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1
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Kluth M, Ahrary R, Hube-Magg C, Ahmed M, Volta H, Schwemin C, Steurer S, Wittmer C, Wilczak W, Burandt E, Krech T, Adam M, Michl U, Heinzer H, Salomon G, Graefen M, Koop C, Minner S, Simon R, Sauter G, Schlomm T. Genomic deletion of chromosome 12p is an independent prognostic marker in prostate cancer. Oncotarget 2016; 6:27966-79. [PMID: 26293672 PMCID: PMC4695038 DOI: 10.18632/oncotarget.4626] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 07/03/2015] [Indexed: 11/25/2022] Open
Abstract
Deletion of 12p is a recurrent alteration in prostate cancer, but the prevalence and clinical consequences of this alteration have not been studied in detail. Dual labeling fluorescence in situ hybridization using probes for 12p13 (CDKN1B; p27) and centromere 12 as a reference was used to successfully analyze more than 3700 prostate cancers with clinical follow-up data assembled in a tissue microarray format. CDKN1B was selected as a probe because it is located in the center of the deletion, which spans > 10 Mb and includes > 50 genes in 80% of cancers with 12p deletion. Deletion of 12p was found in 13.7% of cancers and included 13.5% heterozygous and 0.2% homozygous deletions. 12p deletion were linked to advanced tumor stage (p < 0.0001), high Gleason grade (p < 0.0001), rapid tumor cell proliferation (p < 0.0001), lymph node metastasis (p = 0.0004), and biochemical recurrence (p = 0.0027). Multivariate analysis including pT stage (p < 0.0001), Gleason grade (p < 0.0001), pN status (p = 0.0001), preoperative PSA levels (p = 0.0001), and resection margin status (p = 0.0001) revealed an independent prognostic value of 12p deletion (p = 0.0014). Deletion of 12p was unrelated to the ERG fusion status. Deletion of 12p was only marginally linked to reduced p27 expression, which by itself was unrelated to clinical outcome. This argues against p27 as the key target gene of 12p deletions. In summary, the results of our study demonstrate that 12p deletion is frequent in prostate cancer and provides independent prognostic information. 12p deletion analysis alone, or in combination with other prognostic parameters may thus have clinical utility.
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Affiliation(s)
- Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Ramin Ahrary
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Malik Ahmed
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Heinke Volta
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Catina Schwemin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Corinna Wittmer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Meike Adam
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
| | - Uwe Michl
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
| | - Hans Heinzer
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
| | - Georg Salomon
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
| | - Markus Graefen
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany
| | - Christina Koop
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Germany
| | - Thorsten Schlomm
- Martini-Klinik, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Germany.,Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Germany
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2
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Castro E, Jugurnauth-Little S, Karlsson Q, Al-Shahrour F, Piñeiro-Yañez E, Van de Poll F, Leongamornlert D, Dadaev T, Govindasami K, Guy M, Eeles R, Kote-Jarai Z. High burden of copy number alterations and c-MYC amplification in prostate cancer from BRCA2 germline mutation carriers. Ann Oncol 2015; 26:2293-300. [PMID: 26347108 DOI: 10.1093/annonc/mdv356] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Accepted: 08/17/2015] [Indexed: 02/11/2024] Open
Abstract
BACKGROUND Germline BRCA2 mutations are associated with poorer outcome prostate cancer (PCa) compared with sporadic tumours but this association remains to be characterised. In this study, we aim to assess if there is a signature set of copy number alterations (CNA) that could aid to the identification of BRCA2-mutated tumours and would assist us to understand their aggressive clinical behaviour. METHODS High-resolution array comparative genomic hybridisation profiling of DNA from PCa and matched morphologically normal prostate samples from 9 BRCA2 germline mutation carriers and 16 non-carriers in combination with unsupervised analysis was used to define copy number features. RESULTS PCa from BRCA2 germline mutation carriers (B2T) harbour significantly more CNA than non-carrier tumours (NCTs) (P = 14 × 10(-6)). A hundred and sixteen regions had a significantly different distribution with both false discovery rate (FDR) and P value <0.01, including CNA in the genomic region containing c-MYC that was present in 89% B2T versus 12.5% NCT (P = 3 × 10(-4)). Loss of heterozygosity (LOH) at the BRCA2 locus was observed in 67% of B2T. Elevated CNA are already present in 50% of the morphologically normal prostate tissue from BRCA2 carriers. CONCLUSION The relative high amount of CNAs in morphologically normal prostate tissue of BRCA2 carriers implies a field effect and together with the observed LOH could be used as a marker of PCa risk in these men. Several features previously associated with poor PCa outcome have been found to be significantly more common in BRCA2-mutated PCa than in sporadic tumours and may help to explain their adverse prognosis and be of relevance for targeted therapies.
