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Lee JW, Hruban RH, Wood LD. Molecular Understanding of the Development of Ductal Pancreatic Cancer. THE PANCREAS 2023:912-920. [DOI: 10.1002/9781119876007.ch119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Park D, Shakya R, Koivisto C, Pitarresi JR, Szabolcs M, Kladney R, Hadjis A, Mace TA, Ludwig T. Murine models for familial pancreatic cancer: Histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains. PLoS One 2019; 14:e0226714. [PMID: 31877165 PMCID: PMC6932818 DOI: 10.1371/journal.pone.0226714] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 12/03/2019] [Indexed: 12/14/2022] Open
Abstract
Alterations of the PALB2 tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated Palb2 mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated Brca1/2 pancreatic cancer models. For development of Palb2 pancreatic cancer, we crossed conditional Palb2 null mouse with mice carrying the KrasG12D; p53R270H; Pdx1-Cre (KPC) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of Palb2, Brca1 or Brca2 genes in pancreas per se using Pdx1-Cre was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant KrasG12D and p53R270H, with tumor suppressor inactivated strains in Palb2-KPC, Brca1-KPC or Brca2-KPC, accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most Brca1-KPC and some Palb2-KPC animals developed mucinous cystic neoplasms with PDAC, while Brca2-KPC and KPC animals did not. 26% of Palb2-KPC mice developed MCNs in pancreata, which resemble closely the Brca1 deficient tumors. However, the remaining 74% of Palb2-KPC animals developed PDACs without any cysts like Brca2 deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3+ and F/480+) were significantly increased in Brca1-KPC tumors, but not in Brca2-KPC tumors. Interestingly, the level of ADM lesions and infiltration of CD3+ or F/480+ cells in Palb2-KPC tumors were intermediate between Brca1-KPC and Brca2-KPC tumors. As expected, disruption of Palb2 and Brca1/2 sensitized tumor cells to DNA damaging agents in vitro and in vivo. Altogether, Palb2-KPC PDAC exhibited features observed in both Brca1-KPC and Brca2-KPC tumors, which could be due to its role, as a linker between Brca1 and Brca2.
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Affiliation(s)
- Dongju Park
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Reena Shakya
- The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Christopher Koivisto
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Jason R Pitarresi
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Matthias Szabolcs
- Institute for Cancer Genetics, Department of Pathology and Cell Biology, and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York, United States of America
| | - Raleigh Kladney
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Ashley Hadjis
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
| | - Thomas A Mace
- Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America
| | - Thomas Ludwig
- Department of Cancer Biology and Genetics, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States of America
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Hruban RH, Klimstra DS, Zamboni G, Klöppel G. A semicentennial of pancreatic pathology: the genetic revolution is here, but don't throw the baby out with the bath water! Hum Pathol 2019; 95:99-112. [PMID: 31521627 DOI: 10.1016/j.humpath.2019.08.024] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 08/28/2019] [Indexed: 12/19/2022]
Abstract
The last 50 years have witnessed an explosion in our understanding of the pathology of pancreatic diseases. Entities known to exist 50 years ago have been defined more precisely and are now better classified. New entities, previously not recognized, have been discovered and can now be treated. Importantly, new tools have been developed that have unraveled the fundamental biological drivers of a number of pancreatic diseases. Many of these same tools have also been applied clinically, supplementing the tried and true hematoxylin and eosin stained slide with a plethora of new, highly sensitive and specific tests that improve diagnostic accuracy and delineate best treatments. As exciting as these many advances are, our knowledge of pancreatic pathology remains incomplete, and there is much to be learned.
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Affiliation(s)
- Ralph H Hruban
- The Sol Goldman Pancreatic Cancer Research Center, Departments of Pathology and Oncology, the Johns Hopkins University School of Medicine, Baltimore, 21287, MD, USA.
| | - David S Klimstra
- The Department of Pathology, Memorial Sloan Kettering Cancer Center, NY, USA
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Kaposi Sarcoma in Association With an Extracavitary Primary Effusion Lymphoma Showing Unusual Intravascular Involvement: Report of a Case Harboring a FAM175A Germline Mutation. Am J Dermatopathol 2019; 42:55-60. [PMID: 31361614 DOI: 10.1097/dad.0000000000001491] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Primary effusion lymphoma (PEL) is a rare form of aggressive B-cell lymphoma characterized by a malignant serous effusion involving body cavities. It usually associated with human herpes virus-8 (HHV-8) and coexpression of Epstein-Barr virus and mostly affects patients with HIV. We report a rare case of cutaneous PEL with an unusual intravascular presentation, combined with Kaposi sarcoma involving the skin, lung, and gastrointestinal tract. The molecular genetic analysis of the sarcoma and lymphoma components, using next-generation sequencing was performed. The patient was a 67-year-old man who presented with multiple cutaneous tumors and mass in the left lung. He died 17 hours after the admission to the hospital. At autopsy, in addition to the cutaneous lesions, tumors in the left lung and gastrointestinal mucosa were detected, and no effusions in the body cavities were seen. The biopsy from the cutaneous lesions, pulmonary, and intestinal tumors revealed histological and immunohistochemical features of Kaposi sarcoma. In addition, the skin biopsy specimens contained a diffuse infiltrate composed of large pleomorphic cells, with focal intravascular growth that were negative for pan B-cell markers, weakly positive for CD38 and CD138 but expressed CD3, HHV-8, and Epstein-Barr virus. Molecular genetic studies in this specimen revealed monoclonal rearrangements of the IgH gene. The diagnosis of PEL, solid variant, was made. Next-generation sequencing analysis of the tumorous and normal tissue detected a pathogenic germline mutation of the FAM175A gene and somatic mutations in BRCA2 and RAD51B (in both sarcoma and lymphoma specimens), and INPP4B and RICTOR (in lymphoma specimen only).
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The significance of gene mutations across eight major cancer types. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:88-99. [PMID: 31416581 DOI: 10.1016/j.mrrev.2019.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 04/11/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
Mutations occur spontaneously, which can be induced by either chemicals (e.g. benzene) or biological factors (e.g. virus). Not all mutations cause noticeable changes in cellular functions. However, mutation in key cellular genes leads to developmental disorders. It is one of the main ways in which proto-oncogenes can be changed into their oncogenic state. The progressive accumulation of multiple mutations throughout life leads to cancer. In the past few decades, extensive research on cancer biology has discovered many genes and pathways having role in cancer development. In this review, we tried to summarize the current knowledge of mutational effect on different cancer types and its consequences in brief for future reference and guidance of researchers in cancer biology.
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Sikdar N, Saha G, Dutta A, Ghosh S, Shrikhande SV, Banerjee S. Genetic Alterations of Periampullary and Pancreatic Ductal Adenocarcinoma: An Overview. Curr Genomics 2018; 19:444-463. [PMID: 30258276 PMCID: PMC6128383 DOI: 10.2174/1389202919666180221160753] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 01/31/2018] [Accepted: 02/01/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic Ductal AdenoCarcinoma (PDAC) is one of the most lethal malignancies of all solid cancers. Precancerous lesions for PDAC include PanIN, IPMNs and MCNs. PDAC has a poor prognosis with a 5-year survival of approximately 6%. Whereas Periampulary AdenoCarcinoma (PAC) having four anatomic subtypes, pancreatic, Common Bile Duct (CBD), ampullary and duodenum shows relative better prognosis. The highest incidence of PDAC has been reported with black with respect to white population. Similarly, incidence rate of PAC also differs with different ethnic populations. Several lifestyle, environmental and occupational exposures including long-term diabetes, obesity, and smoking, have been linked to PDAC, however, for PAC the causal risk factors were poorly described. It is now clear that PDAC and PAC are a multi-stage process resulting from the accumulation of genomic alterations in the somatic DNA of normal cells as well as inherited mutations. Approximately 10% of PDAC have a familial inheritance. Germline mutations in CDKN2A, BRCA2, STK11, PALB2, PRSS1, etc., as well as certain syndromes have been well associated with predisposition to PDAC. KRAS, CDKN2A, TP53 and SMAD4 are the 4 "mountains" (high-frequency driver genes) which have been known to earliest somatic alterations for PDAC while relatively less frequent in PAC. Our understanding of the molecular carcinogenesis has improved in the last few years due to extensive research on PDAC which was not well explored in case of PAC. The genetic alterations that have been identified in PDAC and different subgroups of PAC are important implications for the development of genetic screening test, early diagnosis, and prognostic genetic markers. The present review will provide a brief overview of the incidence and prevalence of PDAC and PAC, mainly, increased risk in India, the several kinds of risk factors associated with the diseases as well as required genetic alterations for disease initiation and progression.
