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Laboratory of Cancer Genetics, National Human Genome Research Institute, NIH [L. B., J. K., O-P. K.], Bethesda, Maryland 20892-4470; Laboratory of Cancer Genetics, Tampere University Hospital, 33521 Tampere, Finland [P. K.]; and Institute for Pathology [P. S., H. M., N. W., M. J. M., G. S.] and Urologic Clinics [T. C. G.], University of Basel, CH-4003 Basel, Switzerland
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ABSTRACT |
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3X) amplifications were very rare (<2%) in primary prostate cancers. However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases. In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cancer development and progression. Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer. |
Introduction |
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We recently developed a novel tissue microarray ("tissue chip") technology (3) for rapid molecular profiling of large numbers of cancers in a single experiment. Tissue microarrays are constructed by bringing minute cylindrical tissue samples (diameter, 0.6 mm) from hundreds of different tumors into a single paraffin block. Five-µm sections from these tissue microarray blocks can then be applied in the analysis of copy number or expression of multiple genes by DNA and RNA in situ hybridization or by immunohistochemistry. Here, we constructed a tissue microarray containing samples from different stages of human prostate cancer progression to survey genetic alterations that may contribute to hormone refractory and metastatic disease. We decided to investigate the role of gene amplifications, because these alterations have been implicated in the progression of many tumor types. Most previous studies have found few if any gene amplifications in prostate cancer, but the majority of these have been based on relatively small materials or evaluated only a single gene (4, 5, 6, 7, 8, 9) . The comparison of data from different studies is also difficult, because a large variety of different techniques have been used, including Southern blot, slot blot, quantitative PCR, and FISH.3 For example, substantially discordant results have been published on the role of ERBB2 oncogene with the reported amplification frequencies ranging from 0 to 44% (4 , 10, 11, 12) . The two gene amplifications that have been studied in more detail include the AR and MYC oncogene amplifications reported in hormone-refractory or metastatic tumors, respectively (7, 8, 9) . In this study, we constructed a tissue microarray containing 339 tumor specimens from different stages of prostate cancer progression and assayed five different gene amplifications (AR, MYC, ERBB2, CCND1, and NMYC) by FISH to consecutive formalin-fixed tissue microarray sections. The aim was to obtain a comprehensive survey of gene amplifications in different stages of prostate cancer progression, including specimens from distant metastases.
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Materials and Methods |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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The original array also included 48 pathologically representative samples that consistently failed in the analysis of sections with all FISH probes. The number of samples evaluable with the different probes was variable because: (a) the hybridization efficiency of the probes was slightly different (see "Results"); (b) some samples on the array were occasionally lost during the sectioning or FISH procedure; and (c) some tumors were only representative on the surface of the block, and the morphology changed as more sections were cut.
Construction and Sectioning of Tissue Microarrays.
The prostate tissue microarray was constructed as described previously (3)
. Briefly, a tissue arraying instrument (Beecher Instruments, Silver Spring, MD) was used to create holes in a recipient paraffin block and to acquire tissue cores from the donor block by a thin-walled needle with an inner diameter of 0.6 mm, held in an X-Y precision guide. The cylindrical sample was retrieved from the selected region in the donor and extruded directly into the recipient block with defined array coordinates. A solid steel wire, closely fit in the tube, was used to transfer the tissue cores into the recipient block. After the construction of the array block, multiple 5-µm sections were cut with a microtome using an adhesive-coated tape sectioning system (Instrumedics, Hackensack, NJ). H&E-stained sections were used for histological verification of tumor tissue on the arrayed samples.
FISH to Formalin-fixed Tissue Microarray Sections.
