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Aneusomies of Chromosomes 8 and Y Detected by Fluorescence in Situ Hybridization Are Prognostic Markers for Pathological Stage C (Pt3nom O) Prostate Carcinoma I

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Aneusomies of Chromosomes 8 and Y Detected by Fluorescence in Situ Hybridization Are Prognostic Markers for Pathological Stage C (Pt3nom O) Prostate Carcinoma I Vol. 2, 137-145, January 1996 Clinical Cancer Research 137 Aneusomies of Chromosomes 8 and Y Detected by Fluorescence in Situ Hybridization Are Prognostic Markers for Pathological Stage C (pT3NoM o) Prostate Carcinoma I Satoru Takahashi, Antonio Alcaraz, (P < 0.001), respectively. These results demonstrate that James A. Brown, Thomas J. Borell, aneuploidy and specific aneusomies detected by FISH are potential markers for a poor prognosis in histological high- John F. Herath, Erik J. Bergstralh, grade pathological stage C (pT3NoMo) prostate carcinoma. Michael M. Lieber, and Robert B. Jenkins 2 Departments of Urology [S. T., A. A., J. A. B., M. M. L.] and INTRODUCTION Laboratory Medicine and Pathology [T. J. B., J. F. H., R. B. J.] and Section of Biostatistics [E. J. B.], Mayo Clinic and Foundation, Prostate adenocarcinoma has extensive variability in clin- Rochester, Minnesota 55905 ical behavior. Accurate prediction of individual tumor progres- sion probability and patient survival is a major goal of current prostate cancer research. Parameters such as clinical and patho- ABSTRACT logical stage, histological grade, and pretreatment serum PSA 3 In an attempt to identify new prognostic markers, we are conventionally used to help predict the prognosis for indi- performed fluorescence in situ hybridization (FISH) ploidy vidual patients with clinically localized prostate carcinoma (1). analysis of tumor tissue from patients with a targeted stage Newer factors, such as DNA content ploidy analysis using FCM and histological grade of prostate carcinoma. We identified or static image analysis, can help refine prognostic risks (2). all 227 patients from the Mayo Clinic radical prostatectomy However, it is recognized that FCM or static image ploidy data base who had a high histological grade pathological analysis cannot detect small changes in DNA content or chro- stage C (PT3NoM o) tumor removed between 1966 and 1987. mosome number. After histological review of the paraffin-embedded specimen Interphase cytogenetic analysis FISH, using chromosome blocks, 181 cases were suitable for FISH analysis using enumeration probes, is useful for detecting numerical chromo- chromosome enumeration probes for chromosomes 7, 8, 10, some alterations in a variety of solid tumors (3, 4). Previous 12, X, and Y. FISH detected 80 (44%) diploid, 22 (12%) studies from this laboratory have demonstrated that FISH anal- tetraploid, and 79 (44%) aneuploid tumors. The common ysis is more sensitive than FCM for detecting aneuploidy of aneusomies were of chromosomes 7 and 8, which were radical prostatectomy specimens, and that aneusomies of chro- present in 51 (28%) and 46 (25%) tumors, respectively. mosomes 7 and 8 are associated with higher histological grade Aneusomies of chromosomes 10, 12, X, and Y were ob- and advanced pathological stage (5-7). These results encour- served in 11 (6%), 15 (8%), 12 (7%), and 16 (9%) tumors, aged us to evaluate the hypothesis that nonrandom numerical respectively. chromosome alterations detected by FISH are useful markers for FISH aneuploid tumors showed a trend of more fre- tumor progression and patient prognosis. As a preliminary trial, quent systemic prostate cancer progression than nonaneu- we performed a case-control FISH study using two groups of 25 ploid tumors (P = 0.060). For individual chromosome anom- patients with clinically localized prostate carcinoma who were alies, gains of chromosome 8, aneusomy of chromosome 8, matched for clinicopathological features but who showed dis- and aneusomy of chromosome Y correlated highly with tinctively different prognoses (8). This study demonstrated that systemic cancer progression (P = 0.006, 0.013, and 0.021, overall aneuploidy and aneusomy of chromosome 7 were sig- respectively). Gains of chromosome Y and aneusomy of nificantly associated with relatively rapid prostate cancer death. chromosome Y were associated with an increased prostate We now have performed an inclusive retrospective cancer death rate (P < 0.001 for both). Multivariate analysis FISH tumor analysis of patients with a single defined patho- showed that gains of chromosome 8 and aneusomy of chro- logical stage and histological grade of prostate adenocarci- mosome Y were significant independent "predictors" of noma. We targeted histological high-grade pathological stage systemic cancer progression (P = 0.008) and cancer death C (pT3NoM o) prostate cancers treated by radical prostatec- tomy. Clinical tumor progression rates and cause-specific sur- vival of the patients with this grade and stage of prostate carcinoma are difficult to predict. In an attempt to identify useful new prognostic markers for these cancers, FISH analysis Received 5/9/95; revised 7/21/95; accepted 8/15/95. 