Prostate cancer prognosis defined by the combined analysis of 8q, PTEN and ERG

Prostate cancer (PCa) is the second most frequently diagnosed non-skin cancer in men worldwide and the fifth cause of cancer-related deaths. The introduction of serum prostate-specific antigen (PSA) analysis constituted an important clinical tool for early PCa detection and disease monitoring, but this test has modest sensitivity and specificity and has limited prognostic value. This shows that there is an unmet need of novel diagnostic and prognostic markers for PCa clinical management.

Gene fusions involving the ETS family of transcription factors are a recurrent feature of PCa, with about 50% of patients harboring the TMPRSS2-ERG fusion, which is considered an early event in prostate carcinogenesis. The prognostic value of ERG rearrangements in PCa is a controversial topic, both for authors using biochemical recurrence (BCR) as a clinical endpoint and those using disease-specific survival. On the other hand, ETS gene fusions seem to be insufficient to induce cancer formation on their own and secondary chromosomal changes, such as 8q gain have been associated with poor clinical outcome. We have previously shown that PCa with relative 8q gain is associated with poor disease-specific survival, independently of Gleason score (GS) and TMPRSS2-ERG gene fusion status. Relative 8q gain was also strongly predictive of BCR in radical prostatectomy (RP) treated patients, independently of GS and TNM stage, supporting its role as a biomarker for aggressive PCa.

PTEN deletions are also common genomic aberrations in PCa and this copy number change has been shown to occur more frequently in TMPRSS2-ERG positive tumors and these genetic alterations combined have been suggested as a biomarker of early recurrence. Nevertheless, it is unknown whether loss of PTEN in apparently localized tumors can help to identify which men are at increased risk of future castration-resistant PCa. To address this issue, we assessed the relative 8q copy number status and the expression profiles of ERG and PTEN in 136 RP treated PCa patients with long-term follow-up to evaluate their combined prognostic value. The clinical endpoint of this study was disease recurrence, which was defined as local recurrence, distant metastasis or prostate cancer death. A FISH break-apart probe strategy using commercial probes flanking MYC and a chromosome 18 centromeric probe to control of ploidy, were used. Then, immunohistochemistry was used for quantitative assessment of ERG and PTEN expression. During a median follow-up period of 117.8 months, 66 (49%) patients had disease recurrence. Relative 8q gain, ERG overexpression, and loss of PTEN expression were observed in 18%, 56%, and 33% of the cases, respectively. Only loss of PTEN expression was associated with worse recurrence-free survival (P=0.006). Interestingly, among patients with a normal expression of PTEN, we found that the combined relative 8q gain/ERG overexpression is associated with high risk of recurrence (P=0.008), suggesting that alternative mechanisms exist for progression into clinically aggressive PCa. Additionally, to stratify the patients in different risk groups of disease recurrence, we calculated the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA)-S score. In intermediate-risk patients (CAPRA-S 3-5), with normal PTEN expression, the combination of 8q+/ERG+ associated with a poor recurrence-free survival (P<0.001), thus indicating independent prognostic value.

Although further studies are necessary to fully characterize the molecular mechanisms of clinically aggressive PCa, the data we here present contribute significantly to molecular subtyping of the disease, with significant prognostic information that, if validated in biopsy specimens in large prospective studies with current standard treatment strategies, may allow better treatment stratification if confirmed in independent studies.

Authors and Affiliations:

Maria P. Silva^1,2, João D. Barros-Silva^1,2, Elin Ersvær^3,4, Wanja Kildal^3,4, Tarjei Sveinsgjerd Hveem^3,4,6, Manohar Pradhan^3,4, Joana Vieira¹, Manuel R. Teixeira^1,2,5#*,  and Håvard E. Danielsen^3,4,6,7#*

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

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

³Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway;

⁴Center for Cancer Biomedicine, University of Oslo, Oslo, Norway;

⁵Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; 

⁶Department of Informatics, University of Oslo, 0310 Oslo, Norway;

⁷Nuffield Division of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom

#These authors contributed equally to this work and should be regarded as joint senior authors

Abstract:

Overtreatment is a major concern in men diagnosed with prostate cancer. The aim of this study was to evaluate the combined prognostic role of three frequent molecular alterations in prostate cancer, namely relative 8q gain, ERG overexpression, and loss of PTEN expression, in a series of 136 patients with prostate cancer treated with prostatectomy and with a long follow-up. Fluorescent in situ hybridization was used to detect the relative copy number of 8q and immunohistochemistry was used for quantitative assessment of ERG and PTEN expression. During a median follow-up period of 117.8 months, 66 (49%) patients had disease recurrence. Relative 8q gain, ERG overexpression, and loss of PTEN expression were observed in 18%, 56%, and 33% of the cases, respectively. No association with patient recurrence-free survival was found for relative 8q gain or ERG overexpression on their own, whereas loss of PTEN expression was associated with worse recurrence-free survival (P=0.006). Interestingly, in the subgroup of patients with normal PTEN expression, we found that the combined relative 8q gain/ERG overexpression is associated with high risk of recurrence (P=0.008), suggesting that alternative mechanisms exist for progression into clinically aggressive disease. Additionally, in intermediate-risk patients with normal PTEN expression in their tumors, the combination of 8q gain/ERG overexpression was associated with a poor recurrence-free survival (P<0.001), thus indicating independent prognostic value. This study shows that the combined analysis of 8q, ERG and PTEN contributes to an improved clinical outcome stratification of prostate cancer patients treated with radical prostatectomy. 

Journal: Translational Oncology

LInk: https://www.journals.elsevier.com/translational-oncology