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 prostatic carcinomas (PC) are still poorly understood. Analysis of genes potentially involved in the regulation of tumor cell proliferation and apoptosis might confer better insight into this process and might lead to improved the...

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Bibliographic Details
Published in:Laboratory investigation 2000-09, Vol.80 (9), p.1455-1464
Main Authors: KALTZ-WITTMER, Christine, KLENK, Ulrich, GLAESSGEN, Axel, AUST, Daniela E, DIEBOLD, Joachim, LÖHRS, Udo, BARETTON, Gustavo B
Format: Article
Language:English
Subjects:
Aged
Androgen Antagonists - therapeutic use
Biological and medical sciences
Cyclin D1 - genetics
Gene Dosage
Genes, erbB-2
Genes, myc
Genes, Retinoblastoma
Humans
In Situ Hybridization, Fluorescence
Ki-67 Antigen - analysis
Male
Medical sciences
Middle Aged
Nephrology. Urinary tract diseases
Prostatic Neoplasms - genetics
Prostatic Neoplasms - therapy
Receptors, Androgen - genetics
Tumors of the urinary system
Urinary tract. Prostate gland
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Summary:Genetic mechanisms leading to androgen-independent growth in advanced prostatic carcinomas (PC) are still poorly understood. Analysis of genes potentially involved in the regulation of tumor cell proliferation and apoptosis might confer better insight into this process and might lead to improved therapeutic 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, and 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," > or = 30% of all nuclei with increased FISH signals (centromere and/or gene); "amplification," > or = 15% of nuclei with "increased gene copy number." CCND1 and MYC gene "amplifications" were present before ADT in 25% and 33% of the cases, respectively; the frequency of these "amplifications" increased to 37% and 57% after ADT. Loss of the RB gene was nearly four times more frequent after ADT than before therapy (22% versus 6%). AR and ERBB2 gene "amplifications" occurred only after ADT in 36% and 30% of cases, respectively. With the exception of the AR gene, the copy number increase was low. After treatment, MYC and AR gene "amplifications" correlated with the proliferation rate (Ki-67/MIB1 index; p = 0.01 and p = 0.04), whereas ERBB2 "amplifications" were associated with increased apoptotic index (PCD/TUNEL; p = 0.016). However, no correlation between FISH results and clinical follow-up could be established. FISH analysis of genes putatively involved in PC progression revealed characteristic patterns of aberrations in advanced PC before and after ADT. Distinct changes in gene copy number before and after therapy suggests possible involvement of these genes in the escape from androgen control.
ISSN:0023-6837
1530-0307
DOI:10.1038/labinvest.3780152