, five cases of adult leucosis and three cases of skin leucosis. Exon 2 of tumour suppressor gene p16 was also investigated in the same samples. No sequence variations were present in the analysed areas of the genes. In p53, this fact represents a clear difference in comparison with enzootic bovine leucosis. In p16, no comparative data are available.
Collapse
Affiliation(s)
- B Mayr
- Institute for Animal Breeding and Genetics, Vienna, Austria
| | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
Since its discovery as an inhibitor of cyclin-dependent kinases 4 and 6, the tumor suppressor p16 has continued to gain widespread importance in cancer. The high frequency of deletions of p16 in tumor cell lines first suggested an important role for p16 in carcinogenesis. This initial genetic evidence was subsequently strengthened by numerous studies documenting p16 inactivation in kindreds with familial melanoma. Moreover, a high frequency of p16 gene alterations was found in primary tumors, while recent studies have identified p16 promoter methylation as a major mechanism of tumor-suppressor-gene silencing. Additional insight into p16's role in cancer has come from the genetic analysis of precancerous lesions and various tissue culture models. It is now believed that loss of p16 is an early and often critical event in tumor progression. Consequently, p16 is a major tumor-suppressor gene whose frequent loss occurs early in many human cancers.
Collapse
Affiliation(s)
- J W Rocco
- Department of Otology and Laryngology, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA
| | | |
Collapse
|
|
29
|
Gerdes B, Bartsch DK, Ramaswamy A, Kersting M, Wild A, Schuermann M, Frey M, Rothmund M. Multiple primary tumors as an indicator for p16INK4a germline mutations in pancreatic cancer patients? Pancreas 2000; 21:369-75. [PMID: 11075991 DOI: 10.1097/00006676-200011000-00007] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
Multiple primary tumors in pancreatic cancer patients might indicate a genetic predisposition to the development of malignancies. In this study we evaluated whether the mutation rate of the TP53 and p16INK4a genes of pancreatic cancers differs in pancreatic cancer patients with and without multiple primaries. Furthermore, we investigated whether pancreatic cancer patients with multiple primaries carry germline mutations in either p16INK4a, TP53, or BRCA2 tumor suppressor genes to detect a genetic alteration that predisposes to the development of different primaries. Fourteen (23%) of 60 pancreatic cancer patients developed histologically verified additional primaries during their lifetimes. Normal constitutional and tumor DNA of the 14 patients with a positive cancer history, but negative family history, were analyzed for p16INK4a, TP53, and BRCA2 mutations by single-strand conformational variant (SSCV) analysis and direct sequencing. Hypermethylation of the p16INK4a promoter region in pancreatic cancers was identified by methylation-specific polymerase chain reaction (PCR; MSP). Four of 14 pancreatic carcinomas carried somatic intragenic p16INK4a mutations, and another four tumors revealed hypermethylation of the p16INK4a promoter region. Somatic intragenic TP53 mutations were identified in six of 14 tumors. None of the pancreatic cancer patients carried TP53 or BRCA2 germline mutations. In contrast, one of 14 pancreatic cancer patients with multiple primaries carried the p16INK4a mutation A68V in his germline. This mutation was localized in the conserved second ankyrin repeat of p16INK4a and did not occur in 100 control patients. The frequency of somatic TP53 and p16INK4a mutations in pancreatic cancer is similar in patients with and without multiple primaries. TP53 and BRCA2 germline mutations seem not to be significantly associated with the occurrence of multiple primaries in pancreatic cancer patients. However, p16INK4a germline mutations might be causative for tumor development in some pancreatic cancer patients with multiple primaries. The genetic investigation of patients with accumulation of different cancers even without a positive family history may be a new approach for the understanding of the relation of different cancers.
Collapse
Affiliation(s)
- B Gerdes
- Department of General Surgery, Philipps University of Marburg, Germany.
| | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Abstract
BACKGROUND Pancreatic cancer is the fifth leading cause of cancer death in the Western world. Despite improvement in operative mortality rates, little impact has been made on overall 5-year survival. This review discusses the molecular changes peculiar to pancreatic cancer and how the use of molecular technology might affect detection, screening, diagnosis and treatment of the disease. METHODS A literature review was performed using the National Library of Medicine's Pubmed database; this was combined with ongoing work within the Queen Elizabeth Hospital, Birmingham. RESULTS Over the past 20 years great strides have been made in our understanding of the molecular basis of disease. Advances in molecular biology are now reshaping how diseases are screened for, diagnosed, investigated and treated. In recent years collaboration between clinicians and basic scientists has revealed a unique pattern of genetic and molecular events in pancreatic cancer. This review discusses how these advances may impact on patients with this disease. CONCLUSION The past decade has seen some improvement in outlook for patients with pancreatic cancer, but the 'molecular age' promises to deliver even better results.