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Affiliation(s)
- Nilabja Sikdar
- Address correspondence to this author at the Human Genetics Unit, Indian Statistical Institute, 203, B.T. Road Kolkata 700108, India; Tel (1): +91-33
-25773240 (L); (2): +91-9830780397 (M); Fax: +91 33 35773049;, E-mail:
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Melouane A, Ghanemi A, Aubé S, Yoshioka M, St-Amand J. Differential gene expression analysis in ageing muscle and drug discovery perspectives. Ageing Res Rev 2018; 41:53-63. [PMID: 29102726 DOI: 10.1016/j.arr.2017.10.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Revised: 10/31/2017] [Accepted: 10/31/2017] [Indexed: 12/12/2022]
Abstract
Identifying therapeutic target genes represents the key step in functional genomics-based therapies. Within this context, the disease heterogeneity, the exogenous factors and the complexity of genomic structure and function represent important challenges. The functional genomics aims to overcome such obstacles via identifying the gene functions and therefore highlight disease-causing genes as therapeutic targets. Genomic technologies promise to reshape the research on ageing muscle, exercise response and drug discovery. Herein, we describe the functional genomics strategies, mainly differential gene expression methods microarray, serial analysis of gene expression (SAGE), massively parallel signature sequence (MPSS), RNA sequencing (RNA seq), representational difference analysis (RDA), and suppression subtractive hybridization (SSH). Furthermore, we review these illustrative approaches that have been used to discover new therapeutic targets for some complex diseases along with the application of these tools to study the modulation of the skeletal muscle transcriptome.
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Manthey GM, Clear AD, Liddell LC, Negritto MC, Bailis AM. Homologous recombination in budding yeast expressing the human RAD52 gene reveals a Rad51-independent mechanism of conservative double-strand break repair. Nucleic Acids Res 2017; 45:1879-1888. [PMID: 27923995 PMCID: PMC5389729 DOI: 10.1093/nar/gkw1228] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2016] [Accepted: 11/24/2016] [Indexed: 11/12/2022] Open
Abstract
RAD52 is a homologous recombination (HR) protein that is conserved from bacteriophage to humans. Simultaneously attenuating expression of both the RAD52 gene, and the HR and tumor suppressor gene, BRCA2, in human cells synergistically reduces HR – indicating that RAD52 and BRCA2 control independent mechanisms of HR. We have expressed the human RAD52 gene (HsRAD52) in budding yeast strains lacking the endogenous RAD52 gene and found that HsRAD52 supports repair of DNA double-strand breaks (DSB) by a mechanism of HR that conserves genome structure. Importantly, this mechanism of HR is independent of RAD51, which encodes the central strand exchange protein in yeast required for conservative HR. In contrast, BRCA2 exerts its effect on HR in human cells together with HsRAD51, potentially explaining the synergistic effect of attenuating the expression of both HsRAD52 and BRCA2. This suggests that multiple mechanisms of conservative DSB repair may contribute to tumor suppression in human cells.
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Affiliation(s)
- Glenn M Manthey
- Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Alissa D Clear
- Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.,Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
| | - Lauren C Liddell
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | | | - Adam M Bailis
- Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.,Irell & Manella Graduate School of Biological Sciences, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA
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Kroeger PT, Drummond BE, Miceli R, McKernan M, Gerlach GF, Marra AN, Fox A, McCampbell KK, Leshchiner I, Rodriguez-Mari A, BreMiller R, Thummel R, Davidson AJ, Postlethwait J, Goessling W, Wingert RA. The zebrafish kidney mutant zeppelin reveals that brca2/fancd1 is essential for pronephros development. Dev Biol 2017; 428:148-163. [PMID: 28579318 DOI: 10.1016/j.ydbio.2017.05.025] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Revised: 05/19/2017] [Accepted: 05/22/2017] [Indexed: 12/28/2022]
Abstract
The zebrafish kidney is conserved with other vertebrates, making it an excellent genetic model to study renal development. The kidney collects metabolic waste using a blood filter with specialized epithelial cells known as podocytes. Podocyte formation is poorly understood but relevant to many kidney diseases, as podocyte injury leads to progressive scarring and organ failure. zeppelin (zep) was isolated in a forward screen for kidney mutants and identified as a homozygous recessive lethal allele that causes reduced podocyte numbers, deficient filtration, and fluid imbalance. Interestingly, zep mutants had a larger interrenal gland, the teleostean counterpart of the mammalian adrenal gland, which suggested a fate switch with the related podocyte lineage since cell proliferation and cell death were unchanged within the shared progenitor field from which these two identities arise. Cloning of zep by whole genome sequencing (WGS) identified a splicing mutation in breast cancer 2, early onset (brca2)/fancd1, which was confirmed by sequencing of individual fish. Several independent brca2 morpholinos (MOs) phenocopied zep, causing edema, reduced podocyte number, and increased interrenal cell number. Complementation analysis between zep and brca2ZM_00057434 -/- zebrafish, which have an insertional mutation, revealed that the interrenal lineage was expanded. Importantly, overexpression of brca2 rescued podocyte formation in zep mutants, providing critical evidence that the brca2 lesion encoded by zep specifically disrupts the balance of nephrogenesis. Taken together, these data suggest for the first time that brca2/fancd1 is essential for vertebrate kidney ontogeny. Thus, our findings impart novel insights into the genetic components that impact renal development, and because BRCA2/FANCD1 mutations in humans cause Fanconi anemia and several common cancers, this work has identified a new zebrafish model to further study brca2/fancd1 in disease.
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Affiliation(s)
- Paul T Kroeger
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Bridgette E Drummond
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Rachel Miceli
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Michael McKernan
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Gary F Gerlach
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Amanda N Marra
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Annemarie Fox
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Kristen K McCampbell
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA
| | - Ignaty Leshchiner
- Brigham and Women's Hospital, Genetics and Gastroenterology Division, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | | | - Ruth BreMiller
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Ryan Thummel
- Departments of Anatomy and Cell Biology and Opthamology, Wayne State University School of Medicine, Wayne State University, Detroit, MI 48201, USA
| | - Alan J Davidson
- Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, NZ
| | - John Postlethwait
- Institute of Neuroscience, University of Oregon, Eugene, OR 97403, USA
| | - Wolfram Goessling
- Brigham and Women's Hospital, Genetics and Gastroenterology Division, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02215, USA
| | - Rebecca A Wingert
- Department of Biological Sciences, Center for Stem Cells and Regenerative Medicine, Center for Zebrafish Research, University of Notre Dame, Notre Dame, IN 46556, USA.
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The Role of BRCA2 Mutation Status as Diagnostic, Predictive, and Prognosis Biomarker for Pancreatic Cancer. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1869304. [PMID: 28078281 PMCID: PMC5203890 DOI: 10.1155/2016/1869304] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 11/21/2016] [Accepted: 11/28/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic cancer is one of the deadliest cancers worldwide, and life expectancy after diagnosis is often short. Most pancreatic tumours appear sporadically and have been highly related to habits such as cigarette smoking, high alcohol intake, high carbohydrate, and sugar consumption. Other observational studies have suggested the association between pancreatic cancer and exposure to arsenic, lead, or cadmium. Aside from these factors, chronic pancreatitis and diabetes have also come to be considered as risk factors for these kinds of tumours. Studies have found that 10% of pancreatic cancer cases arise from an inherited syndrome related to some genetic alterations. One of these alterations includes mutation in BRCA2 gene. BRCA2 mutations impair DNA damage response and homologous recombination by direct regulation of RAD51. In light of these findings that link genetic factors to tumour development, DNA damage agents have been proposed as target therapies for pancreatic cancer patients carrying BRCA2 mutations. Some of these drugs include platinum-based agents and PARP inhibitors. However, the acquired resistance to PARP inhibitors has created a need for new chemotherapeutic strategies to target BRCA2. The present systematic review collects and analyses the role of BRCA2 alterations to be used in early diagnosis of an inherited syndrome associated with familiar cancer and as a prognostic and predictive biomarker for the management of pancreatic cancer patients.
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Jamieson NB, Maker AV. Gene-expression profiling to predict responsiveness to immunotherapy. Cancer Gene Ther 2016; 24:134-140. [PMID: 27834354 PMCID: PMC5386795 DOI: 10.1038/cgt.2016.63] [Citation(s) in RCA: 67] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 10/06/2016] [Indexed: 12/17/2022]
Abstract
Recent clinical successes with immunotherapy have resulted in expanding indications for cancer therapy. To enhance anti-tumor immune responses, and to better choose specific strategies matched to patient and tumor characteristics, genomic-driven precision immunotherapy will be necessary. Herein, we explore the role that tumor gene expression profiling (GEP) and transcriptome expression may play in the prediction of an immunotherapeutic response. Genetic markers associated with response to immunotherapy are addressed as they pertain to the tumor genomic landscape, the extent of DNA damage, tumor mutational load, and tumor-specific neoantigens. Furthermore, genetic markers associated with resistance to checkpoint blockade and relapse are reviewed. Finally, the utility of GEP to identify new tumor types for immunotherapy and implications for combinatorial strategies are summarized.
