Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus

The PRACTICAL Consortium

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic. A non-coding risk allele associated with aggressive prostate cancer creates a transcription factor binding site that in turn promotes oncogenesis by impacting expression of nearby genes.

Original languageEnglish
JournalCell
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Prostatic Neoplasms
Genes
Transcription Factors
Clustered Regularly Interspaced Short Palindromic Repeats
Binding Sites
Cell growth
Gene expression
Tumors
Nucleotides
Alleles
Gene Expression
Genome-Wide Association Study
Carcinogenesis
Genotype
Phenotype
Growth
Neoplasms

Keywords

  • aggressive prostate cancer
  • allele-specific DNA-binding of transcription factor
  • CEACAM21
  • eQTL
  • GWAS
  • HOXA2
  • PCAT19
  • risk stratification
  • rs11672691
  • single cell CRISPR/Cas9-mediated editing

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus. / The PRACTICAL Consortium.

In: Cell, 01.01.2018.

Research output: Contribution to journalArticle

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title = "Biology and Clinical Implications of the 19q13 Aggressive Prostate Cancer Susceptibility Locus",
abstract = "Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic. A non-coding risk allele associated with aggressive prostate cancer creates a transcription factor binding site that in turn promotes oncogenesis by impacting expression of nearby genes.",
keywords = "aggressive prostate cancer, allele-specific DNA-binding of transcription factor, CEACAM21, eQTL, GWAS, HOXA2, PCAT19, risk stratification, rs11672691, single cell CRISPR/Cas9-mediated editing",
author = "{The PRACTICAL Consortium} and Ping Gao and Xia, {Ji Han} and C. Sipeky and Dong, {Xiao Ming} and Qin Zhang and Yuehong Yang and Peng Zhang and Cruz, {Sara Pereira} and Kai Zhang and Jing Zhu and Lee, {Hang Mao} and Sufyan Suleman and Nikolaos Giannareas and Song Liu and Tammela, {Teuvo L.J.} and Anssi Auvinen and Xiaoyue Wang and Qilai Huang and Liguo Wang and Aki Manninen and Vaarala, {Markku H.} and Liang Wang and Johanna Schleutker and Wei, {Gong Hong}",
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AU - The PRACTICAL Consortium

AU - Gao, Ping

AU - Xia, Ji Han

AU - Sipeky, C.

AU - Dong, Xiao Ming

AU - Zhang, Qin

AU - Yang, Yuehong

AU - Zhang, Peng

AU - Cruz, Sara Pereira

AU - Zhang, Kai

AU - Zhu, Jing

AU - Lee, Hang Mao

AU - Suleman, Sufyan

AU - Giannareas, Nikolaos

AU - Liu, Song

AU - Tammela, Teuvo L.J.

AU - Auvinen, Anssi

AU - Wang, Xiaoyue

AU - Huang, Qilai

AU - Wang, Liguo

AU - Manninen, Aki

AU - Vaarala, Markku H.

AU - Wang, Liang

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AU - Wei, Gong Hong

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AB - Genome-wide association studies (GWAS) have identified rs11672691 at 19q13 associated with aggressive prostate cancer (PCa). Here, we independently confirmed the finding in a cohort of 2,738 PCa patients and discovered the biological mechanism underlying this association. We found an association of the aggressive PCa-associated allele G of rs11672691 with elevated transcript levels of two biologically plausible candidate genes, PCAT19 and CEACAM21, implicated in PCa cell growth and tumor progression. Mechanistically, rs11672691 resides in an enhancer element and alters the binding site of HOXA2, a novel oncogenic transcription factor with prognostic potential in PCa. Remarkably, CRISPR/Cas9-mediated single-nucleotide editing showed the direct effect of rs11672691 on PCAT19 and CEACAM21 expression and PCa cellular aggressive phenotype. Clinical data demonstrated synergistic effects of rs11672691 genotype and PCAT19/CEACAM21 gene expression on PCa prognosis. These results provide a plausible mechanism for rs11672691 associated with aggressive PCa and thus lay the ground work for translating this finding to the clinic. A non-coding risk allele associated with aggressive prostate cancer creates a transcription factor binding site that in turn promotes oncogenesis by impacting expression of nearby genes.

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