Genetic aberrations in prostate cancer by microarray analysis

Abstract

The aim of this study was to screen genetic as well as expression alterations in prostate cancer. Array comparative genomic hybridization (aCGH) to a 16K cDNA microarray was performed to analyze DNA sequence copy number alterations in 5 prostate cancer cell lines and 13 xenografts. The aCGH confirmed the previously implicated common gains and losses, such as gains at 1q, 7, 8q, 16p and 17q and losses at 2q, 4p/q, 6q, 8p, 13q, 16q, 17p and 18q, which have previously been identified by chromosomal CGH (cCGH). Because of the higher resolution of aCGH, the minimal commonly altered regions were significantly narrowed-down. For example, the gain of 8q was mapped to three independent regions, 8q13.3-q21.11, 8q22.2 and 8q24.13-q24.3. In addition, a novel recurrent gain at 9p13-q21 was identified. The concomitant expression analysis indicated that genome-wide DNA sequence copy number (gene dosage) was significantly associated with the expression level (p < 0.0001). The analyses indicated several individual genes whose expression was associated with the gene copy number. For example, gains of PTK2 and FZD6, were associated with the increased expression, whereas losses of TNFRSF10B (alias DR5) and ITGA4 with decreased expression. In conclusion, the aCGH mapping data will aid in the identification of genes altered in prostate cancer. The combined expression and copy number analysis suggested that even a low-level copy number change may have significant effect on gene expression, and thus on the development of prostate cancer. ' 2006 Wiley-Liss, Inc.Key words: prostatic carcinoma; neoplasia; amplification; deletion; expression; cDNA microarray; molecular cytogenetics Genetic alterations underlying the development and progression of prostate cancer are incompletely known. Chromosomal comparative genomic hybridization (cCGH) as well as analysis of loss of heterozygosity (LOH) have been used to screen prostate tumors for chromosomal aberrations. Several chromosomal regions have been implicated in these studies (reviewed in Ref. 1). The chromosomal arms containing losses most often are 6q, 8p, 10q, 13q, 16q and 18q, whereas the most common gains are found in chromosomes 7, 8q and Xq. The losses at 6q, 8p and 13q seem to be early events, found also in prostate intraepithelial neoplasia (PIN). On the other hand, the gains of chromosome 7 and 8q are late events and are associated with aggressive phenotype. The gain of Xq is found especially in hormone-refractory prostate carcinomas. The actual genes affected in these chromosomal regions are often not known. Moreover, only a few genes that are commonly altered, either genetically or epigenetically, in prostate cancer have been identified (reviewed in Ref. 1).Microarray technologies are now commonly being used for expression analysis of large numbers of genes. Several studies, using either oligo or cDNA microarrays, on expression profiling in prostate cancer have already been published (reviewed in Ref. 2). These have indicated that a number of genes, such as EZH2, 3 AMACR4 hepsin, ...

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“…Moreover, amplification of 1q has frequently been detected in many other solid tumors, including breast, ovarian, prostate, and lung tumors [37][38][39][40]. In our previous study, a focal amplified region has been narrowed down to 1q24.1-24.2, suggesting the existence of a cancer gene at this amplicon.…”

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MicroRNAs and Prostate Cancer

“…A preliminary analysis showed that prostate cancer cell lines and xenografts were clustered by miR expression in nodes correlating with the androgen receptor status. Moreover, a significant association was described between miR levels and the copy number of miR loci reported in previous array comparative genomic hybridization (aCGH) datasets (Saramaki et al 2006). The comparison of the clinical samples identified 51 miRs differentially expressed, specifically 37 downregulated and 14 up-regulated in carcinoma samples versus the BPH group; 15/37 and 6/14 were altered only in hormone-refractory carcinomas.…”

“…Chromosomal CGH and loss of heterozygosity (LOH) studies have verified that in early-stage tumours genomic DNA losses prevail over gains, with 6q, 8p, 10q, 13q, 16q and 17p being implicated most often in these alterations. In hormone-refractory prostate cancer, LOH frequency raises three-to fourfold and chromosomal gains also become prevalent: amplifications at 7p, 7q, 8q and Xq are common late events associated with an aggressive phenotype (Visakorpi et al 1995, Nupponen et al 1998a,b, Porkka & Visakorpi 2004, Saramaki et al 2006. In particular, gain of the 8q region is the most frequent (80-90% of cases) and huge chromosomal alteration in advanced prostate tumours, involving nearly the whole 8q arm.…”