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Affiliation(s)
- E Castro
- Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain Oncogenetics Team, The Institute of Cancer Research, London, UK
| | | | - Q Karlsson
- Oncogenetics Team, The Institute of Cancer Research, London, UK
| | - F Al-Shahrour
- Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain
| | - E Piñeiro-Yañez
- Translational Bioinformatics Unit, Clinical Research Programme, Spanish National Cancer Research Centre, Madrid, Spain
| | - F Van de Poll
- Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain
| | | | - T Dadaev
- Oncogenetics Team, The Institute of Cancer Research, London, UK
| | - K Govindasami
- Oncogenetics Team, The Institute of Cancer Research, London, UK
| | - M Guy
- Oncogenetics Team, The Institute of Cancer Research, London, UK
| | - R Eeles
- Oncogenetics Team, The Institute of Cancer Research, London, UK The Royal Marsden NHS Foundation Trust, London, UK
| | - Z Kote-Jarai
- Oncogenetics Team, The Institute of Cancer Research, London, UK
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3
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Saini S, Majid S, Shahryari V, Tabatabai ZL, Arora S, Yamamura S, Tanaka Y, Dahiya R, Deng G. Regulation of SRC kinases by microRNA-3607 located in a frequently deleted locus in prostate cancer. Mol Cancer Ther 2014; 13:1952-63. [PMID: 24817628 DOI: 10.1158/1535-7163.mct-14-0017] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Genomic studies suggest that deletions at chromosome (chr) 5q region (particularly chr5q14-q23) are frequent in prostate cancer, implicating this region in prostate carcinogenesis. However, the genes within this region are largely unknown. Here, we report for the first time the widespread attenuation of miR-3607, an miRNA gene located at chr5q14 region, in prostate cancer. Expression analyses of miR-3607 in a clinical cohort of prostate cancer specimens showed that miR-3607 is significantly attenuated and low miR-3607 expression is correlated with tumor progression and poor survival outcome in prostate cancer. Our analyses suggest that miR-3607 expression may be a clinically significant parameter with an associated diagnostic potential. We examined the functional significance of miR-3607 in prostate cancer cell lines and found that miR-3607 overexpression led to significantly decreased proliferation, apoptosis induction, and decreased invasiveness. Furthermore, our results suggest that miR-3607 directly represses oncogenic SRC family kinases LYN and SRC in prostate cancer. In view of our results, we propose that miR-3607 plays a tumor-suppressive role in prostate cancer by regulating SRC kinases that in turn regulates prostate carcinogenesis. To our knowledge, this is the first report that: (i) identifies a novel role for miR-3607 located in a frequently deleted region of prostate cancer and (ii) defines novel miRNA-mediated regulation of SRC kinases in prostate cancer. Because SRC kinases play a central role in prostate cancer progression and metastasis and are attractive targets, this study has potential implications in the design of better therapeutic modalities for prostate cancer management.
