Genome Medicine Core, Chang Gung Molecular Medicine Research Center, Graduate Institute of Biomedical Sciences, Chang Gung University, No. 259 Wen-Hwa 1st Road, Kwei-shan,Taoyuan 333, Taiwan.
Hum Mol Genet. 2011 Jul 15;20(14):2889-96. doi: 10.1093/hmg/ddr191. Epub 2011 May 2.
Copy number variations (CNVs), a major source of human genetic polymorphism, have been suggested to have an important role in genetic susceptibility to common diseases such as cancer, immune diseases and neurological disorders. Nasopharyngeal carcinoma (NPC) is a multifactorial tumor closely associated with genetic background and with a male preponderance over female (3:1). Previous genome-wide association studies have identified single-nucleotide polymorphisms (SNPs) that are associated with NPC susceptibility. Here, we sought to explore the possible association of CNVs with NPC predisposition. Utilizing genome-wide SNP-based arrays and five CNV-prediction algorithms, we identified eight regions with CNV that were significantly overrepresented in NPC patients compared with healthy controls. These CNVs included six deletions (on chromosomes 3, 6, 7, 8 and 19), and two duplications (on chromosomes 7 and 12). Among them, the CNV located at chromosome 6p21.3, with single-copy deletion of the MICA and HCP5 genes, showed the highest association with NPC. Interestingly, it was more specifically associated with an increased NPC risk among males. This gender-specific association was replicated in an independent case-control sample using a self-established deletion-specific polymerase chain reaction strategy. To the best of our knowledge, this is the first study to explore the role of constitutional CNVs in NPC, using a genome-wide platform. Moreover, we identified eight novel candidate regions with CNV that merit future investigation, and our results suggest that similar to neuroblastoma and prostate cancer, genetic structural variations might contribute to NPC predisposition.
拷贝数变异（CNVs）是人类遗传多态性的主要来源，据推测在癌症、免疫疾病和神经紊乱等常见疾病的遗传易感性方面发挥着重要作用。鼻咽癌（NPC）是一种多因素肿瘤，与遗传背景密切相关，且男性发病率明显高于女性（3:1）。先前的全基因组关联研究已经确定了与 NPC 易感性相关的单核苷酸多态性（SNPs）。在这里，我们试图探讨 CNVs 与 NPC 易感性的可能关联。利用全基因组 SNP 为基础的阵列和五种 CNV 预测算法，我们发现与健康对照组相比，NPC 患者中存在 8 个 CNV 区域显著过度表达。这些 CNVs 包括 6 个缺失（在染色体 3、6、7、8 和 19 上）和 2 个重复（在染色体 7 和 12 上）。其中，位于染色体 6p21.3 的 CNV，MICA 和 HCP5 基因的单拷贝缺失，与 NPC 关联度最高。有趣的是，它与男性 NPC 风险增加更为相关。使用自行建立的缺失特异性聚合酶链反应策略，在一个独立的病例对照样本中对这种性别特异性关联进行了重复验证。据我们所知，这是首次使用全基因组平台探索 NPC 中染色体结构变异的作用。此外，我们还确定了 8 个具有 CNV 的新候选区域，值得进一步研究，我们的结果表明，与神经母细胞瘤和前列腺癌相似，遗传结构变异可能导致 NPC 易感性。