Collapse
Affiliation(s)
- M Manu
- Department of Surgery and Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK
| | | | | |
Collapse
|
|
31
|
Heinmöller E, Dietmaier W, Zirngibl H, Heinmöller P, Scaringe W, Jauch KW, Hofstädter F, Rüschoff J. Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2000; 157:83-92. [PMID: 10880379 PMCID: PMC1850206 DOI: 10.1016/s0002-9440(10)64520-8] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Little or no data exist concerning the inactivation of tumor suppressor genes in intraductal lesions surrounding invasive ductal pancreatic carcinomas. Using a novel improved primer extension and preamplification polymerase chain reaction, we analyzed microdissected paraffin-embedded specimens of pancreatic carcinoma (n = 29) and their corresponding pancreatic intraductal lesions (PIL, n = 331) for loss of heterozygosity (LOH) of p16(INK4), DPC4, and p53 by microsatellite analysis and for p53 protein by immunohistochemistry. LOH at the p16(INK4) locus (9p21) was found in nine of 22 informative tumors (41%), in 15 of 25 tumors (60%) at the DPC4 locus (18q21.1), and in 22 of 27 tumors (81%) at the p53 locus (17p13). Homozygous deletions of p16(INK4) and DPC4 were found in eight of 22 (36%) and four of 25 tumors (16%), respectively. Furthermore, 24 of 29 tumors (83%) revealed considerable intratumoral genetic heterogeneity. In 165 of 277 PILs (60%) having suitable DNA for microsatellite analysis, alterations in at least one tumor suppressor gene were found. In individual PILs, up to three alterations were detected, and p53 LOH occurred even in morphologically normal-appearing ductal epithelium near the tumor. Although deletions of all three tumor suppressor genes were found in PILs without nuclear atypia, there was a tendency toward earlier LOH of p16(INK4) compared to DPC4 and p53 in these lesions. LOH in tumors accompanied positive p53 immunohistochemistry in 81% but only in 38% in PILs.
Collapse
Affiliation(s)
| | | | - Hubert Zirngibl
- University Clinic Witten-Herdecke, Wuppertal, Germany; and the Department of Molecular Genetics and Molecular Diagnosis,¶
| | - Petra Heinmöller
- the University Clinic of Regensburg, Regensburg, Germany; the Institute of Pathology,§
| | - William Scaringe
- the City of Hope National Medical Center and Beckman Research Institute, Duarte, California
| | - Karl-Walter Jauch
- the University Clinic of Regensburg, Regensburg, Germany; the Institute of Pathology,§
| | | | - Josef Rüschoff
- Klinikum Kassel, Kassel, Germany; the Department of Surgery,†
| |
Collapse
|
|
32
|
Yamano M, Fujii H, Takagaki T, Kadowaki N, Watanabe H, Shirai T. Genetic progression and divergence in pancreatic carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2000; 156:2123-33. [PMID: 10854233 PMCID: PMC1850062 DOI: 10.1016/s0002-9440(10)65083-3] [Citation(s) in RCA: 123] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Genetic alterations of pancreatic intraductal lesions adjacent to invasive ductal carcinoma were investigated. We submitted nine foci of ordinary epithelium, 12 foci of nonpapillary hyperplasia, 12 foci of papillary hyperplasia (pap HP), 66 foci of severe ductal dysplasia, and 27 invasive foci from a total of 10 pancreatic carcinomas for genetic analysis. All foci were individually microdissected and allelic losses of 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11q, 13q, 16q, 17p, and 18q were studied. All invasive and severely dysplastic intraductal foci exhibited loss of heterozygosity (LOH) at more than one chromosomal locus. For each case, allelic loss was frequently observed on 9p (severe ductal dysplasia 90%, invasion 100%), 17p (severe ductal dysplasia 80%, invasion 80%), and 18q (severe ductal dysplasia 88%, invasion 88%). Ninety-four percent of severe ductal dysplasia and 96% of invasive foci had multiple LOH. Seventeen percent of nonpapillary hyperplasia and 33% of pap HP showed LOH. Only one focus of pap HP showed multiple LOH. The patterns of allelic loss identified in severe ductal dysplasia were generally conserved in synchronous infiltrating tumors, supporting the paradigm that infiltrating tumors are clonally derived from severe ductal dysplasia. In eight of 10 cases, however, we found frequent genetic heterogeneity in the intraductal lesion, suggestive of genetic progression or diversion. These findings indicate that invasive pancreatic carcinoma evolves through successive and divergent genetic changes with selection of aggressive subclones in the intraductal component.