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Affiliation(s)
- N B Jamieson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences and the Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland.,West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland
| | - A V Maker
- Department of Surgery, Division of Surgical Oncology; Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA
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Can Molecular Biomarkers Change the Paradigm of Pancreatic Cancer Prognosis? BIOMED RESEARCH INTERNATIONAL 2016; 2016:4873089. [PMID: 27689078 PMCID: PMC5023838 DOI: 10.1155/2016/4873089] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Revised: 07/28/2016] [Accepted: 08/03/2016] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma is one of the most lethal types of tumour, and its incidence is rising worldwide. Although survival can be improved when these tumours are detected at an early stage, this cancer is usually asymptomatic, and the disease only becomes apparent after metastasis. The only prognostic biomarker approved by the FDA to date is carbohydrate antigen 19-9 (CA19-9); however, the specificity of this biomarker has been called into question, and diagnosis is usually based on clinical parameters. Tumour size, degree of differentiation, lymph node status, presence of distant metastasis at diagnosis, protein levels of KI-67 or C-reactive protein, and mutational status of P53, KRAS, or BRCA2 are the most useful biomarkers in clinical practice. In addition to these, recent translational research has provided evidence of new biomarkers based on different molecules involved in endoplasmic reticulum stress, epithelial-to-mesenchymal transition, and noncoding RNA panels, especially microRNAs and long noncoding RNAs. These new prospects open new paths to tumour detection using minimally or noninvasive techniques such as liquid biopsies. To find sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
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Takai E, Yachida S. Genomic alterations in pancreatic cancer and their relevance to therapy. World J Gastrointest Oncol 2015; 7:250-258. [PMID: 26483879 PMCID: PMC4606179 DOI: 10.4251/wjgo.v7.i10.250] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Revised: 07/28/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is a highly lethal cancer type, for which there are few viable therapeutic options. But, with the advance of sequencing technologies for global genomic analysis, the landscape of genomic alterations in pancreatic cancer is becoming increasingly well understood. In this review, we summarize current knowledge of genomic alterations in 12 core signaling pathways or cellular processes in pancreatic ductal adenocarcinoma, which is the most common type of malignancy in the pancreas, including four commonly mutated genes and many other genes that are mutated at low frequencies. We also describe the potential implications of these genomic alterations for development of novel therapeutic approaches in the context of personalized medicine.
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Abstract
There is now compelling evidence that the molecular heterogeneity of cancer is associated with disparate phenotypes with variable outcomes and therapeutic responsiveness to therapy in histologically indistinguishable cancers. This diversity may explain why conventional clinical trial designs have mostly failed to show efficacy when patients are enrolled in an unselected fashion. Knowledge of the molecular phenotype has the potential to improve therapeutic selection and hence the early delivery of the optimal therapeutic regimen. Resolution of the challenges associated with a more stratified approach to health care will ensure more precise diagnostics and enhance therapeutic selection, which will improve overall outcomes.
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Affiliation(s)
- Nigel B Jamieson
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, Glasgow Royal Infirmary, University of Glasgow, Alexandra Parade, Glasgow G31 2ER, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, UK
| | - David K Chang
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Goulburn St, Liverpool, New South Wales 2170, Australia
| | - Andrew V Biankin
- Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK; The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, New South Wales 2010, Australia; Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia; Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Goulburn St, Liverpool, New South Wales 2170, Australia.
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Luo G, Lu Y, Jin K, Cheng H, Guo M, Liu Z, Long J, Liu C, Ni Q, Yu X. Pancreatic cancer: BRCA mutation and personalized treatment. Expert Rev Anticancer Ther 2015; 15:1223-1231. [PMID: 26402249 DOI: 10.1586/14737140.2015.1086271] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The highly heterozygous nature of pancreatic cancer is partially responsible for its therapeutic ineffectiveness and resistance. Therefore, the ability to identify subgroups of pancreatic cancer with unique biological characteristics and treatment response is urgently needed. In addition to breast and ovarian cancer, pancreatic cancer is the third most common cancer type that is related to the early onset (BRCA) gene mutation in breast cancer. Mounting evidence has demonstrated that BRCA1/2-mutant breast and ovarian cancers are highly sensitive to DNA damage-related treatment, including poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum-based agents. Preliminary evidence also showed promising results for DNA damage-related treatment in BRCA1/2-mutant pancreatic cancer. Importantly, several prospective clinical trials of PARPi-based regimens are underway for BRCA1/2-mutated pancreatic cancer. Pancreatic cancer with a BRCA1/2 mutation is a small subgroup with a promising therapeutic strategy.
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Langer P, Slater E, Fendrich V, Habbe N, Bartsch DK. Familial pancreatic cancer: current status. ACTA ACUST UNITED AC 2013; 1:193-201. [PMID: 23489306 DOI: 10.1517/17530059.1.2.193] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The term 'familial pancreatic cancer (FPC) defines families with at least two first-degree relatives with confirmed pancreatic cancer that do not fulfill the criteria of other inherited cancer syndromes with an increased risk for the development of PC, such as Peutz-Jeghers syndrome, hereditary pancreatitis and hereditary breast and ovarian cancer. FPC is a mostly autosomal dominant inherited tumor syndrome with a heterogeneous phenotype. The major genetic defect has not been identified yet, although mutations, for example in the BRCA2 gene, could be identified in some FPC families. Nevertheless, most experts recommend participation in screening and surveillance programs to high-risk individuals. Most board-approved screening programs are based on endoscopic ultrasound. The first data on the prospective screening of high-risk individuals have demonstrated that precursor lesions of PC can be identified, but false-positive findings do occur.
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Affiliation(s)
- Peter Langer
- Philipps-University Hospital, Department of General Surgery, Baldingerstraße, D-35043 Marburg, Germany +49 6421 2866442 ; +49 6421 2868995
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17
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Rothenberg SM, Settleman J. Discovering tumor suppressor genes through genome-wide copy number analysis. Curr Genomics 2011; 11:297-310. [PMID: 21286308 PMCID: PMC2944996 DOI: 10.2174/138920210791616734] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2010] [Revised: 04/07/2010] [Accepted: 04/07/2010] [Indexed: 12/31/2022] Open
Abstract
Classical tumor suppressor gene discovery has largely involved linkage analysis and loss-of-heterozygosity (LOH) screens, followed by detailed mapping of relatively large chromosomal regions. Subsequent efforts made use of genome-wide PCR-based methods to detect rare homozygous deletions. More recently, high-resolution genomic arrays have been applied to cancer gene discovery. However, accurate characterization of regions of genomic loss is particularly challenging due to sample heterogeneity, the small size of deleted regions and the high frequency of germline copy number polymorphisms. Here, we review the application of genome-wide copy number analysis to the specific problem of identifying tumor suppressor genes.
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Affiliation(s)
- S Michael Rothenberg
- Massachusetts General Hospital Cancer Center and Harvard Medical School, 149, 13th Street, Charlestown, MA 02129, USA
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18
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Ottenhof NA, de Wilde RF, Maitra A, Hruban RH, Offerhaus GJA. Molecular characteristics of pancreatic ductal adenocarcinoma. PATHOLOGY RESEARCH INTERNATIONAL 2011; 2011:620601. [PMID: 21512581 PMCID: PMC3068308 DOI: 10.4061/2011/620601] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2010] [Revised: 12/07/2010] [Accepted: 01/10/2011] [Indexed: 12/14/2022]
Abstract
Pancreatic cancer is an almost universally lethal disease and despite extensive research over the last decades, this has not changed significantly. Nevertheless, much progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) suggesting that different therapeutic strategies based on these new insights are forthcoming. Increasing focus exists on designing the so-called targeted treatment strategies in which the genetic characteristics of a tumor guide therapy. In the past, the focus of research was on identifying the most frequently affected genes in PDAC, but with the complete sequencing of the pancreatic cancer genome the focus has shifted to defining the biological function that the altered genes play. In this paper we aimed to put the genetic alterations present in pancreatic cancer in the context of their role in signaling pathways. In addition, this paper provides an update of the recent advances made in the development of the targeted treatment approach in PDAC.