Two-color FISH to sections of the formalin-fixed samples on the tissue microarray was performed using Spectrum Orange-labeled AR, MYC, ERBB2, and CCND1 probes with corresponding FITC-labeled centromeric probes (Vysis, Downer’s Grove, IL). In addition, one-color FISH was done with Spectrum Orange-labeled NMYC probe (Vysis). The hybridization was performed according to the manufacturer’s instructions. The following tissue treatment protocol was developed to allow formalin-fixed tumors on the array to be reliably analyzed by FISH. The slides of the prostate microarray were first deparaffinized, immersed in 0.2 N HCl, incubated in 1 M sodium thiocyanate solution at 80°C for 30 min, and immersed in a protease solution (0.5 mg/ml in 0.9% NaCl; Vysis) for 10 min at 37°C. The slides were then postfixed in 10% buffered formalin for 10 min, air dried, denaturated for 5 min at 73°C in 70% formamide/2x SSC (SSC is 0.3 M sodium chloride and 0.03 M sodium citrate) solution and dehydrated in 70, 80, and 100% ethanol, followed by proteinase K (4 µg/ml PBS; Life Technologies, Inc., Rockville, MD) treatment for 7 min at 37°C. The slides were then dehydrated and hybridized. The hybridization mixture contained 3 µl of each of the probes and Cot1-DNA (1 mg/ml; Life Technologies, Inc.) in a hybridization mixture. After overnight hybridization at 37°C in a humid chamber, slides were washed and counterstained with 0.2 µM DAPI. FISH signals were scored with a Zeiss fluorescence microscope (Jena, Germany) equipped with a double-band pass filter using x40-x100 objectives. The relative number of gene signals in relation to the centromeric signals was evaluated by visual analysis of the hybridization signals. Criteria for gene amplification were: tight clusters of signals in multiple cells or at least three times more test probe signals than centromeric signals per cell in >10% of the tumor cells. Test:control signal ratios in the range between 1 and 3 were regarded as low-level gains and were not scored as evidence of specific gene amplification. Evidence for amplification of NMYC without reference probe was considered in the case of tight clusters of gene signals or >5 signals in at least 10% of the tumor cells.
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Results |
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TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
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. The hybridization efficiency of the probes could be estimated from the analysis of BPH tissue samples that were present on the same tissue microarray. High-quality hybridization signals with both centromeric, and gene-specific probes were obtained in 96% of the BPH samples for chromosome X/AR gene, 84% for chromosome 8/MYC, 81% for chromosome 17/ERBB2, and 83% for chromosome 11/CCND1. In the evaluable BPH samples, the average percentage of epithelial cells with two signals for autosomal probes was 
75%, with 20% showing one signal and 5% no signals. The percentage of cells with one or zero signals is probably mostly attributable to the truncation of nuclei with sectioning (14)
. In the punched samples from biopsy cancer specimens, AR, MYC, ERBB2, and CCND1 FISH data could be obtained from 92, 78, 82, and 86% of the cases, respectively. The success rate of FISH was lower in punches from autopsy tumors (44–58%). Amplifications were only scored to be present when the copy number of the test probe exceeded that of the chromosome-specific centromere reference probe by 3-fold in 10% or more of the tumor cells. This criterion was chosen, because low-level amplification is likely to be less relevant, and because locus-specific probes often display slightly higher copy numbers than centromeric probes, due to signal splitting or the presence of G2-M-phase cells.
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. Amplification was seen equally often (22.0%) in 59 metastases of hormone-refractory tumors. The strong association between AR amplification and hormone-refractory prostate cancer is evident from the fact that only 2 of the 205 evaluable primary tumors (1%) and none of the 32 BPH controls showed any AR amplification. The two exceptions included a patient with locally advanced and metastatic prostate cancer and another patient with clinically localized disease. Whereas the patient records did not mention hormonal therapy, prior exposure of these patients to such therapy cannot definitively be ruled out. Paired tumors from the primary site of the cancer and from a distant metastasis of 17 patients were successfully analyzed for AR amplification. In 11 of these patients, no AR amplification could be seen at either site. Of the six remaining patients, three patients showed amplification in the local tumor mass, as well as in the distant metastases. In two cases, amplification was only found in the sample from the primary site, whereas in another case, only the distant metastasis showed amplification.
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. There was a significant association between AR and MYC amplifications. MYC was amplified in 12.5% of 24 evaluable tumors with AR amplifications but only in 1.8% of 219 tumors without AR amplifications (P = 0.003, contingency table analysis). AR was independently amplified in 21 tumors, whereas only 4 tumors had MYC amplification, but no AR amplification.
CCND1, ERBB2, and NMYC.
CCND1 amplifications were found in 2 (1.2%) of the 172 evaluable primary tumors, in 3 (7.9%) of 38 local recurrencies, and in 2 (4.7%) of the 43 metastases. CCND1 amplification appeared independent from AR or MYC amplification with only two of seven and one of seven CCND1-amplified tumors showing also AR or MYC amplification, respectively. There were no ERBB2 amplifications among any of the 262 evaluable tumors or 31 BPH controls. Finally, a subset of the tumors was analyzed with the NMYC probe in a single-color FISH analysis. Of the 164 tumors available, none showed evidence of amplification.
