title: Prostate cancer risk locus at 8q24 as a regulatory hub by physical interactions with multiple genomic loci across the genome.
abstract: Chromosome 8q24 locus contains regulatory variants that modulate genetic risk to various cancers including prostate cancer (PC). However, the biological mechanism underlying this regulation is not well understood. Here, we developed a chromosome conformation capture (3C)-based multi-target sequencing technology and systematically examined three PC risk regions at the 8q24 locus and their potential regulatory targets across human genome in six cell lines. We observed frequent physical contacts of this risk locus with multiple genomic regions, in particular, inter-chromosomal interaction with CD96 at 3q13 and intra-chromosomal interaction with MYC at 8q24. We identified at least five interaction hot spots within the predicted functional regulatory elements at the 8q24 risk locus. We also found intra-chromosomal interaction genes PVT1, FAM84B and GSDMC and inter-chromosomal interaction gene CXorf36 in most of the six cell lines. Other gene regions appeared to be cell line-specific, such as RRP12 in LNCaP, USP14 in DU-145 and SMIN3 in lymphoblastoid cell line. We further found that the 8q24 functional domains more likely interacted with genomic regions containing genes enriched in critical pathways such as Wnt signaling and promoter motifs such as E2F1 and TCF3. This result suggests that the risk locus may function as a regulatory hub by physical interactions with multiple genes important for prostate carcinogenesis. Further understanding genetic effect and biological mechanism of these chromatin interactions will shed light on the newly discovered regulatory role of the risk locus in PC etiology and progression.
authors.affiliation: Department of Pathology and Cancer Center.
authors.forename: Meijun
authors.initials: M
authors.lastname: Du
authors.affiliation: Department of Pathology and Cancer Center.
authors.forename: Tiezheng
authors.initials: T
authors.lastname: Yuan
authors.affiliation: Department of Pathology and Cancer Center.
authors.forename: Kala F
authors.initials: KF
authors.lastname: Schilter
authors.affiliation: Department of Pathology and Cancer Center.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Dittmar
authors.affiliation: Department of Pathology and Cancer Center.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mackinnon
authors.affiliation: Department of Pathology and Cancer Center.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Huang
authors.affiliation: Human Molecular Genetics Center.
authors.forename: Michael
authors.initials: M
authors.lastname: Tschannen
authors.affiliation: Human Molecular Genetics Center.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Worthey
authors.affiliation: Human Molecular Genetics Center.
authors.forename: Howard
authors.initials: H
authors.lastname: Jacob
authors.affiliation: Department of Pathology and Cancer Center Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Shu
authors.initials: S
authors.lastname: Xia
authors.affiliation: Beijing 3H Medical Technology Co. Ltd., Beijing 100176, China and.
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Lori
authors.initials: L
authors.lastname: Tillmans
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: Department of Pathology and Cancer Center liwang@mcw.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
mesh_terms: D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D056726:Genetic Association Studies / Q000379:methods*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D002843:Chromatin