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Affiliation(s)
- Niki A. Ottenhof
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
| | - Roeland F. de Wilde
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Anirban Maitra
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - Ralph H. Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21287, USA
| | - G. Johan A. Offerhaus
- Department of Pathology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands
- *G. Johan A. Offerhaus:
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19
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Slater EP, Langer P, Fendrich V, Habbe N, Chaloupka B, Matthäi E, Sina M, Hahn SA, Bartsch DK. Prevalence of BRCA2 and CDKN2a mutations in German familial pancreatic cancer families. Fam Cancer 2010; 9:335-43. [PMID: 20195775 DOI: 10.1007/s10689-010-9329-6] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Previous small scale studies reported that deleterious BRCA2 and CDKN2a germline mutations contribute to a subset of families with inherited pancreatic cancer. As the prevalence of those mutations in the setting of familial pancreatic cancer is still not well defined for the German population, we evaluated the presence of BRCA2 and CDKN2a germline mutations in a large cohort of familial pancreatic cancer (FPC) families from the German National Case Collection for Familial Pancreatic Cancer (FaPaCa). Fifty-six FPC families with at least two-first-degree relatives with confirmed pancreatic cancer that did not fulfill the criteria of other tumor predisposition syndromes, were analyzed for BRCA2 and CDKN2a germline mutations by DHPLC and/or direct sequencing. No deleterious CDKN2a mutations were identified in our families suggesting that CDKN2a mutations are unlikely to predispose PC in FPC families without melanoma. No deleterious BRCA2 mutations, but 6 unclassified variants, were detected in our FPC collection. Combining the prevalence of deleterious BRCA2 germline mutations from our previous separate study with the data from this study we were able to much more accurately estimate the BRCA2 carrier frequency for FPC families in the German population. A total of two mutations and 6 unclassified variants (mutation range: 2.8-11.4%) were thus identified in 70 German FPC families, indicating that the prevalence of BRCA2 mutations in the German FPC population is less frequent than previously reported.
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Affiliation(s)
- Emily P Slater
- Department of Visceral-, Thoracic and Vascular Surgery, Philipps-University Marburg, Baldingerstrasse, 35043, Marburg, Germany.
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20
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Rothenberg SM, Mohapatra G, Rivera MN, Winokur D, Greninger P, Nitta M, Sadow PM, Sooriyakumar G, Brannigan BW, Ulman MJ, Perera RM, Wang R, Tam A, Ma XJ, Erlander M, Sgroi DC, Rocco JW, Lingen MW, Cohen EEW, Louis DN, Settleman J, Haber DA. A genome-wide screen for microdeletions reveals disruption of polarity complex genes in diverse human cancers. Cancer Res 2010; 70:2158-64. [PMID: 20215515 PMCID: PMC2881662 DOI: 10.1158/0008-5472.can-09-3458] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In a genome-wide screen of 684 cancer cell lines, we identified homozygous intragenic microdeletions involving genes encoding components of the apical-basal cell polarity complexes. Among these, PARD3 is disrupted in cell lines and primary tumors from squamous carcinomas and glioblastomas. Reconstituting PARD3 expression in both cell types restores tight junctions and retards contact-dependent proliferation. Searching specifically for small intragenic microdeletions using high-resolution genomic arrays may be complementary to other genomic deletion screens and resequencing efforts in identifying new tumor suppressor genes.
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Affiliation(s)
- S Michael Rothenberg
- Massachusetts General Hospital Cancer Center and Center for Molecular Therapeutics, Harvard Medical School, Charlestown, Massachusetts 02129, USA
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21
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Hruban RH, Adsay NV. Molecular classification of neoplasms of the pancreas. Hum Pathol 2009; 40:612-23. [PMID: 19362631 DOI: 10.1016/j.humpath.2009.01.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Accepted: 01/16/2009] [Indexed: 12/17/2022]
Abstract
The recent sequencing of the pancreatic cancer genome provides unprecedented insight into the fundamental nature of this deadly malignancy. Although much work still needs to be done, a molecular classification of neoplasms of the pancreas is emerging. Molecular genetics have been used to identify unique clinical subtypes of pancreatic cancer, to guide the clinical diagnosis of pancreatic tumors, and to identify targeted therapies for select pancreatic neoplasms. This review examines the emerging molecular classification of neoplasms of the pancreas. This classification does not ignore previous histology-based classification systems but instead embraces them, creating an integrated histological-molecular classification.
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Affiliation(s)
- Ralph H Hruban
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
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22
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Kim MP, Evans DB, Vu TM, Fleming JB. The recognition and surgical management of heritable lesions of the pancreas. Surg Oncol Clin N Am 2009; 18:99-119, ix. [PMID: 19056044 DOI: 10.1016/j.soc.2008.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Our knowledge regarding the inherited factors that lead to the development of lesions within the pancreas is clearly incomplete. This article addresses clinical issues in patients at moderate-to-high risk for pancreatic malignancy, with special emphasis on the recognition and diagnosis of known genetic syndromes. Using the current available information, the authors attempt to equip the practicing surgeon with critical information to increase clinical suspicion for heritable syndromes and inform specific surgical management. Additionally, this article is meant to encourage the practicing surgeon to participate in the genetic testing/screening, cancer surveillance, and prevention activities of patients who have heritable cancer syndromes and associated pancreatic lesions that require surgery.
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Affiliation(s)
- Michael P Kim
- Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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23
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Alsop AE, Taylor K, Zhang J, Gabra H, Paige AJW, Edwards PAW. Homozygous deletions may be markers of nearby heterozygous mutations: The complex deletion at FRA16D in the HCT116 colon cancer cell line removes exons of WWOX. Genes Chromosomes Cancer 2008; 47:437-47. [PMID: 18273838 DOI: 10.1002/gcc.20548] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
Homozygous deletions in cancer cells have been thought to harbor tumor suppressor genes. We show that the 25 and 50 kb homozygous deletions in WWOX in the colon cancer cell line HCT116 result from a complex set of heterozygous deletions, some of which overlap to give homozygous loss. One of the heterozygous deletions has removed exons 6-8 of one allele of WWOX, and there is also a third copy of the distal region of WWOX in an unbalanced translocation. The exon 6-8 deletion results in allele-specific expression of a deleted transcript, which seems likely to be the main biological consequence of the deletions, since similar transcripts are found in other tumors. We show that such a complex set of deletions could form in a single exchange event between two homologous chromosomes, so that the selective advantage of such rearrangements need not be within the homozygous deletion. We conclude that homozygous deletions can be markers of complex rearrangements that have targets outside the homozygous deletion itself and that the target of deletions in the FRA16D region is indeed WWOX, the common outcome being the removal of particular WWOX exons. This article contains supplementary material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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Affiliation(s)
- Amber E Alsop
- Hutchison/MRC Research Centre and Department of Pathology, University of Cambridge, Cambridge, UK
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24
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Abstract
Pancreatic cancer is an almost universally lethal disease. Research over the last two decades has shown that pancreatic cancer is fundamentally a genetic disease, caused by inherited germline and acquired somatic mutations in cancer-associated genes. Multiple alterations in genes that are important in pancreatic cancer progression have been identified, including tumor suppressor genes, oncogenes, and genome maintenance genes. Furthermore, the identification of noninvasive precursor lesions of pancreatic adenocarcinoma has led to the formulation of a multi-step progression model of pancreatic cancer and the subsequent identification of early and late genetic alterations culminating in invasive cancer. In addition, an increased understanding of the molecular basis of the disease has facilitated the identification of new drug targets enabling rational drug design. The elucidation of genetic alterations in combination with the development of high-throughput sensitive techniques should lead to the discovery of effective biomarkers for early detection of this malignancy. This review focuses mainly on the current knowledge about the molecular insights of the pathogenesis of pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Jan-Bart M. Koorstra
- Department of Pathology, University Medical Center, Utrecht, The Netherlands, Baltimore, Md., USA
- Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md., USA
| | - Steven R. Hustinx
- Department of Pathology, University Medical Center, Utrecht, The Netherlands, Baltimore, Md., USA
| | - G. Johan A. Offerhaus
- Department of Pathology, University Medical Center, Utrecht, The Netherlands, Baltimore, Md., USA
| | - Anirban Maitra
- Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Md., USA
- Oncology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Md., USA
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25
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Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias. Blood 2008; 111:4716-22. [PMID: 18299447 DOI: 10.1182/blood-2007-10-113068] [Citation(s) in RCA: 71] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Ceramide is a lipid second messenger derived from the hydrolysis of sphingomyelin by sphingomyelinases (SMases) and implicated in diverse cellular responses, including growth arrest, differentiation, and apoptosis. Defects in the neutral SMase (nSMase) gene Smpd3, the primary regulator of ceramide biosynthesis, are responsible for developmental defects of bone; regulation of ceramide levels have been implicated in macrophage differentiation, but this pathway has not been directly implicated in human cancer. In a genomic screen for gene copy losses contributing to tumorigenesis in a mouse osteosarcoma model, we identified a somatic homozygous deletion specifically targeting Smpd3. Reconstitution of SMPD3 expression in mouse tumor cells lacking the endogenous gene enhanced tumor necrosis factor (TNF)-induced reduction of cell viability. Nucleotide sequencing of the highly conserved SMPD3 gene in a large panel of human cancers revealed mutations in 5 (5%) of 92 acute myeloid leukemias (AMLs) and 8 (6%) of 131 acute lymphoid leukemias (ALLs), but not in other tumor types. In a subset of these mutations, functional analysis indicated defects in protein stability and localization. Taken together, these observations suggest that disruption of the ceramide pathway may contribute to a subset of human leukemias.