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Discussion |
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A possible limitation of the tissue microarray technology is that the minute tissue samples acquired from the original tissues may not always be representative of the entire tumor, in light of the intratumor heterogeneity characteristic to most cancers. The frequency of involvement of the different genes in our study is therefore likely to be an underestimate, although the comparison of the present results with the previous literature suggests that this problem is not as substantial as one would expect (see below). The effect of this sampling bias is also primarily reflected in the analysis of absolute frequencies of genetic alterations in a given tumor type. The comparisons between similarly acquired specimens from different stages of tumor progression placed on the same tissue microarray should be less problematic. Also, comparisons of the frequencies of involvement of specific genes with those of other genes evaluated from consecutive tissue microarray experiments should suffer little if at all of sampling biases. Moreover, it is very likely that "punching" from multiple sites from each original tumor can significantly reduce the sampling problem. Nevertheless, at the moment, one should consider the tumor tissue microarray technology as a rapid, high-throughput survey method to pinpoint the biologically most prevalent or clinically most promising genes and molecular markers for detailed studies with conventional tissue specimens.
Gene amplifications have been reported to be more infrequent in prostate cancer than in many other carcinomas. According to our results, this is indeed the case for primary prostate cancers, where high-level amplifications of all of the tested loci were rare (<2%). However, in samples from hormone-refractory local recurrencies or metastatic deposits, the amplification frequencies were substantially more common for three of the five genes evaluated. This is in agreement with the hypothesis that accumulation of multiple genetic changes, perhaps as a result of genetic instability, is associated with prostate cancer progression (15, 16, 17) .
In our previous studies, up to 30% of patients failing hormonal treatment were found to have AR amplification (8 , 9) . In these studies, only tissues from the locally recurrent tumors were available. The present tumor tissue microarray analyses of end-stage metastatic patients indicated that AR amplification is equally common in the distant metastatic deposits. Studies of the molecular genetic changes in the metastatic specimens are important, because the distant metastatic sites are primarily responsible for the clinical outcome, and represent the primary targets of systemic therapies (18) . In one-half of the patients with end-stage hormone-refractory disease associated with AR amplification, amplified cells were present in all sites sampled, both in the locally recurrent tumors, as well as in distant metastases. In the remaining patients, AR amplification was only present in either the local site or in the metastases. Because most of the patients have metastatic disease already before androgen deprivation therapy is initiated, it is likely that the different sites of cancer in the same patient may sometimes respond to hormonal treatment in a unique manner. Our results suggest that tumor progression to hormone refractory cancer develops via different molecular mechanisms. This heterogeneity may also explain why any therapy against metastatic, hormone-refractory prostate cancer often tends to be ineffective.
MYC amplifications were most often found in the distant metastatic deposits sampled at autopsy. This 11% prevalence is somewhat lower than the previously reported 21% frequency of MYC involvement in prostate cancer metastases to pelvic lymph nodes (7)
. It is possible that the sampling from only one distinct region of each tumor may have led to an underestimation of the true prevalence of gene amplification in our study. However, in the study by Jenkins et al. (7)
, also a less stringent criterion (>2X) for amplification was used than in our study (3X). Because low-level increases of copy numbers of the long arm of chromosome 8 are so common (15
, 16
, 19)
, it is possible that the more stringent cutoff is more appropriate to identify cases, where specific amplifications of the MYC oncogene region take place. One should note, however, that the finding of MYC amplification by FISH does not prove that MYC is the target gene of the amplification at 8q24.
Our study provides evidence for CCND1 gene amplification in human prostate cancer in vivo. The amplification frequency was low (1%) in primary prostate cancer, which may explain why it has not been reported previously. In contrast, 4.7–7.9% of the hormone-refractory and metastatic samples had CCND1 amplification. Further studies are required to evaluate the significance of this amplification for prostate cancer progression. Interestingly, CCND1 amplification often appeared to take place independently of AR and MYC amplifications.
