Abstract 3507: PVT1 exons 4A, 4B, and 9 are overexpressed in aggressive prostate cancer, and PVT1 exon 4B may distinguish between indolent and aggressive prostate cancer

Abstract

Aggressive prostate cancer (PCa) disproportionately affects males of African ancestry (MoAA). However, the underlying molecular mechanisms are unclear. Chromosome 8q24 is a PCa susceptibility locus that harbors the PVT1 non-coding gene. We previously demonstrated that PVT1 exon 9 may be involved in aggressive PCa. Moreover, using the most recent full-genome variability panel from the 1000 Genomes project, we recently identified a string of 75 SNPs in a 26-kb region spanning PVT1 exons 4A and 4B as consistently showing the highest level of genetic differentiation between African and non-African populations. However, the expression of PVT1 exons 4A, 4B, and 9 in prostate tissues of MoAA has never been investigated. Our aim was to determine the expression of PVT1 exons 4A, 4B, and 9 in histologically confirmed normal prostate (n=7), benign prostate (n=11) and malignant prostate tissue (n=11) from prostatectomy or transrectal ultrasound-guided biopsies in Nigeria, a sub-Saharan Black African population. Nine patients had tumor tissues with Gleason score ≥ 8. Tissues were collected in compliance with Institutional Ethics Board approved protocols. RNA extraction, cDNA synthesis, and quantitative-PCR were performed to analyze mRNA expression of PVT1 exons 4A, 4B, and 9. There was a statistically significant difference in the relative expression of PVT1 exons 4A (F(2,82)=9.031, p = 0.000), 4B (F(2,82)=5.294, p = 0.007) and 9 (F(2,82)=4.788, p = 0.011) between groups as determined by one-way ANOVA. Tukey posthoc test showed statistically significant differences between relative mean expression of PVT1 exons 4A, 4B and 9 in prostate tumor tissues versus normal prostate tissues: PVT1 exon 4A (prostate tumor: 3.15±0.497, 95% CI [2.13, 4.17]), (benign prostate: 1.74±0.163, 95% CI [1.41,2.07]), and (normal prostate: 1.28±0.141, 95% CI [0.989, 1.57]); PVT1 exon 4B (prostate tumor: 2.217±0.360, 95% CI[1.47, 2.95]), (benign prostate: 1.17±0.176, 95% CI [0.821,1.53]), and (normal prostate: 1.25±0.169, 95% CI [0.900, 1.60]); PVT1 exon 9 (prostate tumor: 1.71±0.190, 95% CI [1.32, 2.10]), (benign prostate: 1.26±0.148, 95% CI [.967,1.57]), and (normal prostate: 0.944±0.151, 95% CI[0.630, 1.25]). Paired t-test showed a significant difference in the expression profile for PVT1 exon 4B in prostate tumors with Gleason score ≥8 (2.98±0.539, 95% CI [1.90,4.06]) as compared to those with Gleason score ≤7 (1.32±0.340, 95% CI [0.645,2.07]) with p =0.009. These results show that overexpression of PVT1 exons 4A, 4B and 9 is characteristic of PCa in MoAA. Further, PVT1 exons 4B and 9 overexpression are specific for PCa, and PVT1 exon 4B may distinguish between indolent and aggressive PCa in MoAA. Citation Format: Akintunde T. Orunmuyi, Adeodat Ilboudo, Olabiyi G. Ogun, Cuong Bach, S A. Adebayo, Ayo A. Salako, E Oluwabunmi Olapade-Olaopa, Olorunseun O. Ogunwobi. PVT1 exons 4A, 4B, and 9 are overexpressed in aggressive prostate cancer, and PVT1 exon 4B may distinguish between indolent and aggressive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3507. doi:10.1158/1538-7445.AM2017-3507

Copy number-based quantification assay for non-invasive detection of PVT1-derived transcripts

“…Further, testing of human prostate tissue samples showed that the number of copies/μl of PVT1 exons 4A, 4B, and 9 is higher in prostate cancer samples in comparison to normal prostate tissues or benign prostatic hyperplasia tissues. These absolute quantitative data agree with the relative expression data we had previously acquired [31], [32]. It is noteworthy that using this novel copy number–based quantification assay, we were able to detect and quantify PVT1 exons 4A, 4B, and 9 in both serum and plasma samples.…”

“…PVT1 is also associated with immune diseases like asthma, vitiligo, and several others [17, 38]. And PVT1 has been demonstrated by multiple studies and research groups to be overexpressed in prostate cancer [32,39]. PVT1 plays an oncogenic role and regulates tumor growth in prostate cancer [18].…”

“…We and others are progressively uncovering the fact that these transcripts of PVT1 are differentially expressed in various cancers, and may have different functions [27–33]. Our lab has previously reported that PVT1 exons 4A, 4B, are 9 are significantly overexpressed in aggressive PCa [27–32]. Due to our focused research interest in PCa, we have decided to focus on PVT1 exons 4A, 4B, and 9 because of their potential role as biomarkers for prostate cancer (PCa).…”

“…Due to our focused research interest in PCa, we have decided to focus on PVT1 exons 4A, 4B, and 9 because of their potential role as biomarkers for prostate cancer (PCa). In the present study, we focus on developing an assay of transcripts derived from PVT1 exons 4A, 4B, and 9, which have been previously described to be potential biomarkers of prostate cancer [29,31,32]. This assay is likely to have applications in all the diseases characterized by dysregulation of PVT1 [3,17].…”