Genetic Alterations in Hormone-Refractory Recurrent Prostate Carcinomas
1998; Elsevier BV; Volume: 153; Issue: 1 Linguagem: Inglês
10.1016/s0002-9440(10)65554-x
ISSN1525-2191
AutoresNina N. Nupponen, Laura Kakkola, Pasi Koivisto, Tapio Visakorpi,
Tópico(s)Cancer-related Molecular Pathways
ResumoTo study the genetic basis of tumor progression, we have screened 37 hormone-refractory prostate carcinomas for genetic changes by comparative genomic hybridization (CGH). All recurrent tumors showed genetic aberrations, with a mean total number of changes per tumor of 11.4 (range, 3 to 23). The most common genetic aberrations were losses of 8p (72.5%), 13q (50%), 1p (50%), 22 (45%), 19 (45%), 10q (42.5%), and 16q (42.5%) and gains of 8q (72.5%), 7q (40%), Xq (32.5%), and 18q (32.5%). The CGH results were further validated with fluorescence in situhybridization (FISH) using probes for pericentromeric regions of chromosomes 7, 8, and 18 as well as probes for caveolin (7q31), c-myc (8q24), and bcl-2 (18q21.3). In addition, the samples had previously been analyzed for androgen receptor gene copy number. CGH and FISH results were concordant in 78% of cases. Seventeen of twenty-two tumors showed an increased copy number of c-myc by FISH. However, only 5 of 17 (29%) of the cases showed high-level (more than threefold) amplification. Both CGH and FISH findings suggested that in most of the cases 8q gain involves the whole q-arm of the chromosome. Four of seventeen (24%) cases showed increased copy number of bcl-2 by FISH; however, no high-level amplifications were found. To evaluate the clonal relationship of the primary and recurrent tumors, six primary-recurrent tumor pairs from the same patients were studied by CGH. In three of six cases (50%), the recurrent tumor had more than one-half of the aberrations found in the corresponding primary tumor, indicating a close clonal relationship. In the rest of the cases, such a linear clonal relationship was less evident. Altogether, these results suggest that recurrent prostate carcinomas are genetically unstable. The resulting heterogeneity may well underlie the poor responsiveness of hormone-refractory tumors to treatment. To study the genetic basis of tumor progression, we have screened 37 hormone-refractory prostate carcinomas for genetic changes by comparative genomic hybridization (CGH). All recurrent tumors showed genetic aberrations, with a mean total number of changes per tumor of 11.4 (range, 3 to 23). The most common genetic aberrations were losses of 8p (72.5%), 13q (50%), 1p (50%), 22 (45%), 19 (45%), 10q (42.5%), and 16q (42.5%) and gains of 8q (72.5%), 7q (40%), Xq (32.5%), and 18q (32.5%). The CGH results were further validated with fluorescence in situhybridization (FISH) using probes for pericentromeric regions of chromosomes 7, 8, and 18 as well as probes for caveolin (7q31), c-myc (8q24), and bcl-2 (18q21.3). In addition, the samples had previously been analyzed for androgen receptor gene copy number. CGH and FISH results were concordant in 78% of cases. Seventeen of twenty-two tumors showed an increased copy number of c-myc by FISH. However, only 5 of 17 (29%) of the cases showed high-level (more than threefold) amplification. Both CGH and FISH findings suggested that in most of the cases 8q gain involves the whole q-arm of the chromosome. Four of seventeen (24%) cases showed increased copy number of bcl-2 by FISH; however, no high-level amplifications were found. To evaluate the clonal relationship of the primary and recurrent tumors, six primary-recurrent tumor pairs from the same patients were studied by CGH. In three of six cases (50%), the recurrent tumor had more than one-half of the aberrations found in the corresponding primary tumor, indicating a close clonal relationship. In the rest of the cases, such a linear clonal relationship was less evident. Altogether, these results suggest that recurrent prostate carcinomas are genetically unstable. The resulting heterogeneity may well underlie the poor responsiveness of hormone-refractory tumors to treatment. Prostate cancer is the most common malignancy among men in many Western industrialized countries. Despite the improved early diagnosis of prostate cancer, approximately one-third of the patients are still diagnosed at a clinically advanced stage.1Kosary CL Ries LAG Miller BA Hankey BF Harras A Edwards BK SEER Cancer Statistics Review, 1973-1992, Tables and Graphs: National Institutes of Health Publication 96–2789. National Cancer Institute, Bethesda, MD1995Google Scholar For these patients, androgen withdrawal remains the only effective treatment. Most of the prostate cancer patients initially respond to hormonal therapy,2Stearns ME McGarvey T Prostate cancer: therapeutic, diagnostic, and basic studies.Lab Invest. 