One group has previously suggested that ERBB2 amplification is a frequent genetic alteration and has prognostic importance in prostate cancer (11 , 12) . However, other investigators have failed to detect ERBB2 amplifications in prostate cancer (4 , 10) . Similarly, we did not detect any ERBB2 amplifications at any stage of cancer progression, including end-stage autopsy tumors. It is likely that the high prevalence of ERBB2 amplifications reported in the study of Ross et al. (11 , 12) was due to a less stringent definition of gene amplification and the lack of a chromosome-specific reference probe to exclude the influence of aneuploidy. On the basis of our comparative analysis of AR, MYC, CCND1, and NMYC amplifications in the identical tumor samples, using the same FISH methodology and interpretation criteria, we do not expect either ERBB2 or NMYC amplifications to play any significant roles in the in vivo progression of human prostate cancer.
Many symptomatic prostate cancers become both hormone-refractory and metastatic, and it is very difficult to distinguish between these two clinical features or the molecular mechanisms that contribute specifically to either one of these processes. Taking our present results together with previous information (7, 8, 9) , one can formulate a hypothesis that AR amplification is more closely associated with the development of hormone-refractory cell growth, whereas MYC amplification is associated with metastatic progression. Our results suggest that the most common gene amplification in prostate cancers is that of the AR gene, which is usually amplified independently of both MYC and CCND1. AR has been shown to be amplified in locally recurrent tumors from patients who do not have evidence of distant metastases (8) , whereas MYC amplifications have been associated with metastatic progression (7) . Indeed, in our present study, MYC amplifications were more common in the distant metastases (11%) than in the locally recurrent tissues (4%; both two patients with end-stage metastatic cancers), whereas AR amplifications were equally common at both anatomical sites (22 and 23%, respectively). This suggests that AR is conferring an advantage for hormone-refractory growth and not metastatic dissemination, whereas the reverse may be true for MYC. MYC-amplified tumors may also often contain AR amplification. One could speculate that the selection force responsible for the development of AR amplification makes it necessary for the cells to overcome the checkpoints that prohibit gene amplification in normal cells. This would lead to amplification of other genes such as MYC.
In conclusion, these results illustrate that the tissue microarray technology is a powerful tool for the molecular profiling of large numbers of tumors representing the entire disease spectrum of human prostate cancer progression in vivo. This high-throughput, tissue microarray-based screening by FISH identified distinct patterns and interrelationships between the different gene amplifications, leading to hypotheses that can now be tested in future studies of large specimens, or by more extensive sampling from each tumor site: (a) the present results suggest that AR gene is the most frequent target, and often the first target, selected for amplification during prostate cancer progression; (b) in contrast to AR, amplifications of the MYC oncogene may be primarily associated with metastatic dissemination; and (c) prostate cancers occasionally also amplify the CCND1 gene, whereas ERBB2 and NMYC amplifications are unlikely to play a significant role at any stage of the progression of prostate cancer. Additional studies with the "tissue chip" approach may be helpful to generate a more comprehensive model of the genetic and molecular steps associated with prostate cancer progression, as well as to help the translation of such biological findings to clinical applications.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 L. B. is supported by the Swiss National Science Foundation (81BS-052807), G. S. is supported by Clinical Cancer Foundation, Basel, Switzerland, and P. K. by the Academy of Finland and the TAUH-EVO Foundation. 
2 To whom requests for reprints should be addressed, at Cancer Genetics Branch, National Human Genome Research Institute, NIH, 49 Convent Drive, MSC 4470, Room 4A24, Bethesda, MD 20892-4470. Phone: (301) 435-2896; Fax: (301) 402-7957; E-mail: okalli{at}nhgri.nih.gov
3 The abbreviations used are: FISH, fluorescence in situ hybridization; AR, androgen receptor; CCND1, Cyclin-D1; BPH, benign prostatic hyperplasia.
Received 11/10/98. Accepted 1/ 6/98.