Collapse
Affiliation(s)
- M Yamano
- First Department of Pathology, Niigata University School of Medicine, Niigata, Japan
| | | | | | | | | | | |
Collapse
|
|
33
|
Groeger AM, Caputi M, Esposito V, De Luca A, Bagella L, Pacilio C, Klepetko W, Giordano GG, Baldi F, Kaiser HE, Wolner E, Giordano A. Independent prognostic role of p16 expression in lung cancer. J Thorac Cardiovasc Surg 1999; 118:529-35. [PMID: 10469971 DOI: 10.1016/s0022-5223(99)70192-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
OBJECTIVES The cyclin-dependent kinase p16 (also known as Ink4A, Mts1, Cdkn2, and Cdkn4i) has been proposed as a tumor suppressor gene mapped on chromosome segment 9p21. This study evaluated p16 protein expression in 135 lung cancer specimens and investigated potential genetic alterations occurring in this gene. RESULTS We found altered p16 immunohistochemical expression to be a frequent event in lung cancer and to be independent of either the histologic type or any other clinical-pathologic feature. Western blot analyses performed on about one third of the specimens correlated highly with these results. In addition, we found p16 immunohistochemical expression to be a favorable prognostic factor in lung cancer in that its reduction or loss correlated with a worse outcome for the patients. Polymerase chain reaction amplification and direct sequencing of p16 exons 1 and 2 revealed no mutations, indicating that p16-altered expression in lung cancer is not necessarily linked to mutational events of these genes. CONCLUSIONS We conclude that p16-altered expression is both an independent and frequent event in lung cancer and may have an important role in tumorigenesis and in malignant progression of a significant proportion of these cancers. However, the actual incidence and relevance of p16 mutations in this neoplasm continues to be debated, and its analysis seems inconclusive. Our results suggest a prognostic role for the immunodetection of this protein on formalin-fixed and paraffin-embedded specimens. They further suggest its routine use in the evaluation of the frequently unpredictable behavior of lung cancer.
Collapse
Affiliation(s)
- A M Groeger
- Depratment of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Sbarro Institute for Cancer Research and Molecular Medicine, Philadelphia, PA 19107, USA
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Bastian D, Ramaswamy A, Barth PJ, Gerdes B, Ernst M, Bartsch D. Malignant fibrous histiocytoma of the pancreas: a case report with genetic analysis. Cancer 1999; 85:2352-8. [PMID: 10357405 DOI: 10.1002/(sici)1097-0142(19990601)85:11<2352::aid-cncr9>3.0.co;2-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Malignant fibrous histiocytoma (MFH) is the most common type of soft tissue sarcoma in adults; it occurs frequently in the extremities, the trunk, or retroperitoneal tissues. MFH rarely is detected in digestive organs, such as the liver or stomach. METHODS The authors report a patient with MFH of the pancreas who was treated with surgery alone. The tumor was studied for genetic alterations in the p53, p16ink4a, and DPC4 tumor suppressor genes as well as the K-ras oncogene by immunohistochemistry, single strand conformation variant (SSCV) analysis, and direct DNA sequencing. RESULTS The authors believe that this is the 13th report of primary pancreatic MFH in the world literature and the first genetic analysis of this rare tumor. The patient is alive with no evidence of recurrence 34 months after surgery. Immunohistochemistry revealed no abnormal accumulation of the p53 protein and normal nuclear p16 expression. Mutation analysis of the p53, p16, DPC4, and K-ras genes showed only a polymorphism at codon 72 of the p53 gene and no mutations in any of the genes. CONCLUSIONS Genotypically, MFH of the pancreas is clearly different from other malignant pancreatic tumors, which further supports the hypothesis that this tumor is a rare but distinct entity.
