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

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 a well-established higher incidence, prevalence, and worse outcomes among men of African ancestry in comparison to other populations. Cross-population comparisons of health outcome measures, such as disease incidence and prevalence, have contributed to progress in public health research. Multiple studies have assessed the contribution of risk factors specific to geographical areas, ethnicity, and several other factors in different diseases.


PCa is the most commonly diagnosed solid organ non-skin cancer in males worldwide and the second most common cause of cancer mortality in the United States. In 2015, PCa had the highest incidence for men in 103 countries or territories. In 2017, there were 1.3 million cases of prostate cancer and 416,000 deaths.1 There are more than 3.1 million American men living with the disease and in 2020, there will be 191,930 new cases of PCa with about 33,330 deaths in the United States. PCa has become the leading cause of cancer-related death in men with increased morbidity in the developing world. The incidence of PCa is almost 60% higher in men of African ancestry and the mortality rate is two to three times greater than among Caucasian men. Surprisingly, these numbers have remained remarkably constant for more than 20 years. African American men have among the highest incidence of PCa worldwide, are more likely to develop PCa at any age, and develop the disease earlier in life than men from all other racial and ethnic groups.

Plasmacytoma Variant Translocation 1 (PVT1) is a long non-protein-coding gene, located at chromosome 8q24 and yields approximately twelve exons and a cluster of six microRNAs.2,3 In PCa, PVT1 amplification is correlated with its incidence. PVT1 promotes proliferation, invasion, and metastasis, and promotes epithelial to mesenchymal transition in PCa. Though the role of PVT1 is well-established in different cancers and other diseases, very few reports are available on the alternatively spliced transcripts of PVT1.4 We previously demonstrated that PVT1 exon 9 is associated with aggressive PCa in men of African ancestry.3

In our recent study published in G3: Genes, Genomes, Genetics, we sought to uncover if there are any population-level genetic differences in PVT1 and to explore any potential implications for PCa. We performed population analysis and interestingly, PVT1 exons 4A and 4B consistently showed the highest level of genetic differentiation between African and non-African populations. To identify racial differences in the PVT1 locus, we scanned for signatures of population differentiation and positive natural selection using the latest full-genome variability panel from the 1000 Genomes Project. A string of 75 single nucleotide polymorphisms in an 11-kb region spanning PVT1 exons 4A and 4B consistently show the highest level of genetic differentiation between African and non-African populations. The 11-kb region shows the highest levels of sequence diversity in non-African populations as well. We observed the signature of positive natural selection in the 11-kb region in non-African populations and negative selection in African populations.

We also assessed the expression of this genetic region in histologically confirmed normal prostate, benign prostatic hyperplasia, and PCa tissues in a cohort of men of African ancestry. Our results confirmed significant overexpression of PVT1 exons 4A and 4B in PCa tissues in comparison to normal prostate tissue and benign prostatic hyperplasia. Furthermore, both transient and stable overexpression of PVT1 exons 4A and 4B in a non-tumorigenic prostate epithelial cell line induced increased cell proliferation and migration, which are among the hallmarks of cancer. These data suggest that PVT1 exons 4A and 4B may have clinical applications for PCa in men of African ancestry. Our work has elucidated that PVT1 exons 4A and 4B may have potential utility as diagnostic, prognostic, and therapeutic biomarkers in PCa.

Written by: Olorunseun Olatunji Ogunwob, MS, MBBS, PhD, Associate Professor of Biology, Department of Biological Sciences, Hunter College, New York, New York

References:

  1. Global Burden of Disease Cancer Collaboration. "Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: a systematic analysis for the global burden of disease study." JAMA oncology 5, no. 12 (2019): 1749-1768.
  2. Pal, Gargi, and Olorunseun O. Ogunwobi. "Copy number-based quantification assay for non-invasive detection of PVT1-derived transcripts." PloS one 14, no. 12 (2019).
  3. Ilboudo, Adeodat, Jyoti Chouhan, Brian K. McNeil, Joseph R. Osborne, and Olorunseun O. Ogunwobi. "PVT1 exon 9: a potential biomarker of aggressive prostate cancer?." International journal of environmental research and public health 13, no. 1 (2016): 12.

  4. Pal, Gargi, Jeannette Huaman, Fayola Levine, Akintunde Orunmuyi, E. Oluwabunmi Olapade-Olaopa, Onayemi T. Onagoruwa, and Olorunseun O. Ogunwobi. "Long Noncoding RNA from PVT1 Exon 9 Is Overexpressed in Prostate Cancer and Induces Malignant Transformation and Castration Resistance in Prostate Epithelial Cells." Genes 10, no. 12 (2019): 964.


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