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The 8q24 Enhancer Region including rs6983267 Directly Interacts with Promoter of Oncogenic LncRNA CARLo-5

ABSTRACT: The mechanism by which rs6983267 at 8q24.21 increases cancer risk is unclear for the lack of protein?coding genes in the region although the variant is strongly associated with cancer pathogenesis. Here we identify long non-coding RNAs (lncRNAs) near the 8q24 region and show that expression of lncRNA CARLo-5 is significantly correlated with the risk allele of the cancer-associated variant rs6883267. We further report that the 8q24 enhancer region including the variant directly interacts with active regulatory region of the lncRNA CARLo-5 promtoer. Finally, we demonstrate that CARLo-5 has an oncogenic function by regulating cell proliferation and cell-cycle. Our data provide new insight of disease-related variants in a gene desert.

ORGANISM(S): Homo sapiens

PROVIDER: GSE48877 | GEO | 2014/03/05

SECONDARY ACCESSION(S): PRJNA212100

REPOSITORIES: GEO

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The 8q24 Enhancer Region including rs6983267 Directly Interacts with Promoter of Oncogenic LncRNA CARLo-5

Project description:The mechanism by which rs6983267 at 8q24.21 increases cancer risk is unclear for the lack of protein?coding genes in the region although the variant is strongly associated with cancer pathogenesis. Here we identify long non-coding RNAs (lncRNAs) near the 8q24 region and show that expression of lncRNA CARLo-5 is significantly correlated with the risk allele of the cancer-associated variant rs6883267. We further report that the 8q24 enhancer region including the variant directly interacts with active regulatory region of the lncRNA CARLo-5 promtoer. Finally, we demonstrate that CARLo-5 has an oncogenic function by regulating cell proliferation and cell-cycle. Our data provide new insight of disease-related variants in a gene desert. Comparison and identification of cell cycle-related genes differentially expressed by CARLo-5 knockdown using Nanostring analysis in HCT116 cells.

2014-03-05 | E-GEOD-48877 | biostudies-arrayexpress

RNA expression at chromosome 8q24 in human colon

Project description:An inherited variant on chromosome 8q24, rs6983267, is significantly associated with cancer pathogenesis. We present evidence that this region is a transcriptional enhancer, that the risk region physically interacts with the MYC proto-oncogene, and that the alleles of rs6983267 differentially bind transcription factor 7-like 2 (TCF7L2). These data provide strong support for a biological mechanism underlying this non-protein coding risk variant.

2009-06-08 | GSE16228 | GEO

RNA expression at chromosome 8q24 in human colon

2010-05-18 | E-GEOD-16228 | biostudies-arrayexpress

Homo sapiens

Project description:The 8q24 Enhancer Region including rs6983267 Directly Interacts with Promoter of Oncogenic LncRNA CARLo-5

| PRJNA212100 | ENA

Colorectal cancer susceptibility loci as predictive markers of rectal cancer prognosis after surgery

Project description:To understand the molecular mechanism of rectal cancer and develop markers for disease prognostication, we generated and explored a dataset from 243 rectal cancer patients by gene expression microarray analysis of cancer samples and matched controls, and SNP-arrays of germline DNA. We found that two of the loci most strongly linked with colorectal cancer (CRC) risk, 8q24 (upstream of MYC) and 18q21 (in the intron of SMAD7), as well as 20q13 (in the intron of LAMA5), are tightly associated with the prognosis of rectal cancer patients. For SNPs on 18q21 (rs12953717 and rs4464148) and 20q13 (rs4925386), alleles that correlate with higher risk for the development of CRC are associated with shorter disease free survival (DFS). However, for rs6983267 on 8q24, the low risk allele is associated with a higher risk for recurrence and metastasis after surgery, and importantly, is strongly correlated with the resistance of CRC cell lines to chemoradiotherapy (CRT). We also found that although MYC expression is dramatically increased in cancer, patients with higher levels of MYC have a better prognosis. The expression of SMAD7 is weakly correlated with DFS. Notably, the presence of the 8q24 and 18q21 SNP alleles is not correlated with expression levels of MYC and SMAD7. rs4464148, and probably rs6983267 and rs4925386, are linked with overall survival time of patients. In conclusion, we show that several CRC risk SNPs detect subpopulations of rectal cancer patients with poor prognosis, and that rs6983267 probably affects prognosis through interfering with the resistance of cancer cells to CRT.

2017-11-28 | GSE87211 | GEO

Expression analysis of prostate tissue on locus 8q24 part 2

Project description:Investigation on expression levels of normal tissue from prostate cancer patients on locus 8q24. The region chr8:127640000-129120000 is tiled with isothermal probes (hg17)

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Expression analysis of prostate tissue on locus 8q24 part 1

Project description:Investigation on expression levels of normal tissue from prostate cancer patients on locus 8q24. The region chr8:127640000-129120000 is tiled with 60 nt probes at 10 nt interval (hg18)

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Expression analysis of prostate tissue on locus 8q24 part 2

2013-04-11 | E-GEOD-45922 | biostudies-arrayexpress

Expression analysis of prostate tissue on locus 8q24 part 1

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Functional enhancers at the gene-poor 8q24 cancer-linked locus

Project description:Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in non-protein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

2009-12-19 | GSE19561 | GEO

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