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Affiliation(s)
- Sharanjot Saini
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Shahana Majid
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Varahram Shahryari
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Z Laura Tabatabai
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Sumit Arora
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Soichiro Yamamura
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Yuichiro Tanaka
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Rajvir Dahiya
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
| | - Guoren Deng
- Authors' Affiliation: Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, San Francisco, California
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4
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Abstract
Epigenetic alterations contribute significantly to the development and progression of prostate cancer, the most prevalent malignant tumor in males of Western industrialized countries. Here, we review recent research on DNA methylation alterations in this cancer type. Hypermethylation of several genes including GSTP1 is well known to occur in a consistent and apparently coordinate fashion during the transition from intraepithelial neoplasia to frank carcinoma. These hypermethylation events have shown promise as biomarkers for detection of prostate carcinoma. Many other individual genes have been shown to undergo hypermethylation, which is typically associated with diminished expression. These investigations indicate additional candidates for biomarkers; in particular, hypermethylation events associated with progression can be employed to identify more aggressive cases. In addition, some of genes silenced by aberrant methylation in prostate have been shown to exhibit properties of tumor suppressors, revealing insights into mechanisms of carcinogenesis. Whereas most studies in the past have used candidate gene approaches, new techniques allowing genome-wide screening for altered methylation are increasingly employed in prostate cancer research and have already yielded encouraging results.
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Affiliation(s)
- Wolfgang Goering
- Department of Urology, Heinrich Heine University, Duesseldorf, Germany
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5
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Bjartell A, Montironi R, Berney DM, Egevad L. Tumour markers in prostate cancer II: diagnostic and prognostic cellular biomarkers. Acta Oncol 2011; 50 Suppl 1:76-84. [PMID: 21604944 DOI: 10.3109/0284186x.2010.531284] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
UNLABELLED The main goal of prostate cancer tissue biomarkers is to improve diagnostic and prognostic accuracy. A particularly important question is whether the cancer needs immediate treatment or if treatment can be deferred. It is highly unlikely that a single biomarker that provides comprehensive prognostic information about a newly diagnosed prostate cancer will be forthcoming. Despite extensive research efforts, very few biomarkers of prostate cancer have been successfully implemented into clinical practice today. This can be partly explained by a lack of standardised methods for performance and interpretation of immunohistochemistry, but also by poor study design with insufficient biomaterial or inappropriate statistical analysis. Also appropriate cohorts to test prostate cancer biomarkers do not exist. It must be kept in mind that unsuccessful integration of new biomarkers in nomograms can also be explained by the good performance of the clinical and pathological base model with serum PSA as the only independent biomarker. A new biomarker must be powerful enough to improve this prediction model and not merely replace. MATERIAL AND METHODS In this report, we focus on diagnostic and prognostic cellular biomarkers in prostate cancer, recent advances and future aspects by reviewing currently available literature. RESULTS Similar to other malignancies, the proliferation marker Ki-67 seems to be a prognostic tissue biomarker and a strong candidate for integration in prediction models. Circulating tumour cells are promising markers of response to treatments in patients with metastatic disease. CONCLUSION Important technical advances together with histological techniques of antibody or probes conjugated with different fluorophores will certainly improve standardisation and make immunohistochemical biomarker research more reliable and precise in the future. Cellular biomarker studies are also expected to change in the future towards a complexed individualised profiling of human tumours with integrative analysis using different technologies, genome-wide scanning and expression profiling.
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Affiliation(s)
- Anders Bjartell
- Department of Urology, Skåne University Hospital Malmö, Sweden.
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6
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Fiorentino M, Capizzi E, Loda M. Blood and tissue biomarkers in prostate cancer: state of the art. Urol Clin North Am 2010; 37:131-41, Table of Contents. [PMID: 20152526 DOI: 10.1016/j.ucl.2009.11.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The prevalence of prostate cancer (PCa) is high and increases with age. PCa is the most common cutaneous cancer in American men. Prostate-specific antigen (PSA) screening has impacted the detection of PCa and is directly responsible for a dramatic decrease in stage at diagnosis. Gleason score and stage at the time of diagnosis remain the mainstay to predict prognosis, in the absence of more accurate and reliable tissue or blood biomarkers. Despite extensive research efforts, very few biomarkers of PCa have been introduced to date in clinical practice. Even screening with PSA has recently been questioned. A thorough analysis of all tissue and serum biomarkers in prostate cancer research cannot be easily synthesized, and goes beyond the scope of the present article. Therefore the authors focus here on the most recently reported tissue and circulating biomarkers for PCa whose application in clinical practice is either current or expected in the near future.
