A functional variant in the transcriptional regulatory region of gene LOC344967 cosegregates with disease phenotype in familial nasopharyngeal carcinoma.
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.
Jiang
Ri-Cheng
RC
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.
Qin
Hai-De
HD
Zeng
Mu-Sheng
MS
Huang
Wei
W
Feng
Bing-Jian
BJ
Zhang
Feng
F
Chen
Han-Kui
HK
Jia
Wei-Hua
WH
Chen
Li-Zhen
LZ
Feng
Qi-Sheng
QS
Zhang
Ru-Hua
RH
Yu
Xing-Juan
XJ
Zheng
Mei-Zhen
MZ
Zeng
Yi-Xin
YX
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
C507739:LOC344967 protein, human; D014157:Transcription Factors