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26
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van Hattem WA, Carvalho R, Li A, Offerhaus GJA, Goggins M. Amplification of EMSY gene in a subset of sporadic pancreatic adenocarcinomas. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2008; 1:343-351. [PMID: 18787609 PMCID: PMC2480540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 08/10/2007] [Accepted: 08/28/2007] [Indexed: 05/26/2023]
Abstract
Mutations in the breast cancer susceptibility gene 2 (BRCA2) are commonly found in familial pancreatic cancer. Recently, EMSY (11q13.5) has been described as a BRCA2 interacting protein capable of binding and inactivating the protein domain encoded by exon 3 of the BRCA2 gene. Amplification of EMSY occurs in 13% of sporadic breast cancers and is directly linked to increased expression. Here we investigate the amplification status of this new potential oncogene in 59 sporadic pancreatic cancers using fluorescence in situ hybridization (FISH) and tissue microarray (TMA). Real-time quantitative RT-PCR was performed on 20 pancreatic cancer cell lines and overexpression was calculated using the delta-delta-Ct-method. Amplification of EMSY was found in 8/59 cases (13.6%). 9/20 (45%) cell line samples showed overexpression of EMSY. In conclusion, sporadic pancreatic cancer shows amplification of EMSY at prevalence similar to that found in other cancers.
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Affiliation(s)
- W Arnout van Hattem
- Department of Pathology, Academic Medical CenterAmsterdam, the Netherlands
- Oncology Center, The Sol Goldman Pancreatic Research Center, The Johns Hopkins University School of MedicineBaltimore, Maryland, USA
- the University Medical CenterUtrecht, the Netherlands
| | - Ralph Carvalho
- Department of Pathology, Academic Medical CenterAmsterdam, the Netherlands
- Oncology Center, The Sol Goldman Pancreatic Research Center, The Johns Hopkins University School of MedicineBaltimore, Maryland, USA
| | - Ang Li
- Department of Pathology, Academic Medical CenterAmsterdam, the Netherlands
| | - G Johan A Offerhaus
- Oncology Center, The Sol Goldman Pancreatic Research Center, The Johns Hopkins University School of MedicineBaltimore, Maryland, USA
- the University Medical CenterUtrecht, the Netherlands
| | - Michael Goggins
- Department of Pathology, Academic Medical CenterAmsterdam, the Netherlands
- Department of Pathology, The Sol Goldman Pancreatic Research Center, The Johns Hopkins University School of MedicineBaltimore, Maryland, USA
- Department of Medicine, The Sol Goldman Pancreatic Research Center, The Johns Hopkins University School of MedicineBaltimore, Maryland, USA
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27
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Suzuki T, Matsuo K, Wakai K, Hiraki A, Hirose K, Sato S, Ueda R, Tajima K. Effect of familial history and smoking on common cancer risks in Japan. Cancer 2007; 109:2116-23. [PMID: 17410537 DOI: 10.1002/cncr.22685] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Inherited genetic predispositions are important risk factors for the development of cancer in general. To determine genetic susceptibility for 14 common cancers, a case-control study of the impact of a family history of cancer in first-degree relatives was conducted. The authors further evaluated the effect modification by habitual smoking with adjustment for other confounding environmental factors. METHODS In total, 18,836 cancer cases and 28,125 age-matched and sex-matched controls, confirmed as being free of cancer, were recruited. Odds ratios (ORs) and 95% confidence intervals were determined by multiple logistic regression analysis, including stratification by family history for 14 cancer sites and interactions with a smoking history. RESULTS The associations between family history and risk of cancer were generally stronger at the same sites than across cancer sites. Risks to first-degree relatives at the same sites were found to be significantly elevated with 8 of 14 cancer sites; especially high ORs were found for prostate and thyroid cancers. Some across-site associations were observed; in particular, a reciprocal association between breast and prostate cancer was found. The interaction between family history and smoking history for breast cancer was found to be statistically significant. There was no statistical evidence for the interactions in other sites, but among subjects with a family history, the ORs were found to be higher in smokers compared with nonsmokers. CONCLUSIONS The results of the current study support the hypothesis of a genetic susceptibility to cancers in family members. For breast cancer, the interaction between family history and smoking history was observed to be significant.
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Affiliation(s)
- Takeshi Suzuki
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
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28
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Salani R, Chang CL, Cope L, Wang TL. Digital karyotyping: an update of its applications in cancer. Mol Diagn Ther 2006; 10:231-7. [PMID: 16884326 DOI: 10.1007/bf03256461] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
DNA copy number alterations, including entire chromosomal changes and small interstitial DNA amplifications and deletions, characterize the development of cancer. These changes usually affect the expression of target genes and subsequently the function of the target proteins. Since the completion of the human genome project, the capacity to comprehensively analyze the human cancer genome has expanded significantly. Techniques such as digital karyotyping have been developed to allow for the detection of DNA copy number alterations in cancer at the whole-genome scale. When compared with conventional methods such as spectral karyotyping, representational difference analysis, comparative genomic hybridization (CGH), or the more recent array CGH; digital karyotyping provides an evaluation of copy number of genetic material at higher resolution. Digital karyotyping has therefore promised to enhance our understanding of the cancer genome. This article provides an overview of digital karyotyping including the principle of the technology and its applications in identifying potential oncogenes and tumor suppressor genes.
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Affiliation(s)
- Ritu Salani
- Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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29
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Carvalho R, Milne ANA, Polak M, Offerhaus GJA, Weterman MAJ. A novel region of amplification at 11p12-13 in gastric cancer, revealed by representational difference analysis, is associated with overexpression of CD44v6, especially in early-onset gastric carcinomas. Genes Chromosomes Cancer 2006; 45:967-75. [PMID: 16868940 DOI: 10.1002/gcc.20360] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Diffuse-type gastric carcinomas (GCs) are often difficult to characterize because of contamination of tumor samples by surrounding normal tissue. As such, information regarding chromosomal aberrations in this subtype of GCs is limited. In this study, we used representational difference analysis to pinpoint genomic amplifications occurring in diffuse-type GCs. We found nine differential products from two novel regions of amplification in two tumors: one product mapped to 19p13.1 and eight mapped to a 1.8-Mb region in chromosomal segment 11p12-13. These amplifications were confirmed using Southern blot analysis and occurred in 3/16 and 6/15 diffuse-type GCs, respectively. CD44, a well characterized cellular adhesion molecule involved in several human malignancies, is encoded by a gene located within 200 kb of the 11p12-13 amplification fragments. We confirmed that overexpression of isoform CD44v6 was correlated with amplification at 11p12-13 in 11/12 diffuse-type GCs. Since diffuse-type GCs occur more frequently in early-onset gastric carcinomas (EOGCs, presented at 45 years of age or younger) than in "conventional" GCs, and the tumors carrying the original amplifications were EOGCs, we investigated overexpression of CD44v6 in 107 EOGCs and 88 conventional GCs using tissue microarrays. We found frequent CD44v6 overexpression in both tumor groups (76% and 57% respectively) and, interestingly, significantly more cases with overexpression of CD44v6 in EOGCs than in conventional GCs (P = 0.005), irrespective of histology. These findings provide further evidence for both the relevance of CD44 in GC and for distinct molecular characteristics of EOGCs when compared with those of GCs occurring at a later age.
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Affiliation(s)
- Ralph Carvalho
- Department of Pathology, Academisch Medisch Centrum, Amsterdam, The Netherlands.
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30
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Abstract
Exocrine pancreatic cancer is one of the neoplasias with a worse prognosis, with conventional treatments having little impact on disease outcome. Research and genomic high-throughput technology is continuously expanding our knowledge of pancreas cancer biology. Characterization of genetic and epigenetic alterations in pancreatic tumors has allowed a better understanding of the progression model of the disease at the molecular level. The development of new therapeutic approaches with target- oriented agents is been tested in the preclinical and clinical settings. This review updates the current available data on pancreatic cancer molecular biology.
