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Aneuploidy and Aneusomy of Chromosome 7 Detected by Fluorescence in Situ Hybridization Are Markers of Poor Prognosis in Prostate Cancer'

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Aneuploidy and Aneusomy of Chromosome 7 Detected by Fluorescence in Situ Hybridization Are Markers of Poor Prognosis in Prostate Cancer' [CANCERRESEARCH54,3998-4002,August1, 19941 Advances in Brief Aneuploidy and Aneusomy of Chromosome 7 Detected by Fluorescence in Situ Hybridization Are Markers of Poor Prognosis in Prostate Cancer' Antonio Alcaraz, Satoru Takahashi, James A. Brown, John F. Herath, Erik J- Bergstralh, Jeffrey J. Larson-Keller, Michael M Lieber, and Robert B. Jenkins2 Depart,nent of Urology [A. A., S. T., J. A. B., M. M. U, Laboratory Medicine and Pathology (J. F. H., R. B. fl, and Section of Biostatistics (E. J. B., J. J. L-JCJ, Mayo Clinic and Foundation@ Rochester, Minnesota 55905 Abstract studies on prostate carcinoma samples. Interphase cytogenetic analy sis using FISH to enumerate chromosomes has the potential to over Fluorescence in situ hybridization is a new methodologj@which can be come many of the difficulties associated with traditional cytogenetic used to detect cytogenetic anomalies within interphase tumor cells. We studies. Previous studies from this institution have demonstrated that used this technique to identify nonrandom numeric chromosomal alter ations in tumor specimens from the poorest prognosis patients with path FISH analysis with chromosome enumeration probes is more sensitive ological stages T2N@M,Jand T3NOMOprostate carcinomas. Among 1368 than FCM for detecting aneuploid prostate cancers (4, 5, 7). patients treated by radical prostatectomy, 25 study patients were ascer We designed a case-control study to test the hypothesis that spe tamed who died most quickly from progressive prostate carcinoma within cific, nonrandom cytogenetic changes are present in tumors removed 3 years of diagnosis and surgery. Tumors from 25 control patients who from patients with prostate carcinomas with poorest prognoses . We survived for more than 5 years and who were matched for age, tumor identified 25 patients with clinically localized prostate carcinoma histological grade, and pathological stage also were evaluated. The tumors treated by radical prostatectomy who died from metastatic prostate from all 25 (100%) poor prognosis patients and from 11 of 25 (44%) cancer within 3 years after treatment. These patients were then control patients were found to be aneuploid by fluorescence in situ hy matched for age, pathological stage, and tumor histological grade with bndization (P < 0.0001). Alterations ofchromosome 7 were observed in 24 a group of patients who survived for more than 5 years after surgery. of the tumors (96%) from the poor prognosis patients versus 3 tumors (12%) from the control group (P < 0.0001). Moreover, a characteristic FISH analysis was then carried out using chromosome enumeration aneuploidy pattern with multiple abnormal chromosomes and a hypertet probes for 12 different chromosomes. rasomic population was generally found in tumors from the poor prog Patients and Methods nosis patients. This preliminary study suggests that fluorescence in situ hybridization studies of prostate cancer specimens may help to identify Study Design. Among 1386 patients with pathological stage T2NOM@Jand those patients at highest risk for early cancer death. T3N@M0prostatecancer who underwent a radical prostatectomy at the Mayo Introduction Clinic from 1966 to 1990, 31 died of prostate cancer between 6 months and 3 years after surgery. These patients (30 stage T3N@MI@and1 stage T2N@,M,@) Prostate cancer is the most common cancer in United States men, were matched for age, pathological stage, and tumor grade with patients with approximately 200,000 newly diagnosed cases and 38,000 deaths surviving for more than 5 years after surgery. For those poor prognosis cases due to prostate cancer per year (1). The distinction between those resected prior to 1988, the control cases were also matched for date of surgery. Six cases were excluded in both groups because the paraffin-embedded tissue cases of prostate cancer destined to progress rapidly to lethal meta blocks did not contain residual tumor, or the cells were poorly preserved. Ten static disease and those with little likelihood of causing morbidity and BPH surgical samples, from the same time period, were studied to obtain mortality is a major goal of current prostate cancer research. normal value information. Factors such as clinical and pathological stage and histological In Situ Hybridization with Chromosome Enumeration Probes. After grade are conventionally used to help predict prognosis for patients pathological confirmation, six adjacent 50-sm tumor tissue sections were used with localized prostate carcinoma (2). Among newer techniques, for FCM and FISH analyses. Tissue deparaffmization was performed. Sections ploidyIDNA analysis using FCM3 may help refine prognostic risk for were washed for 10 mm with 2 ml Histo-Clear (National Diagnostics, Atlanta, patients with tumors of common histological grades and stages (3). GA) three