title: A variant at a potentially functional microRNA-binding site in BRIP1 was associated with risk of squamous cell carcinoma of the head and neck.
abstract: DNA double-strand breaks (DSBs) are one of the most serious forms of DNA damage to the cell, causing genomic instability and ultimately carcinogenesis. In this study, we hypothesized that single nucleotide polymorphisms (SNPs) at the micro RNA (miRNA)-binding sites of DSB repair genes may influence cancer risk by dysregulating target gene expression. To test our hypothesis, we firstly performed functional prediction for common SNPs in DSB genes and found 12 potentially functional SNPs located at the miRNA-binding sites. We then investigated their associations with risk of squamous cell carcinoma of the head and neck (SCCHN) in 1087 patients and 1090 cancer-free controls in a non-Hispanic white population. As a result, SNP rs7213430 in BRIP1 was found to be significantly associated with cancer risk (P trend = 0.021). Compared with the AA homozygotes, the G allele carriers had an increased risk of SCCHN (adjusted OR 1.16, 95 % CI 1.02-1.31). Marginal significance was found for another SNP rs15869 in BRCA2 (P = 0.053). Further, functional analyses showed that SNP rs7213430 is within the miR-101 seed-binding region, and the variant G allele could lead to significantly lower luciferase activity and BRIP1 mRNA expression, compared to the A allele with the presence of miR-101. Our results suggested that SNP rs7213430 in the 3'-UTR of BRIP1 might contribute to SCCHN susceptibility by affecting the binding activity of miR-101 and resulting in a decreased BRIP1 expression. Additional larger population and functional studies are warranted to confirm our findings.
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC, 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC, 27710, USA.|Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.
authors.forename: Fengqin
authors.initials: F
authors.lastname: Gao
authors.affiliation: Departments of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Kristina R
authors.initials: KR
authors.lastname: Dahlstrom
authors.affiliation: Departments of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.|Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Li
authors.affiliation: Departments of Head and Neck Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.|Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: Erich M
authors.initials: EM
authors.lastname: Sturgis
authors.affiliation: Department of Otolaryngology/Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.|Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
authors.forename: Jose P
authors.initials: JP
authors.lastname: Zevallos
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC, 27710, USA. qingyi.wei@duke.edu.|Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA. qingyi.wei@duke.edu.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Wei
authors.affiliation: Duke Cancer Institute, Duke University Medical Center, 905 South Lasalle Street, Durham, NC, 27710, USA. zhensheng.liu@duke.edu.|Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA. zhensheng.liu@duke.edu.
authors.forename: Zhensheng
authors.initials: Z
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D001665:Binding Sites; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D020365:RNA Helicases / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D012372:ROC Curve; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors
chemical_list: D020413:3' Untranslated Regions; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; C000618935:BRIP1 protein, human; D020365:RNA Helicases
keywords: DNA double strands break; Genetic susceptibility; Head and neck cancer; MicroRNA; Polymorphism