Identification of Genes with Allelic Imbalance on 6p Associated with Nasopharyngeal Carcinoma in Southern Chinese

Nasopharyngeal carcinoma (NPC) is a malignancy of epithelial origin. The etiology of NPC is complex and includes multiple genetic and environmental factors. We employed case-control analysis to study the association of chromosome 6p regions with NPC. In total, 360 subjects and 360 healthy controls were included, and 233 single nucleotide polymorphisms (SNPs) on 6p were examined. Significant single-marker associations were found for SNPs rs2267633 (p = 4.49×10−5), rs2076483 (most significant, p = 3.36×10−5), and rs29230 (p = 1.43×10−4). The highly associated genes were the gamma-amino butyric acid B receptor 1 (GABBR1), human leukocyte antigen (HLA-A), and HLA complex group 9 (HCG9). Haplotypic associations were found for haplotypes AAA (located within GABBR1, p-value = 6.46×10−5) and TT (located within HLA-A, p = 0.0014). Further investigation of the homozygous genotype frequencies between cases and controls suggested that micro-deletion regions occur in GABBR1 and neural precursor cell expressed developmentally down-regulated 9 (NEDD9). Quantitative real-time polymerase chain reaction (qPCR) using 11 pairs of NPC biopsy samples confirmed the significant decline in GABBR1 and NEDD9 mRNA expression in the cancer tissues compared to the adjacent non-tumor tissue (pGABBR1 and NEDD9 loss of function.鼻咽癌（Nasopharyngeal carcinoma, NPC）是一种上皮来源的恶性肿瘤。其病因复杂，涉及多种遗传与环境因素。本研究采用病例对照分析方法，探讨6号染色体短臂区域与鼻咽癌的关联。研究共纳入360例鼻咽癌患者与360例健康对照，对6号染色体短臂上的233个单核苷酸多态性（single nucleotide polymorphisms, SNPs）进行了检测。结果发现，SNPs位点rs2267633（P=4.49×10⁻⁵）、rs2076483（最显著位点，P=3.36×10⁻⁵）及rs29230（P=1.43×10⁻⁴）存在显著的单标记关联。与这些位点高度相关的基因包括γ-氨基丁酸B型受体1（gamma-amino butyric acid B receptor 1, GABBR1）、人类白细胞抗原A（human leukocyte antigen, HLA-A）以及HLA复合基因簇9（HLA complex group 9, HCG9）。单体型关联分析显示，位于GABBR1内的单体型AAA（P=6.46×10⁻⁵）与位于HLA-A内的单体型TT（P=0.0014）存在显著关联。进一步对病例组与对照组的纯合基因型频率进行分析发现，GABBR1与神经前体细胞表达发育下调9（neural precursor cell expressed developmentally down-regulated 9, NEDD9）存在微缺失区域。通过11对鼻咽癌活检样本的实时荧光定量聚合酶链反应（Quantitative real-time polymerase chain reaction, qPCR）验证显示，与癌旁正常组织相比，癌组织中GABBR1与NEDD9的mRNA表达量显著降低，且提示二者存在功能丧失现象。