1 This work was supported by a Specialized Project of Research Excel- was carried out using chromosome enumeration probes for six lence P20 Grant from the National Cancer Institute (CA 58225; to different chromosomes. R. B. J. and M. M. L.), by a grant from Vysis, Inc. (to R. B. J.), and by the Hospital Clinic of Barcelona and Fondo de Investigaciones Sanitar- ias (FIS 93/5326; to A. A.) 2 To whom requests for reprints should be addressed, at Cytogenetics Laboratory, Mayo Clinic, 200 First Street S.W., Rochester, MN 55905. 3 The abbreviations used are: PSA, prostate-specific antigen; FCM, flow Phone: (507) 284-4696; Fax: (507) 284-0043. cytometry; FISH, fluorescence in situ hybridization. Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 1996 American Association for Cancer Research. 138 Prognostic Significance of Numeric Chromosome Alterations MATERIALS AND METHODS chromosomes 4, 6, 7, 8, 9, 10, 11, 12, 17, 18, X, and Y (6, 8). Study Design. Of 1786 patients in the Mayo Clinic rad- The FISH procedure was carried out in the same manner as ical prostatectomy data base whose tumors were surgically described previously (8). In brief, slides with isolated nuclei removed between 1966 and 1987, 637 (36%) were found to have were dehydrated in an ethanol series (70, 85, and 100%). DNA pathological stage C (pT3NoMo) prostate cancer. All patients was denatured by incubating the slides in 70% formamide/2X had pelvic lymphadenectomies concurrently and did not have SSC at 75°C for 4 min followed by dehydration in an ice-cold metastatic deposits in the pelvic lymph nodes. Pathological ethanol series. Simultaneously, a dual-color probe solution (7 ~1 stage C (PT3) disease denotes prostate cancers that have perfo- Hybridization Mix II; Vysis, and 2 p~l of each probe) was rated the prostatic capsule and involve periprostatic tissues, denatured for 6 rain at 75°C and subsequently added to the slides. After sealing, the slides were then incubated overnight at seminal vesicles, membranous urethra, and bladder neck (1). 37°C. Following hybridization, the slides were washed in 50% Among this large group, 227 patients who had histological formamide/2X SSC, 2x SSC, and 2XSSC/NP40. Nuclei were high-grade tumors and adequate clinical follow-up were se- counterstained with 1 ~g/ml 4',6-diamidino-2-phenylindole di- lected as our study group. Tumor grade was determined by the hydrochloride. Mayo nuclear morphological grading system, and tumors of The FISH signals were counted with a Zeiss Axioplan grade 3 or 4 were considered "high-grade tumors" for this microscope equipped with single-pass filters (150191 and study (9). 150291; Vysis). The hybridization signals for each probe in 300 The clinicopathological data available for these patients interphase nuclei were counted. To minimize sampling error, included patient age, tumor volume, seminal vesicle involve- two individuals counted signals in 150 nuclei on each half of the ment (if present), preoperative serum PSA level (which became hybridized area. All morphologically intact nuclei (apparently available in 1987), flow cytometric DNA ploidy, and adjuvant truncated or overlapping nuclei were excluded) within that area therapy (if applied). Tumor volume was calculated as described were evaluated. When an obvious discrepancy was observed preyiously (10), and serum PSA level was measured with a between these independent counts by two individuals, a third monoclonal solid-phase two-site immunoradiometric assay (Hy- individual enumerated signals on the same slide without infor- britech, Inc., San Diego, CA). FCM analysis on formalin-fixed mation of the previous results, and the two most concordant paraffin-embedded prostatectomy specimens was performed results of the three were used for analysis. The total percentage with the same method as previously described (5). Systemic of nuclei containing one, two, three, four, five, six, seven, eight, prostate cancer progression and prostate cancer death were used and more than eight signals was determined for each chromo- as clinical end points. Systemic progression was defined as some. clinical evidence of distant metastatic disease and ascertained by Criteria for FISH Ploidy and Aneusomy. To define positive findings on bone scan or other radiological imaging ploidy and aneusomy objectively, previously defined criteria tests. were used (6-8). In brief, based upon the mean + 3 SDs of The patient list was randomized, and the following tumor centromere copy numbers in benign prostate hyperplasia sam- specimen FISH analyses were performed without knowledge of ples and an inspection of prior prostate carcinoma FISH results, the clinicopathological findings and survival data of the patients. the following conservative cutoff values were established. Tissue
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