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K. Freier, S. Joos, C. Flechtenmacher, F. Devens, A. Benner, F. X. Bosch, P. Lichter, and C. Hofele Tissue Microarray Analysis Reveals Site-specific Prevalence of Oncogene Amplifications in Head and Neck Squamous Cell Carcinoma Cancer Res., March 15, 2003; 63(6): 1179 - 1182. [Abstract] [Full Text] [PDF]
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 M. Varella-Garcia Molecular Cytogenetics in Solid Tumors: Laboratorial Tool for Diagnosis, Prognosis, and Therapy Oncologist, February 1, 2003; 8(1): 45 - 58. [Abstract] [Full Text] [PDF]
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C. Kumar-Sinha, K. W. Ignatoski, M. E. Lippman, S. P. Ethier, and A. M. Chinnaiyan Transcriptome Analysis of HER2 Reveals a Molecular Connection to Fatty Acid Synthesis Cancer Res., January 1, 2003; 63(1): 132 - 139. [Abstract] [Full Text] [PDF]
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A. Bar-Shira, J. H. Pinthus, U. Rozovsky, M. Goldstein, W. R. Sellers, Y. Yaron, Z. Eshhar, and A. Orr-Urtreger Multiple Genes in Human 20q13 Chromosomal Region Are Involved in an Advanced Prostate Cancer Xenograft Cancer Res., December 1, 2002; 62(23): 6803 - 6807. [Abstract] [Full Text] [PDF]
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C. G. Tepper, D. L. Boucher, P. E. Ryan, A.-H. Ma, L. Xia, L.-F. Lee, T. G. Pretlow, and H.-J. Kung Characterization of a Novel Androgen Receptor Mutation in a Relapsed CWR22 Prostate Cancer Xenograft and Cell Line Cancer Res., November 15, 2002; 62(22): 6606 - 6614. [Abstract] [Full Text] [PDF]
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 M. J. Urist, C. J. Di Como, M.-L. Lu, E. Charytonowicz, D. Verbel, C. P. Crum, T. A. Ince, F. D. McKeon, and C. Cordon-Cardo Loss of p63 Expression Is Associated with Tumor Progression in Bladder Cancer Am. J. Pathol., October 1, 2002; 161(4): 1199 - 1206. [Abstract] [Full Text] [PDF]
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S. Mohr, G. D. Leikauf, G. Keith, and B. H. Rihn Microarrays as Cancer Keys: An Array of Possibilities J. Clin. Oncol., July 15, 2002; 20(14): 3165 - 3175. [Abstract] [Full Text] [PDF]
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P. P. Massion, W.-L. Kuo, D. Stokoe, A. B. Olshen, P. A. Treseler, K. Chin, C. Chen, D. Polikoff, A. N. Jain, D. Pinkel, et al. Genomic Copy Number Analysis of Non-small Cell Lung Cancer Using Array Comparative Genomic Hybridization: Implications of the Phosphatidylinositol 3-Kinase Pathway Cancer Res., July 1, 2002; 62(13): 3636 - 3640. [Abstract] [Full Text] [PDF]
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 A. W. Hsing, A. P. Chokkalingam, Y.-T. Gao, G. Wu, X. Wang, J. Deng, J. Cheng, I. A. Sesterhenn, F. K. Mostofi, T. Chiang, et al. Polymorphic CAG/CAA Repeat Length in the AIB1/SRC-3 Gene and Prostate Cancer Risk: A Population-based Case-Control Study Cancer Epidemiol. Biomarkers Prev., April 1, 2002; 11(4): 337 - 341. [Abstract] [Full Text] [PDF]
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D. Wu, T. L. Foreman, C. W. Gregory, M. A. McJilton, G. G. Wescott, O. H. Ford, R. F. Alvey, J. L. Mohler, and D. M. Terrian Protein Kinase C{epsilon} Has the Potential to Advance the Recurrence of Human Prostate Cancer Cancer Res., April 1, 2002; 62(8): 2423 - 2429. [Abstract] [Full Text] [PDF]
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D Gancberg, A Di Leo, G Rouas, T Jarvinen, A Verhest, J Isola, M J Piccart, and D Larsimont Reliability of the tissue microarray based FISH for evaluation of the HER-2 oncogene in breast carcinoma J. Clin. Pathol., April 1, 2002; 55(4): 315 - 317. [Abstract] [Full Text] [PDF]
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 A. Nyska, A. Dayan, and R. R. Maronpot New Tools in Therapeutic Research--Prostatic Cancer and Models Toxicol Pathol, February 1, 2002; 30(2): 283 - 287. [PDF]
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J D Oxley, M H Winkler, D A Gillatt, and D S Peat Her-2/neu oncogene amplification in clinically localised prostate cancer J. Clin. Pathol., February 1, 2002; 55(2): 118 - 120. [Abstract] [Full Text] [PDF]
