GENETIC ALTERATIONS IN HORMONE-REFRACTORY RECURRENT PROSTATE CARCINOMAS

To study the genetic basis of turner progression, we have screened 37 hormone-refractory prostate carcinomas for genetic changes by comparat ive genomic hybridization (CGH), All recurrent tumors showed genetic a berrations, with a mean total number of changes per tumor of 11.4 (ran ge, 3 to 23), The most common genetic aberrations were losses of 8p (7 2.5%), 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 hybr idization (FISH) using probes for pericentromeric regions of chromosom es 7, 8, and 18 as well as probes for caveolin (7q31), c-myc (8q24), a nd bcl-2 (18q21.3). In addition, the samples had previously been analy zed for androgen receptor gene copy number. CGH and FISH results were concordant in 78% of cases. Seventeen of twenty-two tumors showed an i ncreased 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 invo lves 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 t he 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 th e 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 car cinomas are genetically unstable. The resulting heterogeneity may well underlie the poor responsiveness of hormone-refractory tumors to trea tment.