Collapse
Affiliation(s)
- D Bastian
- Department of Surgery, Phillipps-University Marburg, Germany
| | | | | | | | | | | |
Collapse
|
|
35
|
Bartsch D, Barth P, Bastian D, Ramaswamy A, Gerdes B, Chaloupka B, Deiss Y, Simon B, Schudy A. Higher frequency of DPC4/Smad4 alterations in pancreatic cancer cell lines than in primary pancreatic adenocarcinomas. Cancer Lett 1999; 139:43-9. [PMID: 10408907 DOI: 10.1016/s0304-3835(98)00380-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The tumor suppressor gene DPC4/Smad4 at 18q21.1 is inactive in about 50% of pancreatic carcinoma xenografts and cell lines. However, the role of DPC4 in the multistep carcinogenesis of primary pancreatic adenocarcinomas remains uncertain. Therefore, we examined 45 primary human pancreatic adenocarcinomas and 12 pancreatic cancer cell lines for DPC4 alterations by single-strand conformational variant (SSCV) analysis and a PCR-based deletion assay. DPC4 was inactivated by either homozygous deletion or point mutation in 6 of 12 cell lines (50%). None of the primary pancreatic carcinomas carried a DPC4 mutation, although 66% revealed LOH of 18q21 sequences. These findings suggest that inactivation of DPC4 occurs more frequently in tumor-derived cell lines than in primary pancreatic adenocarcinomas. In addition, another, yet unidentified, tumor suppressor gene(s) may be linked with the frequent LOH of 18q21 in primary pancreatic adenocarcinomas.
Collapse
Affiliation(s)
- D Bartsch
- Department of Surgery, Philipps-University Marburg, Germany.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Bartsch D, Hahn SA, Danichevski KD, Ramaswamy A, Bastian D, Galehdari H, Barth P, Schmiegel W, Simon B, Rothmund M. Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene 1999; 18:2367-71. [PMID: 10327057 DOI: 10.1038/sj.onc.1202585] [Citation(s) in RCA: 94] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Tumors of the endocrine pancreas are extremely rare, and molecular mechanisms leading to their development are not well understood. A candidate tumor suppressor gene, DPC4, located at 18q21, has recently been shown to be inactivated in half of pancreatic adenocarcinoma xenografts. The close anatomical relationship of the exocrine and endocrine pancreas prompted us to determine the role of DPC4 in the tumorigenesis of 25 pancreatic islet cell tumors (11 insulinomas, nine non-functioning endocrine carcinomas, three gastrinomas, two vipomas). A mutation screening of the highly conserved COOH-terminal domain of DPC4 (exons 8-11) was performed by single-strand conformational variant (SSCP) analysis and a PCR-based deletion assay. Five of nine (55%) non-functioning endocrine pancreatic carcinomas revealed either point mutations, small intragenic deletions or homozygous deletion of DPC4 sequences compared to none of the insulinomas, gastrinomas or vipomas. These results suggest that DPC4 is an important target gene promoting tumorigenesis of non-functioning neuroendocrine pancreatic carcinomas.
Collapse
Affiliation(s)
- D Bartsch
- Department of Surgery, Philipps-University Marburg, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Bullock GJ, Green JL, Baron PL. Impact of p16 expression on surgical management of malignant melanoma and pancreatic carcinoma. Am J Surg 1999; 177:15-8. [PMID: 10037301 DOI: 10.1016/s0002-9610(98)00297-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND Recent advances in molecular oncology have provided explanations at the DNA level for the malignant transformation and metastatic potential of various cancers. Malignant melanoma and pancreatic cancer may be classified together in both these cancers exhibit mutations in, or loss of, the cell-cycle inhibitory gene, p16. This paper reviews the current literature on p16 expression in melanoma and pancreatic cancer, explores factors that place patients with these cancers in categories of high risk for metastases or recurrence, and addresses whether aberrant gene expressions should influence awareness of and current recommendations for the management of these aggressive cancers. METHODS A computerized literature search was performed utilizing OVID Technology's Medline database from 1993 to 1998. RESULTS Both familial as well as sporadic cases of malignant melanoma and pancreatic carcinoma are reported in the literature. Although a low percentage of cases of either malignancy have p16 mutations, a higher risk of their development has been reported to occur in certain families with p16 germline mutations. CONCLUSIONS The increased risk determined in these families may serve to heighten awareness of the influence of positive family history of these cancers in the evaluation of patients.
