FISH analysis of gene aberrations (MYC, CCND1, ERBB2, RB, and AR) in advanced prostatic carcinomas before and after androgen deprivation therapy

Genetic mechanisms leading to androgen-independent growth in advanced prost atic carcinomas (PG) are still poorly understood. Analysis of genes potenti ally involved in the regulation of tumor cell proliferation and apoptosis m ight confer better insight into this process and might lead to improved the rapeutic strategies. Fluorescence in situ hybridization (FISH) analysis of dissociated nuclei with DNA probes for MYC (8q24)#8, cyclin D1 gene (CCND1; 11q13)/#11, ERBB2 (17q13)/#17, the androgen receptor gene (AR; Xq12)/#X, a nd the retinoblastoma gene (RB; 13q14) was applied to formalin-fixed tissue from 63 patients with advanced PC after androgen deprivation therapy (ADT) ; matched tumor tissue before ADT was also available in 22 of these cases. The cut-points used were: "increased copy number," greater than or equal to 30% of all nuclei with increased FISH signals (centromere and/or gene); "a mplification," greater than or equal to 15% of nuclei with "increased gene copy number." CCND1 and MYC gene "amplifications" were present before ADT i n 25% and 33% of the cases, respectively; the frequency of these "amplifica tions" increased to 37% and 57% after ADT. Loss of the RE gene was nearly f our times more frequent after ADT than before therapy (22% versus 6%). AR a nd ERBB2 gene "amplifications" occurred only after ADT in 36% and 30% of ca ses, respectively. With the exception of the AR gene, the copy number incre ase was low. After treatment, MYC and AR gene "amplifications" correlated w ith the proliferation rate (Ki-67/MIB1 index; p = 0.01 and p = 0.04), where as ERBB2 "amplifications" were associated with increased apoptotic index (P CD/TUNEL; p = 0.016). However, no correlation between FISH results and clin ical follow-up could be established. FISH analysis of genes putatively invo lved in PC progression revealed characteristic patterns of aberrations in a dvanced PC before and after ADT. Distinct changes in gene copy number befor e and after therapy suggests possible involvement of these genes in the esc ape from androgen control.