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 R.S.D. Brown, J. Edwards, J.W. Bartlett, C. Jones, and A. Dogan Routine Acid Decalcification of Bone Marrow Samples Can Preserve DNA for FISH and CGH Studies in Metastatic Prostate Cancer J. Histochem. Cytochem., January 1, 2002; 50(1): 113 - 116. [Abstract] [Full Text] [PDF]
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K. J. Savinainen, O. R. Saramaki, M. J. Linja, O. Bratt, T. L. J. Tammela, J. J. Isola, and T. Visakorpi Expression and Gene Copy Number Analysis of ERBB2 Oncogene in Prostate Cancer Am. J. Pathol., January 1, 2002; 160(1): 339 - 345. [Abstract] [Full Text] [PDF]
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 M. E. Grossmann, H. Huang, and D. J. Tindall Androgen Receptor Signaling in Androgen-Refractory Prostate Cancer J Natl Cancer Inst, November 21, 2001; 93(22): 1687 - 1697. [Abstract] [Full Text] [PDF]
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M. Schoenberg Fejzo and D. J. Slamon Frozen Tumor Tissue Microarray Technology for Analysis of Tumor RNA, DNA, and Proteins Am. J. Pathol., November 1, 2001; 159(5): 1645 - 1650. [Abstract] [Full Text] [PDF]
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S. Manley, N. R. Mucci, A. M. De Marzo, and M. A. Rubin Relational Database Structure to Manage High-Density Tissue Microarray Data and Images for Pathology Studies Focusing on Clinical Outcome : The Prostate Specialized Program of Research Excellence Model Am. J. Pathol., September 1, 2001; 159(3): 837 - 843. [Abstract] [Full Text] [PDF]
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R. Simon, A. Nocito, T. Hubscher, C. Bucher, J. Torhorst, P. Schraml, L. Bubendorf, M. M. Mihatsch, H. Moch, K. Wilber, et al. Patterns of HER-2/neu Amplification and Overexpression in Primary and Metastatic Breast Cancer J Natl Cancer Inst, August 1, 2001; 93(15): 1141 - 1146. [Abstract] [Full Text] [PDF]
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 C-C Chiou, C-C Chan, D-L Sheu, K-T Chen, Y-S Li, and E-C Chan Helicobacter pylori infection induced alteration of gene expression in human gastric cells Gut, May 1, 2001; 48(5): 598 - 604. [Abstract] [Full Text] [PDF]
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M. J. Linja, K. J. Savinainen, O. R. Saramäki, T. L. J. Tammela, R. L. Vessella, and T. Visakorpi Amplification and Overexpression of Androgen Receptor Gene in Hormone-Refractory Prostate Cancer Cancer Res., May 1, 2001; 61(9): 3550 - 3555. [Abstract] [Full Text]
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 M. KURELLA, L.-L. HSIAO, T. YOSHIDA, J. D. RANDALL, G. CHOW, S. S. SARANG, R. V. JENSEN, and S. R. GULLANS DNA Microarray Analysis of Complex Biologic Processes J. Am. Soc. Nephrol., May 1, 2001; 12(5): 1072 - 1078. [Abstract] [Full Text]
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G. Buchanan, N. M. Greenberg, H. I. Scher, J. M. Harris, V. R. Marshall, and W. D. Tilley Collocation of Androgen Receptor Gene Mutations in Prostate Cancer Clin. Cancer Res., May 1, 2001; 7(5): 1273 - 1281. [Abstract] [Full Text]
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R. Shah, N. R. Mucci, A. Amin, J. A. Macoska, and M. A. Rubin Postatrophic Hyperplasia of the Prostate Gland : Neoplastic Precursor or Innocent Bystander? Am. J. Pathol., May 1, 2001; 158(5): 1767 - 1773. [Abstract] [Full Text] [PDF]
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 O.-P. Kallioniemi, U. Wagner, J. Kononen, and G. Sauter Tissue microarray technology for high-throughput molecular profiling of cancer Hum. Mol. Genet., April 1, 2001; 10(7): 657 - 662. [Abstract] [Full Text] [PDF]
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A. Hoos, M. J. Urist, A. Stojadinovic, S. Mastorides, M. E. Dudas, D. H. Y. Leung, D. Kuo, M. F. Brennan, J. J. Lewis, and C. Cordon-Cardo Validation of Tissue Microarrays for Immunohistochemical Profiling of Cancer Specimens Using the Example of Human Fibroblastic Tumors Am. J. Pathol., April 1, 2001; 158(4): 1245 - 1251. [Abstract] [Full Text] [PDF]