1992; 67: 540-552PubMed Google Scholar but eventually the disease will progress. And there are no effective second-line treatments for such hormone-refractory tumors.2Stearns ME McGarvey T Prostate cancer: therapeutic, diagnostic, and basic studies.Lab Invest. 1992; 67: 540-552PubMed Google Scholar The mechanisms that lead to progression of prostate cancer during endocrine treatment are poorly understood. Several hypotheses on the molecular mechanisms of tumor recurrence have been suggested. These include overexpression of the bcl-2 oncogene,3McDonnell TJ Troncoso P Brisbay SM Logothetis C Chung LW Hsieh JT Tu SM Campbell ML Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer.Cancer Res. 1992; 52: 6940-6944PubMed Google Scholar, 4Colombel M Symmans F Gil S O'Toole KM Chopin D Benson M Olsson CA Korsmeyer S Buttyan R Detection of the apoptosis-suppressing oncoprotein bcl-2 in hormone-refractory human prostate cancers.Am J Pathol. 1993; 143: 390-400PubMed Google Scholar, 5Krajewska M Krajewski S Epstein JI Shabaik A Sauvageot J Song K Kitada S Reed JC Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers.Am J Pathol. 1996; 148: 1567-1577PubMed Google Scholar activating mutations in the androgen receptor (AR) gene,6Taplin ME Bubley GJ Shuster TD Frantz ME Spooner AE Ogata GK Keer HN Balk SP Mutation of the androgen-receptor gene in metastatic androgen-independent prostate cancer.N Engl J Med. 1995; 332: 1393-1398Crossref PubMed Scopus (1036) Google Scholar, 7Tilley WD Buchanan G Hickey TE Bentel JM Mutations in the androgen receptor gene are associated with progression of human prostate cancer to androgen independence.Clin Cancer Res. 1996; 2: 277-285PubMed Google Scholar and amplification and overexpression of the AR gene.8Visakorpi T Hyytinen E Koivisto P Tanner M Keinänen R Palmberg C Palotie A Tammela T Isola J Kallioniemi O-P In vivo amplification of the androgen receptor gene and progression of human prostate cancer.Nature Genet. 1995; 9: 401-406Crossref PubMed Scopus (1232) Google Scholar, 9Koivisto P Kononen J Palmberg C Tammela T Hyytinen E Isola J Trapman J Cleutjens K Noordzij A Visakorpi T Kallioniemi O-P Androgen receptor gene amplification: A possible molecular mechanism for failure of androgen deprivation therapy in prostate cancer.Cancer Res. 1997; 5: 314-319Google Scholar Comparative genomic hybridization (CGH) is a fairly new molecular cytogenetic method that allows detection of DNA sequence copy number changes throughout the genome in a single hybridization.10Kallioniemi A Kallioniemi O-P Sudar D Rutowitz D Gray JW Waldman F Pinkel D Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors.Science. 1992; 258: 818-821Crossref PubMed Scopus (2820) Google Scholar, 11du Manoir S Speicher MR Joos S Schröck E Popp S Döhner H Kovacs G Robert-Nicoud M Lichter P Cremer T Detection of complete and partial chromosomal gains and losses by comparative genomic hybridization.Hum Genet. 1993; 90: 590-610Crossref PubMed Scopus (504) Google Scholar, 12Kallioniemi O-P Kallioniemi A Piper J Isola J Waldman FM Gray JW Pinkel D Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors.Genes Chromosomes & Cancer. 1994; 10: 231-243Crossref PubMed Scopus (944) Google Scholar CGH is helpful in defining chromosomal regions that may harbor amplified oncogenes or deleted tumor suppressor genes (TSGs). Thus, CGH provides a starting point for positional cloning of cancer-related genes. Several common malignancies, including prostate cancer,13Cher ML MacGrogan D Bookstein R Brown JA Jenkins RB Jensen R Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer.Genes Chromosomes & Cancer. 