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Affiliation(s)
- Michelangelo Fiorentino
- Department of Pathology and Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, D1536, 44 Binney Street, Boston, MA 02115, USA
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7
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Brekke HR, Ribeiro FR, Kolberg M, Agesen TH, Lind GE, Eknaes M, Hall KS, Bjerkehagen B, van den Berg E, Teixeira MR, Mandahl N, Smeland S, Mertens F, Skotheim RI, Lothe RA. Genomic changes in chromosomes 10, 16, and X in malignant peripheral nerve sheath tumors identify a high-risk patient group. J Clin Oncol 2010; 28:1573-82. [PMID: 20159821 DOI: 10.1200/jco.2009.24.8989] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE The purpose of this study was to identify genetic aberrations contributing to clinical aggressiveness of malignant peripheral nerve sheath tumors (MPNSTs). PATIENTS AND METHODS Samples from 48 MPNSTs and 10 neurofibromas were collected from 51 patients with (n = 31) or without (n = 20) neurofibromatosis type 1 (NF1). Genome-wide DNA copy number changes were assessed by chromosomal and array-based comparative genomic hybridization (CGH) and examined for prognostic significance. For a subset of 20 samples, RNA microarray data were integrated with the genome data to identify potential target genes. RESULTS Forty-four (92%) MPNSTs displayed DNA copy number changes (median, 18 changes per tumor; range, 2 to 35 changes). Known frequent chromosomal gains at chromosome arms 8q (69%), 17q (67%), and 7p (52%) and losses from 9p (50%), 11q (48%), and 17p (44%) were confirmed. Additionally, gains at 16p or losses from 10q or Xq identified a high-risk group with only 11% 10-year disease-specific survival (P = .00005). Multivariate analyses including NF1 status, tumor location, size, grade, sex, complete remission, and initial metastatic status showed that the genomic high-risk group was the most significant predictor of poor survival. Several genes whose expression was affected by the DNA copy number aberrations were identified. CONCLUSION The presence of specific genetic aberrations was strongly associated with poor survival independent of known clinical risk factors. Conversely, within the total patient cohort with 34% 10-year disease-specific survival, a low-risk group was identified: without changes at chromosomes 10q, 16p, or Xq in their MPNSTs, the patients had 74% 10-year survival.
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Affiliation(s)
- Helge R Brekke
- Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Rikshospitalet, Oslo University Hospital, Oslo, Norway
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8
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Leversha MA, Han J, Asgari Z, Danila DC, Lin O, Gonzalez-Espinoza R, Anand A, Lilja H, Heller G, Fleisher M, Scher HI. Fluorescence in situ hybridization analysis of circulating tumor cells in metastatic prostate cancer. Clin Cancer Res 2009; 15:2091-7. [PMID: 19276271 DOI: 10.1158/1078-0432.ccr-08-2036] [Citation(s) in RCA: 149] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
PURPOSE To assess the feasibility of characterizing gene copy number alteration by fluorescence in situ hybridization (FISH) of circulating tumor cells (CTC) isolated using the CellSearch system in patients with progressive castration-resistant metastatic prostate cancer. EXPERIMENTAL DESIGN We used probe combinations that included the androgen receptor (AR) and MYC genes for FISH analysis of CTC samples collected from 77 men with castration-resistant metastatic prostate cancer. RESULTS High-level chromosomal amplification of AR was detected in 38% and relative gain of MYC in 56% of samples analyzed. No such abnormalities were detected in samples with CTC counts of <10, reflecting ascertainment difficulty in these lower count samples. CONCLUSION The CTC isolated from our patient cohort present a very similar molecular cytogenetic profile to that reported for late-stage tumors and show that FISH analysis of CTC can be a valuable, noninvasive surrogate for routine tumor profiling. That as many as 50% of these patients have substantial amplification of the AR locus indicates that androgen signaling continues to play an important role in late-stage prostate cancer.
