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. (Am J Pathol 1998, 153:141-148)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.

Loss of p53 and c-myc Overrepresentation in Stage T2-3N1-3M0 Prostate Cancer are Potential Markers for Cancer Progression

“…However, seven patients showed different genetic changes among the multiple metastases in a single case. Usually, these positive nodes with different anomalies were located on opposite sides of the body, indicating that perhaps more contralateral cancer foci give rise to independent metastases and/or that metastatic lesions are genetically unstable (38). In addition, we found that the metastatic cancer cells within the same lymph node usually have homogeneous histologic characteristics and chromosomal anomalies (data not shown on Table 3).…”

MYC oncogenes and human neoplastic disease

“…Signi®cant intratumoral molecular heterogenity was also observed, suggesting the independent and simultaneous evolution of tumor cells within an otherwise histologically uniform focus. A more recent report using both FISH and comparative genomic hybridization (CGH) has provided con®rmation for some of these ®ndings by demonstrating 4threefold ampli®cation of C-MYC in 29% of prostatic carcinomas (Nupponen et al, 1998). However, this study did not determine whether C-MYC ampli®cation was associated with tumor progression.…”

Loss of heterozygosity of M6P/IGF2R gene is an early event in the development of prostate cancer

“…Loss of 6q24-qter has been found in recurrent, androgen-insensitive prostate tumors. 26 In addition, 6q21-6q23 and 6q25-6q27 are two regions with a high frequency of LOH in both prostate cancer and high-grade PIN. 27 The M6P/IGF2R gene is located within these frequently mutated sites, at 6q26, but it had not been previously described as being mutated in prostate cancer.…”