1994; 11: 153-162Crossref PubMed Scopus (190) Google Scholar, 14Joos S Bergerheim U Pan Y Matsuyama H Bentz M du Manoir S Lichter P Mapping of chromosomal gains and losses in prostate cancer by comparative genomic hybridization.Genes Chromosomes & Cancer. 1995; 14: 267-276Crossref PubMed Scopus (129) Google Scholar, 15Visakorpi T Kallioniemi A Syvänen A-C Hyytinen ER Karhu R Tammela T Isola JJ Kallioniemi O-P Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization.Cancer Res. 1995; 55: 342-347PubMed Google Scholar, 16Cher ML Bova GS Moore DH Small EJ Carroll PR Pin SS Epstein JI Isaacs WB Jensen RH Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping.Cancer Res. 1996; 56: 3091-3102PubMed Google Scholar have already been studied by CGH. These studies have also led to the identification of actual amplified genes in cancer.8Visakorpi T Hyytinen E Koivisto P Tanner M Keinänen R Palmberg C Palotie A Tammela T Isola J Kallioniemi O-P In vivo amplification of the androgen receptor gene and progression of human prostate cancer.Nature Genet. 1995; 9: 401-406Crossref PubMed Scopus (1232) Google Scholar, 17Houldsworth J Mathew S Rao PH Dyomina K Louie DC Parsa N Offit K Changanti RS REL proto-oncogene is frequently amplified in extranodal diffuse large cell lymphoma.Blood. 1996; 87: 25-29PubMed Google Scholar, 18Monni O Joensuu H Franssila K Klefstrom J Alitalo K Knuutila S BCL2 overexpression associated with chromosomal amplification in diffuse large B-cell lymphoma.Blood. 1997; 90: 1168-1174PubMed Google Scholar, 19Weber-Hall S McManus A Anderson J Nojima T Abe S Pritchard-Jones K Shipley J Novel formation and amplification of the PAX7-FKHR fusion gene in a case of alveolar rhabdomyosarcoma.Genes Chromosomes & Cancer. 1996; 17: 7-13Crossref PubMed Scopus (47) Google Scholar As CGH detects only clonal genetic aberrations, it is also useful in the investigation of the clonal evolution of tumor progression.20Kuukasjärvi T Karhu R Tanner M Kähkönen M Schäffer A Nupponen N Pennanen S Kallioniemi A Kallioniemi O-P Isola J Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.Cancer Res. 1997; 57: 1597-1604PubMed Google Scholar To identify genetic aberrations that may underlie the progression of prostate cancer during endocrine therapy, we have now screened 37 hormone-refractory prostate tumors for genetic changes by CGH. In addition, we have studied the genetic relationship of six primary-recurrent tumor pairs. CGH findings were also further studied by fluorescence in situ hybridization (FISH) and locus-specific probes. The material consisted of 37 formalin-fixed, paraffin-embedded recurrent prostate carcinomas obtained from the Tampere University Hospital. According to histological grade,21Mostofi FK Histological Typing of Prostate Tumours. World Health Organization, Geneva1980Google Scholar there were 1 grade I, 15 grade II, and 21 grade III recurrent tumors. According to the TNM stage distribution of the recurrent prostate carcinomas, there were 1 T1NXMO, T2NXMX, T2NXM1; 5 T3NXMX; 6 T3NXMO, T3NXM1; 7 T4NXMO; 3 T4NXMX; and 5 T4NXM1. All samples were transurethral resection specimens taken from patients who had received only endocrine therapy (orchiectomy (28 cases), estrogen (3 cases), luteinizing hormone-releasing hormone agonist (1 case), and combinations of these therapies (5 cases)) and who had experienced local progression as evidenced by new onset of urethral obstruction. The choice of endocrine therapy instead of surgical treatment had been based either on clinical stage of the disease or general condition of the patients. An average time from the diagnosis (beginning of hormonal therapy) to progression was 44 (range, 8 to 113) months and from the progression to death was 29 (1 to 101) months. In addition, six primary-recurrent tumor pairs (five paraffin embedded, one freshly frozen) were available. The primary tumors (transurethral resection specimens) were taken before any treatment, and the recurrent tumors were from the same patients at the time of local relapse (urethral obstruction). Five-micron sections were cut from tumor blocks and stained with hematoxylin and eosin to detect the histological representativeness of the malignant tissue. High molecular weight tumor DNAs for CGH and interphase nuclei for FISH were isolated from paraffin-embedded tumor blocks as described before.22Isola JJ De Vries S Chu LW Ghazvini S Waldman FM Analysis of changes in DNA copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples.Am J Pathol. 