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Affiliation(s)
- J L Soto
- Laboratorio de Oncología Molecular, Hospital General Universitario de Elche e Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche, Spain
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31
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Habbe N, Langer P, Sina-Frey M, Bartsch DK. Familial pancreatic cancer syndromes. Endocrinol Metab Clin North Am 2006; 35:417-30, xi. [PMID: 16632103 DOI: 10.1016/j.ecl.2006.02.016] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hereditary pancreatic cancer (PC) is rare and extremely heterogeneous, and it accounts for approximately 2% of all PC cases. The major component of hereditary PC is the familial pancreatic cancer syndrome. Although up to 20% of hereditary PC cases are associated with germline mutations in the BRCA2, CDKN2A, PRSS1,STKI1, or MMR genes, the major underlying gene defect(s) is still unknown. Although hereditary PC is rare, the data on PC families that have been collected by various study groups worldwide provide a unique opportunity to evaluate the natural history, causative gene alterations, new diagnosis and chemoprevention strategies as well as treatment modalities.
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Affiliation(s)
- Nils Habbe
- Department of Surgery, Philipps-University Marburg, Baldiger Strasse, Marburg 35033, Germany
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32
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Abstract
Pancreatic ductal adenocarcinoma is one of the most fatal malignancies. Intensive investigation of molecular pathogenesis might lead to identifying useful molecules for diagnosis and treatment of the disease. Pancreatic ductal adenocarcinoma harbors complicated aberrations of alleles including losses of 1p, 6q, 9p, 12q, 17p, 18q, and 21q, and gains of 8q and 20q. Pancreatic cancer is usually initiated by mutation of KRAS and aberrant expression of SHH. Overexpression of AURKA mapping on 20q13.2 may significantly enhance overt tumorigenesity. Aberrations of tumor suppressor genes synergistically accelerate progression of the carcinogenic pathway through pancreatic intraepithelial neoplasia (PanIN) to invasive ductal adenocarcinoma. Abrogation of CDKN2A occurs in low-grade/early PanIN, whereas aberrations of TP53 and SMAD4 occur in high-grade/late PanIN. SMAD4 may play suppressive roles in tumorigenesis by inhibition of angiogenesis. Loss of 18q precedes SMAD4 inactivation, and restoration of chromosome 18 in pancreatic cancer cells results in tumor suppressive phenotypes regardless of SMAD4 status, indicating the possible existence of a tumor suppressor gene(s) other than SMAD4 on 18q. DUSP6 at 12q21-q22 is frequently abrogated by loss of expression in invasive ductal adenocarcinomas despite fairly preserved expression in PanIN, which suggests that DUSP6 works as a tumor suppressor in pancreatic carcinogenesis. Restoration of chromosome 12 also suppresses growths of pancreatic cancer cells despite the recovery of expression of DUSP6; the existence of yet another tumor suppressor gene on 12q is strongly suggested. Understanding the molecular mechanisms of pancreatic carcinogenesis will likely provide novel clues for preventing, detecting, and ultimately curing this life-threatening disease.
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Affiliation(s)
- Toru Furukawa
- Department of Molecular Pathology, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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33
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Abstract
Several tumor syndromes are known to have an increased incidence of pancreatic carcinoma. Unfortunately, the incidence of pancreatic carcinoma almost equals its mortality. Because of intense research activities in the past decade, several genetic alterations have been identified that are responsible for the so-called sporadic pancreatic carcinoma development. National and international research activities only recently have begun focusing on the molecular pathogenesis of hereditary risk factors for pancreatic carcinoma. It is hoped that these genetic studies will aid the development of clinical management strategies for pancreatic carcinoma prevention.
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Affiliation(s)
- Stephan A Hahn
- Department of Internal Medicine, Knappschaftskrankenhaus University of Bochum, Zentrum für Klinische Forschung, Labor für Molekulare Gastroenterologische Onkologie, Universitätsstrasse 150, 44780 Bochum, Germany.
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34
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Abstract
Several tumor syndromes are known to have an increased incidence of pancreatic carcinoma. Unfortunately, the incidence of pancreatic carcinoma almost equals its mortality. Because of intense research activities in the past decade, several genetic alterations have been identified that are responsible for the so-called sporadic pancreatic carcinoma development. National and international research activities only recently have begun focusing on the molecular pathogenesis of hereditary risk factors for pancreatic carcinoma. It is hoped that these genetic studies will aid the development of clinical management strategies for pancreatic carcinoma prevention.
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Affiliation(s)
- Stephan A Hahn
- Department of Internal Medicine, Knappschaftskrankenhaus University of Bochum, Zentrum für Klinische Forschung (ZKF), Labor für Molekulare Gastroenterologische Onkologie (MGO), Universitätsstrasse 150, 44780 Bochum, Germany.
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35
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Rulyak SJ, Brentnall TA. Inherited pancreatic cancer: improvements in our understanding of genetics and screening. Int J Biochem Cell Biol 2004; 36:1386-92. [PMID: 15147717 DOI: 10.1016/j.biocel.2004.02.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2003] [Revised: 02/09/2004] [Accepted: 02/10/2004] [Indexed: 12/15/2022]
Abstract
Inherited pancreatic cancers represent approximately 5-10% of all pancreatic cancers. Pancreatic cancer may be inherited as part of a known cancer syndrome or in association with hereditary pancreatitis or cystic fibrosis. However, most inherited pancreatic cancers do not occur in the context of a known syndrome, and these are referred to as familial pancreatic cancers. Growing evidence suggests the presence of a single autosomal dominant gene in familial pancreatic cancer kindreds, and a susceptibility locus on chromosome 4 has recently been identified in one such family. Pancreatic cancer is believed to arise from pancreatic dysplasia, and familial pancreatic cancer kindreds represent a particularly high-risk population for whom effective screening strategies are needed. One promising strategy has used endoscopic ultrasound to detected pancreatic dysplasia in members of familial pancreatic cancer kindreds.
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Affiliation(s)
- Stephen J Rulyak
- Division of Gastroenterology, University of Washington Medical Center, Box 356424, 1959 NE Pacific St., Seattle, WA 98195, USA
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Nagaraja GM, Kandpal RP. Chromosome 13q12 encoded Rho GTPase activating protein suppresses growth of breast carcinoma cells, and yeast two-hybrid screen shows its interaction with several proteins. Biochem Biophys Res Commun 2004; 313:654-65. [PMID: 14697242 DOI: 10.1016/j.bbrc.2003.12.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We have characterized the cDNA for a Rho GTPase activating protein (GAP) mapping to chromosome 13q12. The cDNA was characterized by determining the complete sequence of a 4.8 kb cDNA clone that represents the 5' untranslated region (UTR), the translated region, and the 3' UTR. The protein has a sterile alpha-motif (SAM), a distinct GAP domain, and a conserved START (StAR related lipid transfer) domain. The cDNA has 5 instability motifs (ATTTA) in the 3' UTR and one motif in the translated region between GAP and START domains. The RhoGAP transcript is truncated in some breast carcinoma cell lines and it has low expression in other breast cancer cell lines as compared to a normal breast cell line. We have previously observed the absence of RhoGAP transcript in a breast tumor specimen. A GST-fusion of the RhoGAP was tested for its specificity on RhoA, Cdc42, and Rac1. The protein was most active for RhoA. Transfection of RhoGAP into MCF7 cells significantly inhibited cell growth. The introduction of the RhoGAP construct into MDAMB231 cells that had previously been transfected with a p21 construct did not affect cell proliferation, indicating the involvement of p21 in Rho-mediated proliferation of cancer cells. NIH3T3 cells overexpressing RhoGAP showed considerable inhibition of stress fiber formation. Several cDNAs were identified as RhoGAP interactors by using the yeast two-hybrid assay system. These cDNAs correspond to SWI/SNF, alpha-tubulin, HMG CoA reductase, and TAX1 binding protein (TAX1BP1). The interaction with HMG CoA reductase may partially explain the growth inhibition of breast carcinoma cells by statin class of cholesterol lowering drugs. The biological significance of the interacting proteins is discussed in the context of their involvement in tumorigenesis. Our results indicate that loss of RhoGAP or its altered activity suppresses the growth of breast tumor cells. The presence of various motifs in RhoGAP and its interaction with several other proteins suggest that the protein may regulate Rho signaling in multiple ways and possibly function in a Rho-independent manner.
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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.
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Affiliation(s)
- Donna E Hansel
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21231, USA.