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J. C. Alers, P.-J. Krijtenburg, A. N. Vis, R. F. Hoedemaeker, M. F. Wildhagen, W. C. J. Hop, T. H. van der Kwast, F. H. Schroder, H. J. Tanke, and H. van Dekken Molecular Cytogenetic Analysis of Prostatic Adenocarcinomas from Screening Studies : Early Cancers May Contain Aggressive Genetic Features Am. J. Pathol., February 1, 2001; 158(2): 399 - 406. [Abstract] [Full Text] [PDF]
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K. Specht, T. Richter, U. Muller, A. Walch, M. Werner, and H. Hofler Quantitative Gene Expression Analysis in Microdissected Archival Formalin-Fixed and Paraffin-Embedded Tumor Tissue Am. J. Pathol., February 1, 2001; 158(2): 419 - 429. [Abstract] [Full Text] [PDF]
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S. M. Henshall, D. I. Quinn, C. S. Lee, D. R. Head, D. Golovsky, P. C. Brenner, W. Delprado, P. D. Stricker, J. J. Grygiel, and R. L. Sutherland Altered Expression of Androgen Receptor in the Malignant Epithelium and Adjacent Stroma Is Associated with Early Relapse in Prostate Cancer Cancer Res., January 1, 2001; 61(2): 423 - 427. [Abstract] [Full Text]
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H. I. Scher HER2 in Prostate Cancer--a Viable Target or Innocent Bystander? J Natl Cancer Inst, December 6, 2000; 92(23): 1866 - 1868. [Full Text] [PDF]
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S. Signoretti, R. Montironi, J. Manola, A. Altimari, C. Tam, G. Bubley, S. Balk, G. Thomas, I. Kaplan, L. Hlatky, et al. Her-2-neu Expression and Progression Toward Androgen Independence in Human Prostate Cancer J Natl Cancer Inst, December 6, 2000; 92(23): 1918 - 1925. [Abstract] [Full Text] [PDF]
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 C. Abate-Shen and M. M. Shen Molecular genetics of prostate cancer Genes & Dev., October 1, 2000; 14(19): 2410 - 2434. [Full Text]
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K. Oode, T. Furuya, K. Harada, S. Kawauchi, K. Yamamoto, T. Hirano, and K. Sasaki The Development of a Cell Array and Its Combination with Laser-Scanning Cytometry Allows a High-Throughput Analysis of Nuclear DNA Content Am. J. Pathol., September 1, 2000; 157(3): 723 - 728. [Abstract] [Full Text] [PDF]
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J. Richter, U. Wagner, J. Kononen, A. Fijan, J. Bruderer, U. Schmid, D. Ackermann, R. Maurer, G. Alund, H. Knonagel, et al. High-Throughput Tissue Microarray Analysis of Cyclin E Gene Amplification and Overexpression in Urinary Bladder Cancer Am. J. Pathol., September 1, 2000; 157(3): 787 - 794. [Abstract] [Full Text] [PDF]
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M. Drobnjak, I. Osman, H. I. Scher, M. Fazzari, and C. Cordon-Cardo Overexpression of Cyclin D1 Is Associated with Metastatic Prostate Cancer to Bone Clin. Cancer Res., May 1, 2000; 6(5): 1891 - 1895. [Abstract] [Full Text] [PDF]
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A. K. Walch, H. F. Zitzelsberger, J. Bruch, G. Keller, D. Angermeier, M. M. Aubele, J. Mueller, H. Stein, H. Braselmann, J. R. Siewert, et al. Chromosomal Imbalances in Barrett’s Adenocarcinoma and the Metaplasia-Dysplasia-Carcinoma Sequence Am. J. Pathol., February 1, 2000; 156(2): 555 - 566. [Abstract] [Full Text] [PDF]
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P. Schraml, J. Kononen, L. Bubendorf, H. Moch, H. Bissig, A. Nocito, M. J. Mihatsch, O.-P. Kallioniemi, and G. Sauter Tissue Microarrays for Gene Amplification Surveys in Many Different Tumor Types Clin. Cancer Res., August 1, 1999; 5(8): 1966 - 1975. [Abstract] [Full Text] [PDF]
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A. Dellas, J. Torhorst, F. Jiang, J. Proffitt, E. Schultheiss, W. Holzgreve, G. Sauter, M. J. Mihatsch, and H. Moch Prognostic Value of Genomic Alterations in Invasive Cervical Squamous Cell Carcinoma of Clinical Stage IB Detected by Comparative Genomic Hybridization Cancer Res., July 1, 1999; 59(14): 3475 - 3479. [Abstract] [Full Text] [PDF]
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