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Integration of ERG gene mapping and gene expression profiling identifies distinct categories of human prostate cancer

ABSTRACT: OBJECTIVE: Previous expression microarray analyses have failed to take into consideration the genetic heterogeneity and complex patterns of ERG gene alteration frequently found in cancerous prostates. The objective of this study is for the first time, to integrate the mapping of ERG gene alterations with the collection of expression microarray data. PATIENTS AND METHODS: We have deterimined genome-wide expression levels with Affymetrix GeneChip Human Exon 1.0 ST arrays using RNA prepared from 35 specimens of prostate cancer from 28 prostates. RESULTS: The expression profiles exhibit clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG gene status. Through analysis of the data we identify a subgoup of cancers lacking ERG gene rearrangements that exhibit an outlier pattern of SPINK1 mRNA expression. We also show that a major distinction between ERG gene rearranged and non-rearranged cancers involves the levels of expression of genes linked to exposure to beta-estradiol, and to retinoic acid. CONCLUSIONS: Our studies show that expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG gene status are the major determinants of poor clinical outcome. Keywords: disease state analysis

ORGANISM(S): Homo sapiens

PROVIDER: GSE12378 | GEO | 2009/08/01

SECONDARY ACCESSION(S): PRJNA113125

REPOSITORIES: GEO

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Project description:TMPRSS2-ERG gene fusions that are frequently identified in prostate cancer can be generated either through chromosomal translocation or via interstitial deletion. The latter mechanism deletes an interstitial region of ~3Mb and it remains largely unanswered whether genes deleted within this region contribute to prostate cancer. By characterizing two knockin mouse models recapitulating TMPRSS2-ERG fusions with or without the interstitial deletion, we found that only those with deletion developed poorly differentiated adenocarcinomas with epithelial-to-mesenchymal transition, when under a Pten-null background. We identified several interstitial genes, including ETS2 and BACE2, whose reduced expression correlates with worse disease-free survival and lethal disease. By using an Ets2 conditional knockout allele, we demonstrated that loss of one copy of Ets2 was sufficient for prostate cancer progression when under a Pten-null background. Collectively, our data suggest that ETS2 is a prostate tumor suppressor and haploinsufficiency of one or more interstitial genes contributes to prostate cancer progression. Genotyped male mice were euthanized at 12 months of age and prostates isolated. Prostates were fixed overnight in 10% formalin and stored in 70% ethanol until tissue processing and paraffin embedding. Serial sections were cut from paraffin blocks which were stained for H&E and analyzed by a trained rodent histopathologist. Using these sections as a visual guide for specific types of lesions, the sequential sections were stained with hematoxylin and used for laser capture microdissection on ArcturusXT system. Epithelial cells within notable high grade prostate intraepithelial neoplasia (HG-PIN) lesions were microdissected from 3 mice from each corresponding genotype. In addition, poorly differentiated adenocarcinomas from PbCre;T-3Mb-Erg/+;PtenL/L mice were also dissected. RNA was isolated from the microdissected tissue using the Qiagen RNeasy FFPE kit and subjected to Nugen Amplification before microarray analysis on an Affymetrix Mouse Gene 2.0 ST chip.

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Integration of ERG gene mapping and gene expression profiling identifies distinct categories of human prostate cancer

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