1994; 145: 1301-1398PubMed Google Scholar, 23Hyytinen E Visakorpi T Kallioniemi A Kallioniemi O-P Isola J Improved technique for analysis of formalin-fixed paraffin-embedded tumors by fluorescence in situ hybridization.Cytometry. 1994; 16: 93-99Crossref PubMed Scopus (109) Google Scholar CGH was done as described before.12Kallioniemi O-P Kallioniemi A Piper J Isola J Waldman FM Gray JW Pinkel D Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors.Genes Chromosomes & Cancer. 1994; 10: 231-243Crossref PubMed Scopus (944) Google Scholar, 22Isola JJ De Vries S Chu LW Ghazvini S Waldman FM Analysis of changes in DNA copy number by comparative genomic hybridization in archival paraffin-embedded tumor samples.Am J Pathol. 1994; 145: 1301-1398PubMed Google Scholar Briefly, DNA samples from prostate tumors were labeled with fluorescein isothiocyanate (FITC)-dUTP (DuPont, Boston, MA) and normal reference male DNA with Texas Red-dUTP (DuPont) using nick translation. Labeled DNAs (400 ng) were hybridized to normal male lymphocyte metaphase slides (Vysis, Downers Grove, IL) together with unlabeled Cot-1 DNA (10 μg; Gibco BRL, Gaithersburg, MD). After hybridization, the slides were washed and counterstained with an anti-fade solution containing 4,6-diamidino 2-phenylindole (DAPI; Vector Laboratories, Burlingame, CA). Five high quality metaphases from each hybridization were captured using a Xillix CCD camera (Xillix Technologies Corp., Vancouver, British Columbia, Canada) mounted on an Olympus BX50 epifluorescence microscope (Tokyo, Japan) and interfaced to a Sun LX workstation (Sun Microsystems Computer Corp., Mountain View, CA). Relative DNA sequence copy number changes were detected by analyzing the fluorescence intensities of green (tumor) and red (normal) signals along the length of all chromosomes in the metaphase spreads using Quips CGH analysis program (Resource of Molecular Cytogenetics, Lawrence Berkeley National Laboratory, Berkeley, CA) based on the Scilimage program (TNO, Delft, The Netherlands). CGH results were plotted as a series of green-to-red ratio profiles and the interpretation of results followed previously described guidelines.12Kallioniemi O-P Kallioniemi A Piper J Isola J Waldman FM Gray JW Pinkel D Optimizing comparative genomic hybridization for analysis of DNA sequence copy number changes in solid tumors.Genes Chromosomes & Cancer. 1994; 10: 231-243Crossref PubMed Scopus (944) Google Scholar Hybridizations of FITC-labeled normal male DNA against Texas-Red-labeled normal female DNA, in each hybridization batch, were used as negative controls. The mean green-to-red ratio and corresponding SD for all autosomes remained between 0.85 and 1.15. Based on these control hybridizations, chromosomal regions with a mean ratio of 0.85 or less were considered lost, and those with a ratio 1.15 or more were considered gained in the prostate tumors. Chromosome Y was excluded from CGH analysis. The MCF-7 breast cancer cell line was used as a positive control in each hybridization batch. Interphase FISH was performed with locus-specific probes for caveolin (obtained by screening the human PAC library with PCR using primers specific to caveolin) located at 7q31, c-myc (P1, c-myc, RMC08P001, Lawrence Berkeley National Laboratory) located at 8q24, and bcl-2 (obtained by screening the human P1 library with PCR using primers specific to bcl-2) at 18q21.3. Chromosomes 7 (p7αtet), 8 (pJM128), and 18 (p18r) pericentromeric alphoid probes were used as reference probes. Locus-specific probes were labeled with digoxigenin-11-dUTP (myc) (Gibco BRL) or biotin-14-dATP (caveolin, bcl-2; Gibco BRL) and centromeric probes with FITC-dUTP (chromosome 8; DuPont) or Texas-Red-dUTP (chromosomes 7 and 18; DuPont). FISH was performed as described in detail elsewhere.23Hyytinen E Visakorpi T Kallioniemi A Kallioniemi O-P Isola J Improved technique for analysis of formalin-fixed paraffin-embedded tumors by fluorescence in situ hybridization.Cytometry. 