Discovering biological mechanisms and clinical implications of three prostate cancer risk loci
Thesis event information
Date and time of the thesis defence
Place of the thesis defence
Auditorium F202, Aapistie 5 B, Oulu, Finland
Topic of the dissertation
Discovering biological mechanisms and clinical implications of three prostate cancer risk loci
Doctoral candidate
Master of Animal Breeding and Genetics Jihan Xia
Faculty and unit
University of Oulu Graduate School, Faculty of Biochemistry and Molecular Medicine, FBMM
Subject of study
Biochemistry and Molecular Medicine
Opponent
PhD, Assistant Professor Jian Yan , Department of Biomedical Sciences, City University of Hong Kong
Custos
PhD, Professor Gonghong Wei, University of Oulu
Discovering biological mechanisms and clinical implications of three prostate cancer risk loci
The thesis focuses in particular on the functional characterization of three PCa susceptibility loci: rs13215402 at 6q25; the haplotype formed by rs6579003, rs7123299 and rs7123418 at 11p15, and rs11672691 at 19q13. The latter has also been reproducible found in association with PCa aggressiveness.
We find that the SNPs co-localize with functional enhancers enriched with epigenetic signature of H3K4me1 and H3K27ac, and the binding of prostate master transcription factors including AR, FOXA1 and HOXB13 in addition to a novel transcriptional regulator HOXA2 at rs11672691. The eQTL analyses revealed significant associations of the rs13215402 genotype with RGS17 expression, the rs6579003, rs7123299, and rs7123418 haplotype with ASCL2, as well as rs11672691 with PCAT19 and CEACAM21. Further CRISPR/Cas9-mediated single-base editing in single cells demonstrated the direct effects of rs13215402 genotype on RGS17 expression, and remarkably, rs11672691 on the expression of PCAT19 and CEACAM21, and PCa cellular aggressive phenotype. Clinical data indicate that the upregulation of RGS17, HOXA2 or CEACAM21 in human PCa specimens correlates with tumor progression, metastasis, and an increased risk of biochemical recurrence. Finally, we observed a synergistic effect of the 19q13 allele rs11672691 and PCAT19/CEACAM21 gene expression on PCa prognosis.
We find that the SNPs co-localize with functional enhancers enriched with epigenetic signature of H3K4me1 and H3K27ac, and the binding of prostate master transcription factors including AR, FOXA1 and HOXB13 in addition to a novel transcriptional regulator HOXA2 at rs11672691. The eQTL analyses revealed significant associations of the rs13215402 genotype with RGS17 expression, the rs6579003, rs7123299, and rs7123418 haplotype with ASCL2, as well as rs11672691 with PCAT19 and CEACAM21. Further CRISPR/Cas9-mediated single-base editing in single cells demonstrated the direct effects of rs13215402 genotype on RGS17 expression, and remarkably, rs11672691 on the expression of PCAT19 and CEACAM21, and PCa cellular aggressive phenotype. Clinical data indicate that the upregulation of RGS17, HOXA2 or CEACAM21 in human PCa specimens correlates with tumor progression, metastasis, and an increased risk of biochemical recurrence. Finally, we observed a synergistic effect of the 19q13 allele rs11672691 and PCAT19/CEACAM21 gene expression on PCa prognosis.
Last updated: 1.3.2023