title: A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma.
abstract: Nasopharyngeal carcinoma is a common malignancy in Southeast Asian countries, and genetic background is a well-known component of the complexity underlying its tumorigenic process. We have mapped a nasopharyngeal carcinoma susceptibility locus to chromosome 4p15.1-q12 in a previous linkage study on nasopharyngeal carcinoma pedigrees. In this study provided in this communication, we screened all the genes in this region, with a focus on exons, promoters, and the exon-intron boundary to identify nasopharyngeal carcinoma-associated mutations or functional variants. Importantly, we found a novel gene (LOC344967) with a single nucleotide polymorphism -32G/A in the promoter region. This gene is a member of the acyl CoA thioesterase family that plays an important role in fatty acid metabolism and is involved in the progression of various types of tumors. The -32A variant was found cosegregated with the disease phenotype in the nasopharyngeal carcinoma pedigrees that we previously used for the linkage study. Moreover, this -32A variant creates an activator protein (AP-1)-binding site in the transcriptional regulatory region of LOC344967, which significantly enhanced the binding of AP-1 to the promoter region and the transcription activity of the promoter in vivo. Furthermore, the expression of LOC344967 was significantly up-regulated at both mRNA and protein levels in nasopharyngeal carcinoma cells sharing the -32G/A genotype compared with nasopharyngeal carcinoma cells with the -32G/G genotype. Collectively, these results provide evidence that the -32A variant is a functional sequence change and may be related to nasopharyngeal carcinoma susceptibility in the families studied.
authors.affiliation: State Key Laboratory of Oncology in Southern China; Departments of Experimental Research, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou 510-060, China.
authors.forename: Ri-Cheng
authors.initials: RC
authors.lastname: Jiang
authors.forename: Hai-De
authors.initials: HD
authors.lastname: Qin
authors.forename: Mu-Sheng
authors.initials: MS
authors.lastname: Zeng
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Bing-Jian
authors.initials: BJ
authors.lastname: Feng
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Han-Kui
authors.initials: HK
authors.lastname: Chen
authors.forename: Wei-Hua
authors.initials: WH
authors.lastname: Jia
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Chen
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.forename: Ru-Hua
authors.initials: RH
authors.lastname: Zhang
authors.forename: Xing-Juan
authors.initials: XJ
authors.lastname: Yu
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Zheng
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D005091:Exons; D020022:Genetic Predisposition to Disease; D006801:Humans; D009303:Nasopharyngeal Neoplasms / Q000235:genetics* / Q000473:pathology*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic
chemical_list: C507739:LOC344967 protein, human; D014157:Transcription Factors