1994; 16: 93-99Crossref PubMed Scopus (109) Google Scholar Before FISH, the slides were pretreated by heating in 59% glycerol/0.1X standard saline citrate (SSC; pH 7.5) solution at 90°C for 3 minutes to improve hybridization efficiency. After hybridization, the slides were washed and counterstained with an anti-fade solution containing DAPI (Vector). In addition, 30 tumors had earlier been analyzed for chromosome X centromere and AR gene copy number by FISH.9Koivisto P Kononen J Palmberg C Tammela T Hyytinen E Isola J Trapman J Cleutjens K Noordzij A Visakorpi T Kallioniemi O-P Androgen receptor gene amplification: A possible molecular mechanism for failure of androgen deprivation therapy in prostate cancer.Cancer Res. 1997; 5: 314-319Google Scholar The entire slide was first scanned through, and 120 to 150 randomly chosen individual nuclei were scored in detail to calculate signals for the locus-specific probes and centromeric probes. Control hybridizations to normal lymphocyte metaphase preparations were done to ascertain that the probes recognized a single-copy target and to evaluate the hybridization efficiencies of the probes. The mean total number of changes per tumor in recurrent prostate cancer was 11.4 (range, 3 to 23). The average number of gains per tumor was 4.5 (range, 0 to 13) and of losses was 6.6 (range, 1 to 15). The most frequently lost chromosome arms were (Figure 1) 8p (73%), 1p (54%), 13q (51%), 22q (46%), 10q (46%), 16q (46%), 19 (43%, both arms), 15q (35%), 6q (27%), 18q (19%), 10p (22%), 17p (41%), and 20q (22%). The minimal commonly lost regions in these chromosome arms were 1p36-pter, 1p31, 5q15-q23, 6q16, 6q24-qter, 8p12-p22, 8p23, 10cen-q21, 10q26, 10p11, 13q12, 13q21, 15cen-q21, 15q25-qter, 16q24, 17p, 18q22-qter, 19pter-q13.1, 20cen-q22, and 22q13. The most frequently gained chromosome arms were (Figure 1) 8q (73%), 7q (43%), Xq (35%), 7p (32%), 18q (30%), 2q (27%), 3q (24%), Xp (24%), 11q (22%), 12q (22%), 13q (19%), 4q (19%), and 5q (14%). And the minimal commonly gained regions were 1q25-q32, 2q33, 3q25-q26, 4q13-q23, 5q14-q31, 7p15-p21, 7q21, 7q31, 8q21, 8q23-qter, 11q22, 12q21, 13q31, 18q12, Xpter-Xp21, and Xcen-q13. Figure 2 shows examples of different types of CGH findings of chromosome 8 in hormone-refractory prostate carcinomas. Table 1 summarizes the results of CGH analysis of the primary-recurrent prostate tumor pairs. On average, 51% of the genetic alterations found in the primary tumors were also found in the recurrent tumors. Three recurrent tumors showed more than 50% of the genetic aberrations found in the corresponding primary tumor. However, there was, for example, a case in which only 8% of the aberrations were shared by both tumors (case 1).Table 1Genetic Alterations in the Primary and Recurrent Tumor PairsCasePrimary tumorRecurrent tumorTime to progression (months)1Gains: 22p, 22qGains: 3q, 7p, 7q, 8q, 13q, Xq15Losses: 1p, 1q, 2q, 4q, 5q, 6q, 8p, 12q, 13q, XqLosses: 8p, 19, 17, 20q2Gains: 7, 8q, 9pGains: 7, 8q36Losses: 8p, 13qLosses: 8p, 13q3Gains: noneGains: 3q, 8q, 17q, Xp, Xq59Losses: 1p, 6q, 11q, 12q, 13q, XLosses: 6q, 8p, 10q, 11q, 13q, 15q, 184Gains: 8q, 20pGains: 8q, 4q, 5p46Losses: 16p, 17Losses: 6q5Gains: 2q, 3q, 5q, 7, 8q, 11q, 12qGains: 8q, 10q, 12q, 21q12Losses: 1p, 8p, 16p, 17p, 19, 22Losses: 1p, 8p, 13q, 15q, 16p, 17p, 18q, 19, 226Gains: 2p, 8q, 16pGains: 8q, 16p, Xq22Losses: 1p, 2q, 5p, 5q, 6q, 8p, 9p, 13q, 16q, 18qLosses: 1p, 2q, 3, 5p, 5q, 6q, 8p, 9p, 13q, 16q, 18q, XqThe chromosome arms that contain either gains or losses are given. Genetic alterations that are shared by primary and recurrent tumors are in bold. The histological grades of the primary and the corresponding recurrent tumors were the same in each of the six sample pairs. Open table in a new tab The chromosome arms that contain either gains or losses are given. Genetic alterations that are shared by primary and recurrent tumors are in bold. The histological grades of the primary and