Collapse
Affiliation(s)
- G J Bullock
- Department of Surgery, Medical University of South Carolina, Charleston 29425, USA
| | | | | |
Collapse
|
|
38
|
Hruban R, Wilentz R, Goggins M, Offerhaus G, Yeo C, Kern S. Pathology of incipient pancreatic cancer. Ann Oncol 1999. [DOI: 10.1093/annonc/10.suppl_4.s9] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
|
|
39
|
Ruas M, Peters G. The p16INK4a/CDKN2A tumor suppressor and its relatives. BIOCHIMICA ET BIOPHYSICA ACTA 1998; 1378:F115-77. [PMID: 9823374 DOI: 10.1016/s0304-419x(98)00017-1] [Citation(s) in RCA: 338] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- M Ruas
- Imperial Cancer Research Fund, London, UK
| | | |
Collapse
|
|
40
|
Gorunova L, Höglund M, Andrén-Sandberg A, Dawiskiba S, Jin Y, Mitelman F, Johansson B. Cytogenetic analysis of pancreatic carcinomas: intratumor heterogeneity and nonrandom pattern of chromosome aberrations. Genes Chromosomes Cancer 1998; 23:81-99. [PMID: 9739011 DOI: 10.1002/(sici)1098-2264(199810)23:2<81::aid-gcc1>3.0.co;2-0] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Twenty-nine nonendocrine pancreatic carcinomas (20 primary tumors and nine metastases) were studied by chromosome banding after short-term culture. Acquired clonal aberrations were found in 25 tumors and a detailed analysis of these revealed extensive cytogenetic intratumor heterogeneity. Apart from six carcinomas with one clone only, 19 tumors displayed from two to 58 clones, bringing the total number of clones to 230. Karyotypically related clones, signifying evolutionary variation, were found in 16 tumors, whereas unrelated clones were present in nine, the latter finding probably reflecting a distinct pathogenetic mechanism. The cytogenetic profile of pancreatic carcinoma was characterized by multiple numerical and structural changes. In total, more than 500 abnormal chromosomes, including rings, markers, homogeneously stained regions, and double minutes, altogether displaying 608 breakpoints, were detected. This complexity and heterogeneity notwithstanding, a nonrandom karyotypic pattern can be discerned in pancreatic cancer. Chromosomes 1, 3, 6, 7, 8, 11, 12, 17, and 19 and bands 1q12, 1q21, 3q11, 6p21, 6q21, 7q11, 7q22, 7q32, 11q13, 13cen, 14cen, 17q11, 17q21, and 19q13 were most frequently involved in structural rearrangements. A total of 19 recurrent unbalanced structural changes were identified, 11 of which were not reported previously: del(1)(q11), del(3)(p11), i(3)(q10), del(4)(q25), del(11)(p13), dup(11)(q13q23), i(12)(p10), der(13;15)(q10;q10), del(18)(q12), del(18)(q21), and i(19)(q10). The main karyotypic imbalances were entire-copy losses of chromosomes 18, Y, and 21, gains of chromosomes 7, 2, and 20, partial or whole-arm losses of 1p, 3p, 6q, 8p, 9p, 15q, 17p, 18q, 19p, and 20p, and partial or whole-arm gains of 1q, 3q, 5p, 6p, 7q, 8q, 11q, 12p, 17q, 19q, and 20q. In general, the karyotypic pattern of pancreatic carcinoma fits the multistep carcinogenesis concept. The observed cytogenetic heterogeneity appears to reflect a multitude of interchangeable but oncogenetically equivalent events, and the nonrandomness of the chromosomal alterations underscores the preferential pathways involved in tumor initiation and progression.
