Survey of gene amplifications during prostate cancer progression by high-throughout fluorescence in situ hybridization on tissue microarrays.

TLDR

Prostate cancer development and progression is driven by accumulating genetic changes, whose nature remains incompletely understood. We constructed a tissue microarray of 371 samples and applied fluorescence in situ hybridization with probes for five genes to analyze consecutive sections. High‑level amplifications were rare in primary tumors (<2%) but occurred in 22 % of metastatic androgen‑receptor, 11 % of MYC, and 5 % of Cyclin‑D1 cases, with similar patterns in locally recurrent tumors (AR 23 %, MYC 4 %, Cyclin‑D1 8 %); ERBB2 and NMYC were never amplified, and the data suggest AR amplification contributes to hormone‑therapy failure while MYC amplification drives metastatic progression.

Abstract

Prostate cancer development and progression is driven by the accumulation of genetic changes, the nature of which remains incompletely understood To facilitate high-throughput analysis of molecular events taking place in primary, recurrent, and metastat prostate cancer, we constructed a tissue microarray containing small 0.6-mm cylindrical samples acquired from 371 formalin-fixed blocks, including benign prostatic hyperplasia (n = 32) and primary tumors (n = 223), as well as both locally recurrent tumors (n = 54) and metastases (n = 62) from patients with hormone-refractory disease. Fluorescence in situ hybridization (FISH) was applied to the analysis of consecutive tissue microarray sections with probes for five different genes. High-level (> or =3X) amplifications were very rare (<2%) in primary prostate cancers However, in metastases from patients with hormone-refractory disease, amplification of the androgen receptor gene was seen in 22%, MYC in 11%, and Cyclin-D1 in 5% of the cases. In specimens from locally recurrent tumors, the corresponding percentages were 23, 4, and 8%. ERBB2 and NMYC amplifications were never detected at any stage of prostate cancer progression. In conclusion, FISH to tissue microarray sections enables high-throughput analysis of genetic alterations contributing to cancer development and progression. Our results implicate a role for amplification of androgen receptor in hormonal therapy failure and that of MYC in the metastatic progression of human prostate cancer.