Population Differentiation at the PVT1 Gene Locus: Implications for Prostate Cancer

Abstract

<jats:p>Genetic variation in susceptibility to complex diseases, such as cancer, is well-established. Enrichment of disease associated alleles in specific populations could have implications for disease incidence and prevalence. Prostate cancer (PCa) is a disease with well-established higher incidence, prevalence, and worse outcomes among men of African ancestry in comparison to other populations. PCa is a multi-factorial, complex disease, but the exact mechanisms for its development and progression are unclear. The gene desert located on chromosome 8q24 is associated with aggressiveness of PCa. Interestingly, the non-protein coding gene locus Plasmacytoma Variant Translocation (PVT1) is present at chromosome 8q24 and is overexpressed in PCa. PVT1 gives rise to multiple transcripts with potentially different molecular and cellular functions. In an analysis of the PVT1 locus using data from the 1000 Genomes Project, we found the chromosomal region spanning PVT1 exons 4A and 4B to be highly differentiated between African and non-African populations. We further investigated levels of gene expression of PVT1 exons 4A and 4B and observed significant overexpression of these exons in PCa tissues relative to benign prostatic hyperplasia and to normal prostate tissues obtained from men of African ancestry. These results indicate that PVT1 exons 4A and 4B may have clinical implications in PCa a conclusion supported by the observation that transient and stable overexpression of PVT1 exons 4A and 4B significantly induce greater prostate epithelial cell migration and proliferation. We anticipate that further exploration of the role of PVT1 exons 4A and 4B may lead to the development of diagnostic, therapeutic, and other clinical applications in PCa.</jats:p>

Prostac: A New Composite Score With Potential Predictive Value in Prostate Cancer

“…The expression levels of all three exons were significantly higher in MDA PCa 2b cells than in RWPE1 cells ( Figure 1 ). This is consistent with our previous observation of overexpression of these non-protein coding RNAs in PCa tissues ( 14 , 16 ). We found the concentration of PVT1 exons 4A and 9 to be positively correlated across both MDA PCa 2b and RWPE1 cells.…”

“…It would have made sense to remove it from our 3-marker composite score since the 2-marker score with just PVT1 exon 9 and PVT1 exon 4A had an error rate similar to the 3-marker score. However, we recently reported that PVT1 exon 4B is significantly over expressed in prostate tumors with Gleason score ≥8 as compared to those with Gleason score ≤7 ( 16 ), suggesting that PVT1 exon 4B expression may be well suited for distinguishing between indolent and aggressive PCa. In the absence of data to fully test our assertion, we have chosen to leave PVT1 exon 4B in our composite score in anticipation of improving our ability to distinguish between indolent and aggressive PCa.…”

“…We found the concentration of PVT1 exons 4A and 9 to be positively correlated across both MDA PCa 2b and RWPE1 cells. In recent studies, the overexpression of PVT1 exons 4A and 9 have both been associated with increased epithelial cell migration and increased proliferation ( 15 , 16 ). PVT1 exon 9 was also found to induce the formation of malignant tumors in mice, a phenotype that strongly suggests an association with aggressive forms of PCa ( 15 ).…”

Targeting PVT1 Exon 9 Re-Expresses Claudin 4 Protein and Inhibits Migration by Claudin—Low Triple Negative Breast Cancer Cells

“…Our group previously reported that PVT1 exon 9 was differentially expressed in prostate cancer. More specifically, PVT1 exon 9 was overexpressed in prostate cancer tissue [ 18 ]. Furthermore, PVT1 exon 9 expression was reported to be significantly higher in prostate cancer cell lines with an aggressive phenotype [ 17 ].…”

“…Aberrant alternative splicing of pre-mRNAs is one of the characteristics of cancer [ 16 ]. Previously, we have reported that PVT1 exon 9 is overexpressed in prostate cancer cell lines, especially in aggressively tumorigenic prostate cancer cell lines derived from men of African Ancestry [ 17 ] Furthermore, we have observed that PVT1 exon 9 is significantly overexpressed in prostate cancer tissue relative to both normal prostate tissue and benign prostatic hyperplasia [ 18 ]. Also, we have demonstrated that PVT1 exon 9 induces malignant transformation and resistance to androgen deprivation therapy in prostate epithelial cells [ 19 ].…”