Exploring prostate cancer genome reveals simultaneous losses of PTEN, FAS and PAPSS2 in patients with PSA recurrence after radical prostatectomy

Abstract

The multifocal nature of prostate cancer (PCa) creates a challenge to patients' outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients' clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0-9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients' PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2-10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2-10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy.

Figure 1

Summary illustration of genes with copy number losses located on chromosomes 10q23.31 and 10q23.2–0q23.31 (PAPSS2). Red shaded boxes indicate tumor foci with losses for specified genes. For tumor sample IDs, multifocal prostate cancers are highlighted in green and unifocal prostate cancers are not highlighted with color. In addition, the tumor foci were sub-categorized into groups based on the patients’ PSA recurrence status.

Figure 2

Hypothetical influence of PAPSS2 gene in PSA recurrence. The encoded PAPSS2 protein may have an effect on androgen biosynthesis and PSA recurrence. (A) PAPSS2 regulates the formation of PAPS, which subsequently regulates the conversion of excess DHEA to inactive DHEAS; (B) The absence of PAPSS2 and PAPS, results in the accumulation of DHEAS, formation of active androgens, activation of the androgen receptor. PAPSS2 = 3'-phosphoadenosine 5'-phosphosulfate synthase 2; PAPS = phosphoadenosine-phosphosulfate; DHEA = dehydroepiandrosterone; DHEAS = Dehydroepiandrosterone sulfate; SULT2A1 = DHEA sulfotransferase; PSA = prostate specific antigen. Adapted from [34,39].