the corresponding recurrent tumors were the same in each of the six sample pairs. To validate the CGH findings, we chose a subset of tumors for FISH analysis of caveolin (7q31), c-myc (8q24), bcl-2 (18q21.3), and AR (Xq12). These were the regions that were most commonly gained by CGH. Table 2 summarizes the comparison of CGH and FISH findings. Altogether, 78% of cases showed similar results by CGH and FISH (κ value of 0.57). Figure 2 shows recurrent tumors studied by FISH for c-myc, caveolin, and bcl-2. Seventeen of twenty-two tumors showed increased copy number of c-myc. Of the seventeen tumors, five (29%) showed high-level (more than three times more signals of c-myc versus the chromosome 8 centromere) amplification of c-myc with a mean ± SD copy number of signals (excluding the nuclei with only two signals) of 6.2 ± 0.9. Occasional nuclei with more than 10 copies of c-myc were also found. Four of eight cases showed equally increased copy number of the chromosome 7 centromere and 7q31 (caveolin) with a mean copy number of signals of 3.9 ± 0.6. And four of seventeen cases showed equally increased copy number of the chromosome 18 centromere and bcl-2, with a mean copy number of signals of 4.4 ± 1.3.Table 2Condordance between CGH and FISH Data for the 7q31 (Caveolin), 8q24 (c-myc), 18q21.3 (bcl-2), and Xq12 (AR) RegionsFISHCGHAberrantNormalAberrant312Normal1529The κ value was 0.57. Open table in a new tab The κ value was 0.57. Here, we report results from the analyses of 37 recurrent hormone-refractory prostate carcinomas for genetic aberrations using CGH. The high number of alterations per tumors found by CGH emphasizes the genetic instability as an underlying mechanism of cancer development and progression. As compared with our previous CGH analysis of 31 unselected primary prostate carcinomas,15Visakorpi T Kallioniemi A Syvänen A-C Hyytinen ER Karhu R Tammela T Isola JJ Kallioniemi O-P Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization.Cancer Res. 1995; 55: 342-347PubMed Google Scholar the recurrent tumors in this study contained almost four times more alterations than the primary tumors supporting our earlier findings that the clinical progression of prostate cancer is associated with genetic progression of the tumors.8Visakorpi T Hyytinen E Koivisto P Tanner M Keinänen R Palmberg C Palotie A Tammela T Isola J Kallioniemi O-P In vivo amplification of the androgen receptor gene and progression of human prostate cancer.Nature Genet. 1995; 9: 401-406Crossref PubMed Scopus (1232) Google Scholar, 24Koivisto P Hyytinen E Palmberg C Tammela T Visakorpi T Isola J Kallioniemi O-P Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy.Am J Pathol. 1995; 147: 624-630Google Scholar We analyzed also six primary-recurrent tumor pairs. Three tumor pairs (50%) showed a close genetic relationship as evidenced by a high number of shared genetic alterations in primary and recurrent tumors. For example, in case 6, 13/14 of the alterations (93%) found in the primary tumor were also present in the recurrent tumor (Table 1). The aberrations that were solely found in the recurrent tumors were losses of whole chromosome 3 and the telomeric part of Xq (Xq23-qter), as well as gain of Xcen-q13, indicating a relatively linear genetic progression of the tumor. The most likely target for the Xq gain in this tumor is the AR gene, which was found to be fivefold amplified in the specimen.8Visakorpi T Hyytinen E Koivisto P Tanner M Keinänen R Palmberg C Palotie A Tammela T Isola J Kallioniemi O-P In vivo amplification of the androgen receptor gene and progression of human prostate cancer.Nature Genet. 