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Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.

Pittman, AM; Naranjo, S; Jalava, SE; Twiss, P; Ma, Y; Olver, B; Lloyd, A; ... Houlston, RS; + view all (2010) Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H. PLoS Genet , 6 (9) , Article e1001126. 10.1371/journal.pgen.1001126. Green open access

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Abstract

Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC.

Type: Article
Title: Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1001126
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1001126
Language: English
Additional information: © 2010 Pittman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund), provided principal funding for the study. Additional funding was provided by the European Union (CPRB LSHC-CT-2004-503465). JLG-S acknowledges grants from the Spanish Ministry of Education and Science (BFU2007-60042/BMC, Petri PET2007-0158 and CSD2007-00008) and Junta de Andalucí­a (CVI-3488). MM acknowledges support from the ProCNIC Foundation. HM and TVW acknowledge support by Dutch Cancer Society grant UL2003-2807. MM acknowledges support from the Spanish Government (BFU2008-00838, CSD2007-00008) and the ProCNIC Foundation. Work in Finland was supported by grants from the Academy of Finland (Finnish Center of Excellence Program 2006-2011), the Finnish Cancer Society, the Sigrid Juselius Foundation, the European Commission (LSHG-CT-2004-512142), Ida Montin Foundation (ST), and Biomedicum Helsinki Foundation (ST). The Funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Keywords: Alleles, Cell Line, Tumor, Cell Proliferation, Chromosomes, Human, Pair 8, Colorectal Neoplasms, Electrophoretic Mobility Shift Assay, Eukaryotic Initiation Factor-3, Female, Gene Expression Regulation, Neoplastic, Genes, Reporter, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Humans, Linkage Disequilibrium, Male, Middle Aged, Polymorphism, Single Nucleotide, Protein Binding, Regulatory Sequences, Nucleic Acid, Risk Factors
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/1356616
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