23 Jul Novel Mechanisms and Clinical Aspects for an Aggressive Prostate Cancer Risk Locus Uncovered
MedicalResearch.com Interview with:
Gong-Hong Wei, PhD
Professor, Academy Research Fellow
Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu
University of Oulu, Finland
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: Prostate cancer is the second most common cancer and the fifth leading cause of cancer-related death in men, with more than 1,100,000 new cases diagnosed and 300,000 deaths yearly around the globe. Among the risk factors for prostate cancer development, the genetic heritability of prostate cancer has been reported near 60%. Over the past decade, genome-wide association studies have identified more than 150 independent single nucleotide polymorphisms (SNPs) associated with prostate cancer risk. However, we know very little mechanisms accounting for these associations.
SNP rs11672691 at the chromosome 19q13 locus has been found not only associated with prostate cancer risk but also aggressiveness, a form of prostate cancer often with worse prognosis and eventually progression to incurable stage. However, how this genomic variant accounts for prostate cancer severity remains totally unknown. Here we found the association of rs11672691 with additional clinical features of aggressive prostate cancer in an independent cohort of patients with prostate cancer, and discovered a rs11672691-mediated gene regulatory network including several novel genes, HOXA2, CEACAM21 and PCAT19, likely causing prostate cancer progression to incurable stage. In particular, the risk G (guanine) allele of rs11672691 was associated with higher RNA levels of PCAT19 and CEACAM21, and poor prognosis in prostate cancer patients. Rs11672691 G allele enhances chromatin binding of HOXA2 to regulate the expression of CEACAM21 and PCAT19. Using the CRISPR-Cas9 genome editing method, we revealed that rs11672691 genotype directly influence HOXA2 in regulating PCAT19 and CEACAM21 expression, and prostate cancer cellular phenotype.
MedicalResearch.com: What should readers take away from your report?
Response: Although additional large cohorts of prostate cancers are needed to further validate the findings, our current study demonstrates an increased chance of relapse and progression for the prostate cancer patients with rs11672691 G genotype and higher levels of CEACAM21 and PCAT19 expression.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Given that the genes uncovered at this locus are novel, it would be worthwhile to assess how this gene regulatory network accounts for pathogenesis and progression of prostate cancer. Clinically, we shall explore diagnostic values of combining the genotype of rs11672691 and the expression data of PCAT19 or CEACAM2, and thereby examine if this joint analysis can improve prediction of prostate cancer prognosis and progression. Further larger cohort study may help repurpose the findings to stratify prostate cancer patients for precision treatment and care.
Published: 19 July 2018
Biology and clinical implications of the 19q13 aggressive prostate cancer susceptibility locus
Ping Gao, Ji-Han Xia, Csilla Sipeky
Liang Wang, Johanna Schleutker, Gong-Hong Wei.
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