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Affiliation(s)
- Margaret A Leversha
- Molecular Cytogenetics Core Laboratory, Department of Medicine, Memorial Sloan-kettering Cancer Center, New York, New York, USA
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9
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Schulz WA, Hoffmann MJ. Epigenetic mechanisms in the biology of prostate cancer. Semin Cancer Biol 2009; 19:172-80. [PMID: 19429481 DOI: 10.1016/j.semcancer.2009.02.006] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2008] [Accepted: 02/11/2009] [Indexed: 01/07/2023]
Abstract
Prostate cancer is one of the most frequent cancers in males in Western industrialized countries. Its course is highly variable, from indolent to highly lethal. Genetic changes vary accordingly, with chromosomal losses, gains and translocations, although often recurrent, differing between individual cases of the disease. In contrast, certain epigenetic changes are highly consistent, in particular hypermethylation of a specific set of genes, and others regularly associated with progression, such as global DNA hypomethylation, certain chromatin modifications and altered levels and composition of polycomb complexes. Although changes in polycombs and DNA methylation appear to both accompany the progression of prostate cancer, recent studies do not suggest that they cause one another. However, they may contribute to establishing and maintaining an aberrant differentiation potential of prostate cancer initiating cells. Global DNA hypomethylation in prostate cancer may relate to adaptative changes in several signaling pathways typical of this cancer type, including innate immunity responses. Similarly, adaptative changes in the expression and function of chromatin regulators required to diminish the dependency of prostate cancer cells on androgens may shape the epigenome, beyond individual genes regulated by the androgen receptor. Because of their crucial role, epigenetic alterations may become highly useful for diagnostics and therapy of prostate cancer.
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Affiliation(s)
- Wolfgang A Schulz
- Urologische Klinik, Heinrich Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany.
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10
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Rauhala HE, Porkka KP, Saramäki OR, Tammela TLJ, Visakorpi T. Clusterin is epigenetically regulated in prostate cancer. Int J Cancer 2008; 123:1601-9. [PMID: 18649357 DOI: 10.1002/ijc.23658] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Lack of good models has complicated investigations on the mechanisms of prostate cancer. By far, the most commonly used transgenic mouse model of prostate cancer is TRAMP, which, however, has not been fully characterized for genetic and epigenetic aberrations. Here, we screened TRAMP-derived C2 cell line for the alterations using different microarray approaches, and compared it to human prostate cancer. TRAMP-C2 had relatively few genomic copy number alterations according to array comparative genomic hybridization (aCGH). However, the gene copy number and expression were significantly correlated (p < 0.001). Screening genes for promoter hypermethylation using demethylation treatment with 5-aza-2'-deoxycytidine and subsequent expression profiling indicated 43 putatively epigenetically silenced genes. Further studies revealed that clusterin is methylated in the TRAMP-C2 cell line, as well as in the human prostate cancer cell line LNCaP. Its expression was found to be significantly reduced (p < 0.01) in untreated and hormone-refractory human prostate carcinomas. Together with known function of clusterin, the data suggest an epigenetic component in the regulation of clusterin in prostate cancer.
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Affiliation(s)
- Hanna E Rauhala
- Institute of Medical Technology, University of Tampere, and Tampere University Hospital, Tampere, Finland
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11
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Lu T, Hano H. Deletion at chromosome arms 6q16-22 and 10q22.3-23.1 associated with initiation of prostate cancer. Prostate Cancer Prostatic Dis 2008; 11:357-61. [PMID: 18227855 DOI: 10.1038/pcan.2008.4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Loss of heterozygosity (LOH) at 6q16-22 and 10q22.3-23.1 is common chromosomal alteration in advanced prostate cancer and suggests that one or more tumor suppressor genes may lie within these chromosome arms. However, the genetic changes in early stage prostate cancer and premalignant lesions remain to be investigated. We used 11 informative microsatellite markers at 6q16-22 and 10q22.3-23.1 in Japanese patients to compare the frequency of LOH in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC) and 107 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 6q16-22 with at least one marker was 38 and 49% in IPC and CPC cases, respectively. Similarly, allelic loss at 10q22.3-23.1 was present in 35 and 39% of IPC and CPC, respectively. High-frequency LOH was detected in both the clinically insignificant and significant prostate cancers at 6q16-22 and 10q22.3-23.1 (P>0.05). However, no allelic loss was detected in any markers at the same regions in HGPIN (0%), which is usually considered a premalignant lesion to prostate cancer. Deletions of both the chromosome regions, 6q16-22 and 10q22.3-23.1, are more likely important events in the initiation and/or promotion of prostate cancer.
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Affiliation(s)
- T Lu
- Department of Pathology, The Jikei University School of Medicine, Tokyo, Japan.