times. The tissue was then dehydratedin 100% ethanol (5 min, However, it is widely recognized that FCM ploidy analysis cannot twice) and then rinsed in water (5 mm, twice). Tissues were digested in pepsin detect small changes in DNA content or chromosome number. Rou solution (Sigma P.7012; Sigma Chemical Co., St Louis, MO; 4 mg/mI in 0.9% NaC1,pH 1.5) for 2.5 h at 37%. After filtering, isolated nuclei were washed tine cytogenetic studies of solid tumors are a more precise approach to twice with phosphate-buffered saline and vortexed. The resultant nuclear detect numerical and/or structural defects. However, because met suspension was applied to Superfrost slides, and the slides were oven-dried at aphase cells are required for analysis, cytogenetic studies are ham 65°Cfor 10 min. FISH probes, labeled with SpectrumOrange or Spec pered by the difficulties of specifically stimulating tumor cells to trumGreen, specific for the centromere region of 11 chromosomes (4, 6—12, divide. It has been particularly difficult to perform routine cytogenetic 17, 18, and X) and for the mid-distal Yq (Yq12) region, were obtained from Imagenetics (Framingham, MA). Only single-probe hybridizations were per Received 4/6/94; accepted 6/14/94. formed. All of the currently available Imagenetics chromosome enumeration The costs of publication of this article were defrayed in part by the payment of page probes were used in the study. charges. This article must therefore be hereby marked advertisement in accordance with Slides containing isolated nuclei were dehydrated in an ethanol series (70, 18 U.S.C. Section 1734 solely to indicate this fact. I Supported in part by a grant from Imagenetics Inc., Naperville, IL (to R. B. J.); Grant 85, and 100%)for 2 mmeach. DNA was denaturedbyincubatingtheslides in CA 58225 from NIH (to R. B. J., M. M. L., S. T.); and by Grant FIS 93/5326 from the 70% formamide/2X SSC (300 mM sodium chloride and 30 mM sodium citrate) Hospital ainic de Barcelona and Fondo de Investigaciones Sanitarias (to A. A.). at 75°Cfor 4 mm, followed by dehydration in an ice-cold ethanol series. 2 To whom requests for reprints should be addressed, at Cytogenetics Laboratory, Simultaneously, the probe solution (7 @lHybridizationMix II; Imagenetics; Mayo Clinic, 200 First Street SW, Rochester, MN 55905. 2 @.tlprobe) was denatured for 6 min at 75°C and kept on ice until it was added 3 The abbreviations used are: FCM, flow cytometry; FISH, fluorescence in situ hybridization; BPH, benign prostatic hyperplasia; SSC, standard sodium citrate; 2SD, two to the slides. After sealing, the slides were then incubated overnight at 37°C. standard deviations. Following hybridization, the slides were washed in 50% formamide/2X SSC 3998 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1994 American Association for Cancer Research. FI5H MARKERS OF POOR PROGNOSIS IN PROSTATE CANCER for 10 s, 2X SSC for 1 aria,and2X SSC/NonidetP-40 for 1 mmat 37°C.The most likely the result of homologous pairing (7). The mean + 2SD for counterstain 4,6-diamidino-2-phenylindole with antifade compound p-phe monosomy (for autosomes) and nullisomy (sex chromosomes) was nylenediaminewas addedpriorto analysis. lower than 10% for all chromosomes. All of the autosomes had an Analysis of Interphase in Situ Hybrkllzatlon. For each probe hybridiza average trisomy or tetrasomy level of less than 1.5% (Fig. 1B). For tion, signals from 300 nuclei were counted. For this number of enumerated each of the autosomes, mean + 2SD for trisomy was less than 3% and nuclei, the 95% confidence limits ofthe 0, 1, 2, 3, 4 and 5 signal proportions for tetrasomy less than 4%. The percentage nuclei with 4 signals for (p) were estimated as ±1.96V@j@00 using the binomial distribution and were at most ±0.057atP 0.5. each autosome was averaged to estimate the normal percentage of Flow Cytometry. The method for DNA content analysis of paraffin tetraploid cells with prostate tissue. The mean for all BPH specimens embedded tissues has been described previously (4). was 2.58% with an SD of 0.62%. Statistical Analysis Comparisons of age and tumor characteristics be Because of relative loss of chromosomes, inefficient hybridization, tween the poor prognosis (cases) and control groups were made using the and/or homologous pairing, it was also necessary to establish the @ rank-sum and tests as appropriate. Matched analyses were not performed as normal proportion of trisomic to tetrasomic cells in apparently pure the primary goal of the matching was to obtain similar groups with respect to tetraploid tumors. Several tumors in the control group and in our tumor stage and grade. Age, which is not a risk factor for cause-specific previous studies of two series of unselected prostate carcinomas (5, 7) survival, was used as a convenient way to select a specific control. contained a significant population of cells with 4 signals for all Within the case group, the generalized estimating equations of Liang and autosomes. In the control tumors from the current study, the tetra Zeger (6) were used to model aneusomyfrequencyas a functionof chromo some, taking into account within patient correlations.
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