Collapse
Affiliation(s)
- L Gorunova
- Department of Clinical Genetics, University Hospital, Lund, Sweden
| | | | | | | | | | | | | |
Collapse
|
|
41
|
Höglund M, Gorunova L, Jonson T, Dawiskiba S, Andrén-Sandberg A, Stenman G, Johansson B. Cytogenetic and FISH analyses of pancreatic carcinoma reveal breaks in 18q11 with consistent loss of 18q12-qter and frequent gain of 18p. Br J Cancer 1998; 77:1893-9. [PMID: 9667665 PMCID: PMC2150326 DOI: 10.1038/bjc.1998.315] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Chromosome 18 was analysed using a banding technique and fluorescence in situ hybridization (FISH) in 13 pancreatic carcinoma samples. The cytogenetic analysis revealed that chromosome 18 abnormalities were present in all cases and that several different rearrangements, such as translocations, deletions, dicentrics and ring chromosomes, were often found together. FISH mapping using 18q YAC probes showed that all tumours had lost at least one copy of 18q and that 18p was over-represented in 6 of the 13 cases. Furthermore, out of 13 identified deletion breakpoints on 18q, 11 were mapped to 18q11. The clustering of breaks close to the centromere indicates that loss of genes in bands 18q11 and 18q12, in addition to those located in 18q21, e.g. DPC4 and DCC, are important in the development of pancreatic tumours.
Collapse
Affiliation(s)
- M Höglund
- Department of Clinical Genetics, University Hospital, Lund, Sweden
| | | | | | | | | | | | | |
Collapse
|
|
42
|
Höglund M, Gorunova L, Andrén-Sandberg Å, Dawiskiba S, Mitelman F, Johansson B. Cytogenetic and fluorescence in situ hybridization analyses of chromosome 19 aberrations in pancreatic carcinomas: Frequent loss of 19p13.3 and gain of 19q13.1-13.2. Genes Chromosomes Cancer 1998. [DOI: 10.1002/(sici)1098-2264(199801)21:1<8::aid-gcc3>3.0.co;2-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
|
|
43
|
|
|
44
|
Abstract
Pancreatic cancer is the fifth leading cause of cancer death in the United States, and despite improvements in the results of surgical treatment for this disease, little impact has been made upon overall mortality. New advances in treatment will depend upon improved adjuvant therapy, early diagnosis, and a better understanding of tumor biology. This article summarizes the results of molecular genetic studies in pancreatic cancer and their potential clinical significance. Familial predisposition to pancreatic cancer, cytogenic studies, DNA ploidy analysis, and examination of specific oncogenes and tumor suppressor genes are reviewed. The most frequent mutations detected have been in the K-ras oncogene, which occur in 80% of pancreatic cancers. These mutations do not correlate with tumor stage or survival, but can be useful in differentiating pancreatic exocrine from endocrine tumors and chronic pancreatitis. Mutations in the p53 gene occur in approximately 50% of tumors, and appear to be an independent prognostic factor for patient survival. Mutations in the CDKN2 gene are frequently seen in sporadic pancreatic cancers, and have been implicated in cases of familial pancreatic cancer. The significance of mutations in APC, MCC, DCC, c-erbB-2, RB-1, and mismatch repair genes in the genesis of pancreatic cancer is less clear.
Collapse
Affiliation(s)
- J R Howe
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, USA
| | | |
Collapse
|
|
45
|
Imai Y, Tsurutani N, Oda H, Nakatsuru Y, Inoue T, Ishikawa T. p16INK4 gene mutations are relatively frequent in ampullary carcinomas. Jpn J Cancer Res 1997; 88:941-6. [PMID: 9414654 PMCID: PMC5921281 DOI: 10.1111/j.1349-7006.1997.tb00312.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
A high incidence of gene mutations or deletions of p16INK4, a cell cycle regulator which inhibits the activity of cyclin-dependent kinase 4/cyclin D complex and blocks the G1-to-S transition, has been reported in pancreato-biliary tract cancers. In order to investigate p16INK4 gene alterations in sporadic ampullary carcinomas, 17 sporadic ampullary carcinomas were examined. After histological diagnosis, DNA samples extracted separately from both cancerous and normal paraffin-embedded tissues were investigated. Loss of heterozygosity (LOH) was investigated utilizing 3 microsatellite markers on 9p21-22, and a mutational analysis was performed by cloning and sequencing. LOH was observed in 3 cases (17.6%) and somatic mutations with retention of heterozygosity were found in 7 cases (41.2%). Of note was that two mutations resulted in truncated incomplete proteins and one was a point mutation at the consensus site in the conserved ankyrin repeats, which would be crucial for function. Although two-hit inactivation was not evident in any of the mutation cases and further investigation would be needed to elucidate the role of altered p16INK4, these results suggest that the p16INK4 gene mutations are relatively frequent and its inactivation might be important in ampullary carcinogenesis.