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Israeli O, Gotlieb WH, Friedman E, Goldman B, Ben-Baruch G, Aviram-Goldring A, Rienstein S. Familial vs sporadic ovarian tumors: characteristic genomic alterations analyzed by CGH. Gynecol Oncol 2003; 90:629-36. [PMID: 13678737 DOI: 10.1016/s0090-8258(03)00375-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
OBJECTIVE Our purpose was to get an overview of the genetic events leading to the development of familial and sporadic ovarian tumors and to identify chromosomal regions that may contain genes important in tumor progression. METHODS The comparative genomic hybridization (CGH) technique was employed in a total of 46 epithelial ovarian or peritoneal tumors: 27 sporadic tumors, 11 tumors disected from BRCA1 mutation (185delAG) carriers, and eight from BRCA2 mutation (6174delT) carriers (familial tumors). RESULTS The average number of genetic alterations (deletions and amplifications) was significantly (alpha=0.0069) higher in familial tumors (9.17 +/- 4.25 alterations per tumor in the BRCA1 mutation carriers and 7.25 +/- 6.06 in the BRCA2 mutation carriers) compared to the sporadic group (4.26 +/- 3.61 alterations per tumor). The pattern of the chromosome amplifications resembled in the three groups and the most common amplifications detected were at chromosomes 8q, 3q, and 2q. The pattern of the chromosomal deletions varied between the groups. Among the BRCA1 group, the most common deletions were in chromosomes 9 and 19. The BRCA2 group showed a lower frequency of deletions. Deletion of chromosome 16 and 22 were the most frequent ones. No specific chromosomal deletion was significantly indicated in the sporadic group. CONCLUSIONS Familial ovarian tumors exhibit a significantly higher number of chromosomal aberrations and genomic imbalances and nonrandom genetic changes were characterized in the BRCA1 and BRCA2 groups.
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Affiliation(s)
- Ofir Israeli
- Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel
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Affiliation(s)
- Richard Wooster
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom
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Yajnik V, Paulding C, Sordella R, McClatchey AI, Saito M, Wahrer DCR, Reynolds P, Bell DW, Lake R, van den Heuvel S, Settleman J, Haber DA. DOCK4, a GTPase activator, is disrupted during tumorigenesis. Cell 2003; 112:673-84. [PMID: 12628187 DOI: 10.1016/s0092-8674(03)00155-7] [Citation(s) in RCA: 185] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
We used representational difference analysis to identify homozygous genomic deletions selected during tumor progression in the mouse NF2 and TP53 tumor model. We describe a deletion targeting DOCK4, a member of the CDM gene family encoding regulators of small GTPases. DOCK4 specifically activates Rap GTPase, enhancing the formation of adherens junctions. DOCK4 mutations are present in a subset of human cancer cell lines; a recurrent missense mutant identified in human prostate and ovarian cancers encodes a protein that is defective in Rap1 activation. The engulfment defect of C. elegans mutants lacking the CDM gene ced-5 is rescued by wild-type DOCK4, but not by the mutant allele. Expression of wild-type, but not mutant, DOCK4 in mouse osteosarcoma cells with a deletion of the endogenous gene suppresses growth in soft agar and tumor invasion in vivo. DOCK4 therefore encodes a CDM family member that regulates intercellular junctions and is disrupted during tumorigenesis.
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Affiliation(s)
- Vijay Yajnik
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA
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Hahn SA, Greenhalf B, Ellis I, Sina-Frey M, Rieder H, Korte B, Gerdes B, Kress R, Ziegler A, Raeburn JA, Campra D, Grützmann R, Rehder H, Rothmund M, Schmiegel W, Neoptolemos JP, Bartsch DK. BRCA2 germline mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003; 95:214-21. [PMID: 12569143 DOI: 10.1093/jnci/95.3.214] [Citation(s) in RCA: 336] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Although as many as 10% of pancreatic cancer cases may have an inherited component, familial pancreatic cancer has not been linked to defects in any specific gene. Some studies have shown that families with germline mutations in the breast cancer susceptibility gene BRCA2 have an increased risk of breast and ovarian cancers, as well as a modestly increased risk of pancreatic cancer. To study these relationships in more detail, we examined whether BRCA2 germline mutations are associated with familial pancreatic cancer. METHODS We identified 26 European families in which at least two first-degree relatives had a histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. We sequenced genomic DNA isolated from peripheral blood lymphocytes obtained from participating family members to identify germline mutations in BRCA2. RESULTS Three (12%, exact 95% confidence interval [CI] = 2% to 30%) families carried germline frameshift mutations in the BRCA2 gene that are predicted to result in a truncated BRCA2 protein. Two additional families harbored mutations previously designated as unclassified variants of BRCA2. Thus, 19% (exact 95% CI = 7% to 39%) of the families in our study had either a frameshift mutation or an unclassified variant of BRCA2. None of the families in our study met the criteria for familial breast or ovarian cancer. CONCLUSIONS Our data support an important role for BRCA2 germline mutations in a subpopulation of families with familial pancreatic cancer. BRCA2 mutation analysis should be included in molecular genetic testing and counseling strategies in families with at least two first-degree relatives affected with ductal adenocarcinoma of the pancreas.
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Affiliation(s)
- Stephan A Hahn
- Department of Internal Medicine, Knappschaftskrankenhaus University of Bochum, Germany
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Real FX, Malats N, Lesca G, Porta M, Chopin S, Lenoir GM, Sinilnikova O. Family history of cancer and germline BRCA2 mutations in sporadic exocrine pancreatic cancer. Gut 2002; 50:653-7. [PMID: 11950811 PMCID: PMC1773218 DOI: 10.1136/gut.50.5.653] [Citation(s) in RCA: 26] [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] [Indexed: 01/07/2023]
Abstract
BACKGROUND Hereditary factors have been reported in 5-10% of cases with exocrine pancreatic cancer and recent data support a role for BRCA2. AIMS We have studied the prevalence of germline BRCA2 mutations in two groups of patients with exocrine pancreatic cancer from an unselected series in Spain: group A included 24 cases showing familial aggregation of cancer and group B included 54 age, sex, and hospital matched cases without such evidence. METHODS Information was obtained by interview of patients and was validated by a telephone interview with a structured questionnaire. In patients from group A, >80% of the coding sequence of BRCA2 was analysed; in patients from group B, the regions in which germline BRCA2 mutations have been described to be associated with pancreatic cancer were screened. RESULTS Telephone interviews led to reclassification of 7/54 cases (13%). Familial aggregation of cancer was found in 24/165 cases (14.5%); six patients had a first degree relative with pancreatic cancer (3.6%) and nine patients had relatives with breast cancer. Germline BRCA2 mutations were not identified in any patient from group A (0/23). Among group B cases, one germline variant (T5868G>Asn1880Lys) was found in a 59 year old male without a family history of cancer. The 6174delT mutation was not found in any of the 71 cases analysed. CONCLUSIONS The overall prevalence of BRCA2 mutations among patients with pancreatic cancer in Spain is low and the 6174delT mutation appears to be very infrequent. Our data do not support screening patients with cancer of the pancreas for germline BRCA2 mutations to identify relatives at high risk of developing this tumour.
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Affiliation(s)
- F X Real
- Unitat de Biologia Cellular i Molecular, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Barcelona, Spain.
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Thiagalingam S, Foy RL, Cheng KH, Lee HJ, Thiagalingam A, Ponte JF. Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrence. Curr Opin Oncol 2002; 14:65-72. [PMID: 11790983 DOI: 10.1097/00001622-200201000-00012] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
High frequency of chromosomal deletions elicited as losses of heterozygosity is a hallmark of genomic instability in cancer. Functional losses of tumor suppressor genes caused by loss of heterozygosity at defined regions during clonal selection for growth advantage define the minimally lost regions as their likely locations on chromosomes. Loss of heterozygosity is elicited at the molecular or cytogenetic level as a deletion, a gene conversion, single or double homologous and nonhomologous mitotic recombinations, a translocation, chromosome breakage and loss, chromosomal fusion or telomeric end-to-end fusions, or whole chromosome loss with or without accompanying duplication of the retained chromosome. Because of the high level of specificity, loss of heterozygosity has recently become invaluable as a marker for diagnosis and prognosis of cancer. The molecular defects for the occurrence of loss of heterozygosity are derived from disabled caretaker genes, which protect the integrity of DNA, or chromosome segregator genes, which mediate faithful chromosome disjunction.
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Affiliation(s)
- Sam Thiagalingam
- Genetics & Molecular Medicine Programs and Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
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Niketeghad F, Decker HJ, Caselmann WH, Lund P, Geissler F, Dienes HP, Schirmacher P. Frequent genomic imbalances suggest commonly altered tumour genes in human hepatocarcinogenesis. Br J Cancer 2001; 85:697-704. [PMID: 11531255 PMCID: PMC2364116 DOI: 10.1054/bjoc.2001.1963] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent-occurring malignant tumours worldwide, but molecular changes of tumour DNA, with the exception of viral integrations and p53 mutations, are poorly understood. In order to search for common macro-imbalances of genomic tumour DNA, 21 HCCs and 3 HCC-cell lines were characterized by comparative genomic hybridization (CGH), subsequent database analyses and in selected cases by fluorescence in situ hybridization (FISH). Chromosomal subregions of 1q, 8q, 17q and 20q showed frequent gains of genomic material, while losses were most prevalent in subregions of 4q, 6q, 13q and 16q. Deleted regions encompass tumour suppressor genes, like RB-1 and the cadherin gene cluster, some of them previously identified as potential target genes in HCC development. Several potential growth- or transformation-promoting genes located in chromosomal subregions showed frequent gains of genomic material. The present study provides a basis for further genomic and expression analyses in HCCs and in addition suggests chromosome 4q to carry a so far unidentified tumour suppressor gene relevant for HCC development.
