NCOA2 is a candidate target gene of 8q gain associated with clinically aggressive prostate cancer

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NCOA2 is a candidate target gene of 8q gain associated with clinically aggressive prostate cancer

Monday, 08.02.2016

 

Prostate cancer (PCa) remains a major health burden in men, being the second most common non-skin cancer and the fifth leading cause of death from cancer worldwide. Despite the use of serum prostate-specific antigen (PSA) as an important clinical tool for early PCa detection, this test has many shortcomings and has limited prognostic value. Therefore, there is a need of more reliable diagnostic markers to complement PSA, as well as better prognostic markers to differentiate aggressive from indolent tumors.

The finding of gene fusions involving the ETS family of transcription factors in prostate carcinomas was an important breakthrough in this field of research, with about 50% of patients harboring the TMPRSS2-ERG fusion. Although this fusion is an early molecular event in PCa, ETS gene fusions seem to be insufficient to induce cancer formation on their own, and secondary chromosomal changes, such as 8q gain have been shown to be associated with poor clinical outcome. Moreover, it has been demonstrated that 8q gain is associated with poor disease-specific survival independently of either Gleason score (GS) or TMPRSS2-ERG fusion status, supporting its role as a biomarker of aggressive PCa.

Despite the strong evidence associating 8q gains with poor clinical outcome, the potential target genes underlying the aggressive phenotype remain to be clarified. The amplified chromosomal region in 8q encompasses hundreds of genes and among the possible target genes of 8q gain, MYC is the most frequently pointed, but other candidate genes such as TCEB1, TPD52, EIF3S3 or NCOA2 have also been proposed. To address this issue, we analyzed a series of 50 prostatectomy specimens from patients with clinically localized PCa, with available global gene expression and typed for ETS rearrangements. A FISH break-apart probe strategy using BAC clones flanking MYC, and a chromosome 18 centromeric probe to control of ploidy, were used. Then, we compared the gene expression profile of tumors with and without 8q24 gain using a significance analysis of exon-level expression microarrays (SAM). In the ERG-positive subgroup of tumors, five significantly overexpressed genes were highlighted in the group with relative 8q24 gain, namely VN1R1, ZNF417, CDON, IKZF2, and NCOA2.  Among these, NCOA2 was the only located in 8q (8q13.3), and emerged as a strong candidate of relative 8q gain when the whole series was considered (P=0.008). Combining the cases with higher mRNA and protein expression, we identified a group of tumors with NCOA2 copy number increase, independently of 8q24 and ETS rearrangement status, suggesting a localized gain of this gene. We also detected for the first time a structural rearrangement involving NCOA2 in PCa that occurs in an 8q24 gain context. Further studies with larger series are necessary to evaluate if NCOA2 relative copy number gain presents prognostic value, independently of the well-established poor prognosis associated with MYC relative copy number increase.

 

Authors and Affiliations:

Maria P. Silva1,2, João D. Barros-Silva1,2, Joana Vieira1, Susana Lisboa1, Lurdes Torres1, Cecília Correia1,2, Márcia Vieira-Coimbra3, Ana T. Martins3,4, Carmen Jerónimo3,5, Rui Henrique3,4,5, Paula Paulo1,2 and Manuel R. Teixeira1,2,5*

1 Department of Genetics, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

2 Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

3 Cancer Biology and Epigenetics Group, IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal

4 Department of Pathology, Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal 5 Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

 

Abstract:

Prostate carcinomas harboring 8q gains are associated with poor clinical outcome, but the target genes of this genomic alteration remain to be unveiled. In this study, we aimed to identify potential 8q target genes associated with clinically aggressive prostate cancer (PCa) using fluorescence in situ hybridization (FISH), genome-wide mRNA expression, and protein expression analyses. Using FISH, we first characterized the relative copy number of 8q (assessed with MYC flanking probes) of a series of 50 radical prostatectomy specimens, with available global gene expression data and typed for E26 transformation specific (ETS) rearrangements, and then compared the gene expression profile of PCa subsets with and without 8q24 gain using Significance Analysis of Microarrays. In the subset of tumors with ERG fusion genes (ERG+), five genes were identified as significantly overexpressed (false discovery rate [FDR], ≤5%) in tumors with relative 8q24 gain, namely VN1R1, ZNF417, CDON, IKZF2, and NCOA2. Of these, only NCOA2 is located in 8q (8q13.3), showing a statistically higher mRNA expression in the subgroup with relative 8q gain, both in the ERG+ subgroup and in the whole series (P=0.000152 and P=0.008, respectively). Combining all the cases with NCOA2 overexpression, either at the mRNA or at the protein level, we identified a group of tumors with NCOA2 copy-number increase, independently of ETS status and relative 8q24 gain. Furthermore, for the first time, we detected a structural rearrangement involving NCOA2 in PCa. These findings warrant further studies with larger series to evaluate if NCOA2 relative copy-number gain presents prognostic value independently of the well-established poor prognosis associated with MYC relative copy-number gain.

 

Journal: Genes, Chromosomes and Cancer

 

Linkhttp://onlinelibrary.wiley.com/doi/10.1002/gcc.22340/abstract;jsessionid=A33E40D9B7D90FABD282D415DD8DAC7F.f01t03