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12
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Yoshimoto M, Cunha IW, Coudry RA, Fonseca FP, Torres CH, Soares FA, Squire JA. FISH analysis of 107 prostate cancers shows that PTEN genomic deletion is associated with poor clinical outcome. Br J Cancer 2007; 97:678-85. [PMID: 17700571 PMCID: PMC2360375 DOI: 10.1038/sj.bjc.6603924] [Citation(s) in RCA: 221] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
This study examines the clinical impact of PTEN genomic deletions using fluorescence in situ hybridisation (FISH) analysis of 107 prostate cancers, with follow-up information covering a period of up to 10 years. Tissue microarray analysis using interphase FISH indicated that hemizygous PTEN losses were present in 42/107 (39%) of prostatic adenocarcinomas, with a homozygous PTEN deletion observed in 5/107 (5%) tumours. FISH analysis using closely linked probes centromeric and telomeric to the PTEN indicated that subband microdeletions accounted for ∼70% genomic losses. Kaplan–Meier survival analysis of PTEN genomic losses (hemizygous and homozygous deletion vs not deleted) identified subgroups with different prognosis based on their time to biochemical relapse after surgery, and demonstrated significant association between PTEN deletion and an earlier onset of disease recurrence (as determined by prostate-specific antigen levels). Homozygous PTEN deletion was associated with a much earlier onset of biochemical recurrence (P=0.002). Furthermore, PTEN loss at the time of prostatectomy correlated with clinical parameters of more advanced disease, such as extraprostatic extension and seminal vesicle invasion. Collectively, our data indicates that haploinsufficiency or PTEN genomic loss is an indicator of more advanced disease at surgery, and is predictive of a shorter time to biochemical recurrence of disease.
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Affiliation(s)
- M Yoshimoto
- Division of Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, M5G 2M9, Canada
| | - I W Cunha
- Departamento de Patologia, Centro de Tratamento e Pesquisa, Hospital do Câncer, A.C. Camargo, São Paulo, 01509 010, Brazil
| | - R A Coudry
- Departamento de Patologia, Centro de Tratamento e Pesquisa, Hospital do Câncer, A.C. Camargo, São Paulo, 01509 010, Brazil
| | - F P Fonseca
- Serviço de Urologia, Departamento de Cirurgia Pélvica, Hospital do Câncer, A.C. Camargo, São Paulo, 01509 010, Brazil
| | - C H Torres
- Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, 01509 010, Brazil
| | - F A Soares
- Departamento de Patologia, Centro de Tratamento e Pesquisa, Hospital do Câncer, A.C. Camargo, São Paulo, 01509 010, Brazil
| | - J A Squire
- Division of Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital, Toronto, Ontario, M5G 2M9, Canada
- Department of Medical Biophysics, Faculty of Medicine, University of Toronto, M5G 2M9, Canada
- Division of Applied Molecular Oncology, Ontario Cancer Institute, Princess Margaret Hospital. 610 University Avenue, Room 9-721, Toronto, Ontario, M5G 2M9, Canada. E-mail:
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13
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Hosseini HA, Ahani A, Galehdari H, Froughmand AM, Hosseini M, Masjedizadeh A, Zali MR. Frequent loss of heterozygosity at 8p22 chromosomal region in diffuse type of gastric cancer. World J Gastroenterol 2007; 13:3354-8. [PMID: 17659675 PMCID: PMC4172716 DOI: 10.3748/wjg.v13.i24.3354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the loss of heterozygosity (LOH) at 8p21-23 locus in diffuse gastric cancer.
METHODS: To evaluate the involvement of this region in gastric cancer, we used eight microsatellite markers covering two Mb of mentioned region, to perform a high-resolution analysis of allele loss in 42 cases of late diffuse gastric adenocarcinoma.
RESULTS: Six of these STS makers: D8S1149, D8S1645, D8S1643, D8S1508, D8S1591, and D8S1145 showed 36%, 28%, 37%, 41%, 44% and 53% LOH, respectively.
CONCLUSION: A critical region of loss, close to the NAT2 locus and relatively far from FEZ1 gene currently postulated as tumor suppressor gene in this region.
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