Genetic alterations in hormone-refractory recurrent prostate carcinomas

Abstract

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 situ hybridization (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.

Figure 1.

Summary of all DNA sequence copy number changes in 37 recurrent prostate carcinomas detected by CGH. Gains are shown on the left side of the chromosome ideograms and losses on the right. One bar represents one tumor. Chromosome Y was excluded from the analysis.

Figure 2.

Mean green-to-red ratio profiles with ±1 SD from pter to qter obtained from CGH analysis of four locally recurrent hormone-refractory paraffin-embedded prostate tumors. The dotted lines represent ratio values of 0.85 and 1.15. a: Normal; b: Loss of 8p22-pter, gain of 8q21-q22; c: Gain of 8q12-qter with higher-level amplification at 8q24; d: Loss of 8p and gain of 8q12-qter; e: Chromosome 8 idiogram.

Figure 3.

Interphase FISH analyses of hormone-refractory prostate cancer with probes for chromosome 8 centromere (in green) and c-myc (in red) (a), chromosome 7 centromere (in red) and caveolin (in green) (b), and chromosome 18 centromere (in red) and bcl-2 (in green) (c). a: Multiple copies of c-myc and three copies of centromere are seen. b: Four copies of centromere and caveolin are seen. c: Three copies of centromere and five copies of bcl-2 are found. Nuclei are counterstained with DAPI.