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DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs


Autoři: James Y. Dai aff001;  Xiaoyu Wang aff001;  Bo Wang aff003;  Wei Sun aff001;  Kristina M. Jordahl aff001;  Suzanne Kolb aff001;  Yaw A. Nyame aff001;  Jonathan L. Wright aff001;  Elaine A. Ostrander aff005;  Ziding Feng aff001;  Janet L. Stanford aff001
Působiště autorů: Division of Public Health Sciences, Fred Hutchison Cancer Research Center, Seattle, Washington, United States of America aff001;  Department of Biostatistics, University of Washington School of Public Health, Seattle, Washington, United States of America aff002;  Department of Laboratory Medicine, Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China aff003;  Department of Urology, University of Washington School of Medicine, Seattle, Washington, United States of America aff004;  Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, United States of America aff005;  Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, United States of America aff006
Vyšlo v časopise: DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs. PLoS Genet 16(3): e32767. doi:10.1371/journal.pgen.1008667
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1008667

Souhrn

Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.

Klíčová slova:

DNA methylation – Gene expression – Gene regulation – Histology – Prostate cancer – Prostate gland – Variant genotypes – Benign tumors


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