1995; 9: 401-406Crossref PubMed Scopus (1232) Google Scholar On the other hand, in case 1, only 1 of the 12 genetic aberrations found in the primary tumor were present in the recurrent counterpart. Prostate cancer is commonly considered to be heterogeneous disease. Studies on the whole-mount prostatectomy specimens have shown that prostate gland may contain several carcinoma foci, which appear not always to be physically in contact with each other. These foci may contain different genetic changes.25Sakr WA Macoska JA Benson P Grignon DJ Wolman SR Pontes JR Grissman JD Allelic loss in locally metastatic, multisampled prostate cancer.Cancer Res. 1994; 54: 3273-3277PubMed Google Scholar, 26Greene DR Taylor SR Wheeler TM Scardinoa PT DNA ploidy by image analysis of individual foci of prostate cancer: a preliminary report.Cancer Res. 1991; 51: 4084-4089PubMed Google Scholar, 27Jenkins RB Qian J Lieber MM Bostwick DG Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization.Cancer Res. 1997; 57: 524-531PubMed Google Scholar Jenkins and co-authors27Jenkins RB Qian J Lieber MM Bostwick DG Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization.Cancer Res. 1997; 57: 524-531PubMed Google Scholar have also shown that in some cases it is the minor, instead of the major, primary carcinoma focus that metastasizes. Still, the significance of such multifocality of prostate cancer is inadequately known. The results in this study suggest that the androgen ablation therapy acts as a strong selection force in a similar fashion as a metastases event.20Kuukasjärvi T Karhu R Tanner M Kähkönen M Schäffer A Nupponen N Pennanen S Kallioniemi A Kallioniemi O-P Isola J Genetic heterogeneity and clonal evolution underlying development of asynchronous metastasis in human breast cancer.Cancer Res. 1997; 57: 1597-1604PubMed Google Scholar, 27Jenkins RB Qian J Lieber MM Bostwick DG Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization.Cancer Res. 1997; 57: 524-531PubMed Google Scholar In some cases, it may select for a clone that has acquired only a few additional genetic alterations, such as AR gene amplification. In other cases, the treatment may select for a genetically very different clone or a completely different clone than the primary tumor, suggesting that there are several different mechanisms that may underlie the progression of prostate cancer during endocrine treatment. The fact that recurrent tumors may share only a few genetic alterations with primary tumors indicates also that biomarkers measured exclusively from primary tumors give only a restricted view on the biological properties of hormone-refractory prostate cancer. In this study, every chromosome arm showed genetic alterations in at least one tumor by CGH, probably as a result of random genetic instability. However, some of the chromosomal regions were often altered, suggesting that these regions contain oncogenes and tumor suppressor genes (TSGs) that are important in the development and progression of prostate cancer. The most commonly lost regions were 8p, 13q, 1p, 10q, 17q, 19, and 22, whereas the most commonly gained regions were 8q, 7q, Xq, 18q, and 7p. Most of these regions had been implicated in prostate cancer earlier by either CGH or loss of heterozygosity (LOH) studies.13Cher ML MacGrogan D Bookstein R Brown JA Jenkins RB Jensen R Comparative genomic hybridization, allelic imbalance, and fluorescence in situ hybridization on chromosome 8 in prostate cancer.Genes Chromosomes & Cancer. 1994; 11: 153-162Crossref PubMed Scopus (190) Google Scholar, 14Joos S Bergerheim U Pan Y Matsuyama H Bentz M du Manoir S Lichter P Mapping of chromosomal gains and losses in prostate cancer by comparative genomic hybridization.Genes Chromosomes & Cancer. 1995; 14: 267-276Crossref PubMed Scopus (129) Google Scholar, 15Visakorpi T Kallioniemi A Syvänen A-C Hyytinen ER Karhu R Tammela T Isola JJ Kallioniemi O-P Genetic changes in primary and recurrent prostate cancer by comparative genomic hybridization.Cancer Res. 1995; 55: 342-347PubMed Google Scholar, 16Cher ML Bova GS Moore DH Small EJ Carroll PR Pin SS Epstein JI Isaacs WB Jensen RH Genetic alterations in untreated metastases and androgen-independent prostate cancer detected by comparative genomic hybridization and allelotyping.Cancer Res. 1996; 56: 3091-3102PubMed Google Scholar, 28Carter BS Ewing CM Ward WS Treiger BF Aalders TW Schalken JA Epstein JI Isaacs WB Allelic loss of chromosomes 16q and 10q in human prostate cancer.Proc Natl Acad Sci USA. 1990; 22: 8751-8755Crossref Scopus (468) Google Scholar, 29Kunimi K Bergerheim USP Larsson I-L Ekman P Collins VP Allelotyping of human prostatic aden
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