Collapse
Affiliation(s)
- Y Imai
- Department of Pathology, Faculty of Medicine, University of Tokyo
| | | | | | | | | | | |
Collapse
|
|
46
|
|
|
47
|
Jarrard DF, Bova GS, Ewing CM, Pin SS, Nguyen SH, Baylin SB, Cairns P, Sidransky D, Herman JG, Isaacs WB. Deletional, mutational, and methylation analyses of CDKN2 (p16/MTS1) in primary and metastatic prostate cancer. Genes Chromosomes Cancer 1997. [DOI: 10.1002/(sici)1098-2264(199706)19:2<90::aid-gcc4>3.0.co;2-v] [Citation(s) in RCA: 123] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
|
|
48
|
Abstract
Cellular protooncogenes, tumor suppressor genes (antioncogenes), and DNA mismatch repair mutators are generally the key molecular genetic biomarkers undergoing alterations during carcinogenesis, i.e., activation of oncogenes, inactivation of tumor suppressors, and DNA mismatch repair gene defects are essential events in cancer causation. In pancreas cancer, high incidence of oncogene K-ras point mutations at the codon 12th is associated with premalignant and malignant transformation. Mutation in p53 tumor suppressor is also detected in pancreas adenocarcinoma. Concurrent loss of p53 and K-ras function may contribute to the clinical aggressiveness of pancreas cancer. Microsatellite instability and DNA mismatch repair defects may represent new mutator phenotype for pancreas carcinogenesis. Mutation of cell cycle regulators, such as inhibitor of CDK4 or p16 tumor suppressor gene, is a new molecular event in pancreas cancer. Mutation of cyclin-dependent kinases also may be involved in pancreas carcinogenesis. Loss or mutation of a new candidate tumor suppressor, DPC4 (deleted in pancreas carcinoma locus 4), is reported in pancreas cancer. The protein products of these gene mutations are potential tumor antigens, thus genotype expression can be detected by phenotype. Most of these emerging molecular genetic biomarkers are associated with regulation of cell growth and recognition, as well as gene expression, and may offer new insight into the cellular precursors to and genesis of pancreas cancer.
Collapse
Affiliation(s)
- T M Chu
- Department of Diagnostic Immunology Research and Biochemistry, Roswell Park Cancer Institute, Buffalo, New York 14263, USA
| |
Collapse
|
|
49
|
Foulkes WD, Flanders TY, Pollock PM, Hayward NK. The CDKN2A (p16) Gene and Human Cancer. Mol Med 1997. [DOI: 10.1007/bf03401664] [Citation(s) in RCA: 72] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022] Open
|
|
50
|
McKie AB, Iwamura T, Leung HY, Hollingsworth MA, Lemoine NR. Alu-polymerase chain reaction genomic fingerprinting technique identifies multiple genetic loci associated with pancreatic tumourigenesis. Genes Chromosomes Cancer 1997; 18:30-41. [PMID: 8993978 DOI: 10.1002/(sici)1098-2264(199701)18:1<30::aid-gcc4>3.0.co;2-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
DNA fingerprinting can be used to detect genetic rearrangements in cancer that may be associated with activation of oncogenes and inactivation of tumour suppressor genes. We have developed a fingerprinting strategy based on polymerase chain reaction (PCR) amplification of genomic DNA with primers specific for the Alu repeat sequences, which are highly abundant in the human genome. This has been applied to DNA from pancreatic cancer and paired normal samples to isolate and identify fragments of genomic DNA rearranged in the malignant cells. These fragments have been sequenced and used as probes to isolate hybridising clones from gridded bacteriophage P1, phage artificial chromosome, and cosmid libraries for fluorescent in situ hybridisation mapping and the identification of expressed sequences. Further characterisation has identified a putative novel gene (ART1) that is up-regulated specifically in pancreatic cancer as well as another sequence with similarity to genes involved in differentiation (POU domains). In conclusion, we suggest that Alu-PCR fingerprinting may be a useful technique for the identification of genes involved in tumourigenesis.
Collapse
Affiliation(s)
- A B McKie
- Imperial Cancer Research Fund Oncology Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom
| | | | | | | | | |
Collapse
|