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Affiliation(s)
- F Niketeghad
- Institute of Pathology, University of Cologne, Joseph Stelzmann Str. 9, Cologne, D-50931, Germany
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Abstract
This is a review of the approaches that can be used to analyze genetic changes in ovarian cancer. Traditional gene localization methods are discussed, followed by a section on gene identification techniques. Once a putative disease-associated gene has been cloned, mutations have to be identified and analyzed. There are numerous mutation detection methods, and the most common ones are outlined. In the penultimate section, the role of immunohistochemistry as a surrogate method for mutation analysis is considered. Finally, the possible use of functional assays is discussed. At present, it would appear that DNA chip technology for the detection of mutations, and microarray analysis of gene expression, are two important techniques likely to have a significant impact on the genetic analysis of ovarian cancer.
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Affiliation(s)
- A N Shelling
- Research Centre in Reproductive Medicine, Department of Obstetrics and Gynaecology, National Women's Hospital, Auckland, New Zealand.
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Chen YZ, Soeda E, Yang HW, Takita J, Chai L, Horii A, Inazawa J, Ohki M, Hayashi Y. Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36. Genes Chromosomes Cancer 2001; 31:326-32. [PMID: 11433523 DOI: 10.1002/gcc.1151] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Recent molecular studies have shown a relatively high rate of loss of heterozygosity (LOH) in neuroblastoma (NB) as well as other types of tumors in human chromosome band 1p36. To identify candidate tumor suppressor genes in NB, we searched for homozygous deletions in NB cell lines with PCR according to a high-density sequence tagged site (STS)-content map spanning 1p35-36. Among 25 NB cell lines examined, only one cell line, NB-1, showed no signal with 27 STSs in a 480 kb region in 1p36.2. The sequence analysis has revealed that the defective region included seven known genes (E4, KIF1B, SCYA5, PGD, Cortistatin, DFF45, and PEX14), nine expressed sequence tags (ESTs), and two microsatellite markers. These genes are related to apoptosis, an ubiquitin-proteasome pathway, a neuronal microtubule-associated motor molecule, and components of a common translocation machinery. The region between the DFF45 and KIF1B genes was defined as homozygous deletion by Southern blotting. The search in LOH regions with high-density STSs may be useful for the isolation and identification of tumor suppressor genes in other tumors as well as NBs.
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Affiliation(s)
- Y Z Chen
- Gene Bank, Tsukuba Institute, The Institute of Physical and Chemical Research (RIKEN), Tsukuba, Japan
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Geck P, Sonnenschein C, Soto AM. The D13S171 marker, misannotated to BRCA2, links the AS3 gene to various cancers. Am J Hum Genet 2001; 69:461-3. [PMID: 11452363 PMCID: PMC1235319 DOI: 10.1086/321968] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
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MacGrogan D, Alvarez S, DeBlasio T, Jhanwar SC, Nimer SD. Identification of candidate genes on chromosome band 20q12 by physical mapping of translocation breakpoints found in myeloid leukemia cell lines. Oncogene 2001; 20:4150-60. [PMID: 11464281 DOI: 10.1038/sj.onc.1204540] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2000] [Revised: 04/09/2001] [Accepted: 04/12/2001] [Indexed: 11/09/2022]
Abstract
Deletions of the long arm of chromosome 20 have been reported in a wide range of myeloid disorders and may reflect loss of critical tumor suppressor gene(s). To identify such candidate genes, 65 human myeloid cell line DNAs were screened by polymerase chain reaction (PCR) for evidence of allelic loss at 39 highly polymorphic loci on the long arm of chromosome 20. A mono-allelic pattern was present in eight cell lines at multiple adjacent loci spanning the common deleted regions (CDRs) previously defined in primary hematological samples, suggesting loss of heterozygosity (LOH) at 20q. Fluorescence in situ hybridization (FISH) was then performed using a series of yeast artificial chromosomes (YACs) ordered in the CDR, and in five of eight cell lines, the deletions resulted from cytogenetically detectable whole chromosomal loss or large interstitial deletion, whereas in another cell line deletion was associated with an unbalanced translocation. LOH in the CMK megakaryocytic cell line, which has a hypotetraploid karyotype, was associated with a der(20)t(1;20)(q32;q12)x2 leading to complete deletion of the CDR. Three additional unbalanced translocations were found within the CDR and all three breakpoints mapped to a single YAC. We then used a series of P1 artificial chromosomes (PACs) spanning this YAC clone, and two PACs produced 'split' signals suggesting that they each span one of these breakpoints. Exon trapping using PACs that overlap the breakpoint regions yielded portions of six genes and evaluation of these genes as candidate tumor suppressor genes is underway. The limited information available about these genes suggests that the h-l(3)mbt gene is the most attractive candidate.
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MESH Headings
- Base Sequence
- Blotting, Southern
- Chromosome Fragility
- Chromosomes, Artificial, Yeast
- Chromosomes, Human, Pair 20
- DNA Primers
- Gene Expression
- Humans
- In Situ Hybridization, Fluorescence
- Leukemia, Myeloid/genetics
- Leukemia, Myeloid/pathology
- Loss of Heterozygosity
- Microsatellite Repeats/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Translocation, Genetic
- Tumor Cells, Cultured
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Affiliation(s)
- D MacGrogan
- Laboratory of Molecular Aspects of Hematopoiesis, Sloan Kettering Institute for Cancer Research, New York, NY 10021, USA
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Teng DH, Chen Y, Lian L, Ha PC, Tavtigian SV, Wong AK. Mutation analyses of 268 candidate genes in human tumor cell lines. Genomics 2001; 74:352-64. [PMID: 11414763 DOI: 10.1006/geno.2001.6551] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
We have performed a homozygous deletion screen on 268 candidate genes in 90 human tumor cell lines derived from multiple types of cancers. Most of the candidate genes investigated have been proposed to be involved in cellular processes that are germane to cancer progression, such as cell cycle control, genome maintenance, chromatin remodeling, cell adhesion, and apoptosis. We have detected novel homozygous deletions affecting four independent loci: Brahma-related gene (SMARCA4) on chromosome 19p in the TSU-Pr1 prostate and A427 lung carcinoma lines, Map Kinase Kinase 3 (MAP2K3) on 17q in the NCI-H774 lung tumor cell line, TMPRSS2 on 21q in the Bx PC-3 pancreatic carcinoma line, and Cadherin 6 (CDH6) on 5p in the SK-LU-1 lung carcinoma line. Subsequent analyses of the coding sequences of these four genes using cDNAs from a panel of tumor cell lines revealed multiple sequence variants. The results of this mutation study serve to demonstrate the feasibility of performing high-throughput screens of candidate genes in tumor cell lines to identify genes that may be targeted for mutation during the development of cancer.
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Affiliation(s)
- D H Teng
- Myriad Genetics, Inc., 420 Wakara Way, Salt Lake City, Utah 84108, USA.
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Cummings M, Brown KW. Low frequency of genetic lesions in Wilms tumors by representational difference analysis. CANCER GENETICS AND CYTOGENETICS 2001; 127:155-60. [PMID: 11425456 DOI: 10.1016/s0165-4608(01)00387-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Genomic representational difference analysis (RDA) was carried out on a total of nine Wilms tumors and one cystic partially differentiated nephroblastoma (CPDN; a sub-type of Wilms) to look for novel genetic deletions involving tumor suppressor genes. Genomic DNA from either short-term cultured Wilms tumor cells or a WT xenograft was used to create driver representations, and genomic DNA from matched normal kidney or normal kidney cells grown in short-term culture was used to create the tester. Genuine difference products were obtained from only one of the tumors. However, none of these fragments were found to be deleted in the original tumor biopsy, microdissected tumor or in the lung metastasis from this patient. It is, therefore, likely that the deletions were due to random losses associated with the genetic instability of the cultured cells from this particular tumor. We did not isolate difference products from any of the other tumors, showing that they did not have chromosomal losses, homozygous deletions or regions of LOH that were detectable by RDA.
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Affiliation(s)
- M Cummings
- CLIC Research Unit, Department of Pathology and Microbiology, School of Medical Sciences, University of Bristol, University Walk, Bristol, BS8 1TD, UK
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