Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism Coactivating CD9 and PLEKHG6
Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the und...
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| Published in | Cancer epidemiology, biomarkers & prevention Vol. 29; no. 4; pp. 850 - 859 |
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| Main Authors | , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.04.2020
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| Online Access | Get full text |
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| Abstract | Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms.
Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes.
The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92,
= 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of
and
, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma.
Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes
and
in 12p13.31 for colon and rectal adenocarcinoma.
These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub. |
|---|---|
| AbstractList | Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms.BACKGROUNDGenome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms.Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes.METHODSThrough a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes.The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, P = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of CD9 and PLEKHG6, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma.RESULTSThe SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, P = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of CD9 and PLEKHG6, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma.Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma.CONCLUSIONSOur integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma.These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.IMPACTThese findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub. Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms. Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case-control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR-Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes. The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82-0.92, = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of and , which are both putative tumor suppressor genes for colon and rectal adenocarcinoma. Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes and in 12p13.31 for colon and rectal adenocarcinoma. These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub. |
| Author | Mei, Shufang Zhu, Ying Gong, Jing Tian, Jianbo Ke, Juntao Wang, Zhihua Miao, Xiaoping Wang, Xiaoyang Zou, Danyi Yang, Yang Yang, Nan Gong, Yajie Zhong, Rong Peng, Xiating Chang, Jiang Ying, Pingting |
| Author_xml | – sequence: 1 givenname: Juntao surname: Ke fullname: Ke, Juntao – sequence: 2 givenname: Jianbo surname: Tian fullname: Tian, Jianbo – sequence: 3 givenname: Shufang surname: Mei fullname: Mei, Shufang – sequence: 4 givenname: Pingting surname: Ying fullname: Ying, Pingting – sequence: 5 givenname: Nan surname: Yang fullname: Yang, Nan – sequence: 6 givenname: Xiaoyang surname: Wang fullname: Wang, Xiaoyang – sequence: 7 givenname: Danyi surname: Zou fullname: Zou, Danyi – sequence: 8 givenname: Xiating surname: Peng fullname: Peng, Xiating – sequence: 9 givenname: Yang surname: Yang fullname: Yang, Yang – sequence: 10 givenname: Ying surname: Zhu fullname: Zhu, Ying – sequence: 11 givenname: Yajie surname: Gong fullname: Gong, Yajie – sequence: 12 givenname: Zhihua surname: Wang fullname: Wang, Zhihua – sequence: 13 givenname: Jing surname: Gong fullname: Gong, Jing – sequence: 14 givenname: Rong surname: Zhong fullname: Zhong, Rong – sequence: 15 givenname: Jiang orcidid: 0000-0001-8551-9458 surname: Chang fullname: Chang, Jiang – sequence: 16 givenname: Xiaoping orcidid: 0000-0002-6818-9722 surname: Miao fullname: Miao, Xiaoping |
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| CitedBy_id | crossref_primary_10_1038_s41419_022_04673_4 crossref_primary_10_1080_14787210_2020_1761333 crossref_primary_10_3390_genes14010114 crossref_primary_10_1126_scisignal_adp9377 crossref_primary_10_1007_s00018_024_05314_z |
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| Title | Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism Coactivating CD9 and PLEKHG6 |
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