Genetic variants associated with expression of TCF19 contribute to the risk of head and neck cancer in Chinese population
Genetic variants associated with expression of TCF19 contribute to the risk of head and neck cancer in Chinese population
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与TCF19表达相关的基因变异导致中国人群患头颈癌的风险
DOI：
10.1136/jmedgenet-2020-107410
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发表时间：
2021-03-05
影响因子：
4
通讯作者：
Ma, Hongxia
中科院分区：
文献类型：
--
作者：
Ji, Pei;Chang, Jiang;Ma, Hongxia
背景 头颈鳞状细胞癌（SCCHN）是世界范围内最常见的癌症之一，包括口腔、咽部和喉部产生的癌症。全基因组关联研究发现了几种与 SCCHN 风险相关的基因变异；然而，他们只能解释遗传力的一小部分。因此，需要鉴定更多与 SCCHN 相关的易感位点。方法通过对中国人群中 555 名 SCCHN 患者和 1367 名对照者进行基因分型进行关联研究。对 63 373 个 SNP 进行了单变异关联分析，然后通过对 1875 个 SCCHN 病例和 4637 个对照进行两阶段验证来确认有希望的变异。应用生物信息学分析和功能测定来揭示与 SCCHN 相关的有希望的变异和基因的潜在致病机制。结果我们首先发现了与 SCCHN 风险显着相关的三个新的遗传变异（rs2517611 在 6p22.1 的 p=7.45x10(-7)、rs2524182 在 6p21.33 的 p=1.76x10(-9) 和 rs3131018 在 6p21.33 的 p=2.17x10(-10)。 6p21.33）。进一步的分析和生化检测表明，rs3094187与rs3131018处于高度连锁不平衡区域，可以通过调节转录因子SREBF1与TCF19启动子的结合亲和力来修饰TCF19的表达。此外，实验表明，抑制TCF19可能会影响肿瘤发生的几个重要途径，并减弱SCCHN的细胞增殖和迁移。结论 这些发现提供了重要的证据，表明功能性遗传变异可能有助于 SCCHN 的发生，并且 TCF19 可能作为 SCCHN 的假定易感基因。
Background Squamous cell carcinoma of the head and neck (SCCHN) is one of the most common cancers worldwide and includes cancers arising from the oral cavity, pharynx and larynx. Genome-wide association studies have found several genetic variants related to the risk of SCCHN; however, they could only explain a small fraction of the heritability. Thus, more susceptibility loci associated with SCCHN need to be identified. Methods An association study was conducted by genotyping 555 patients with SCCHN and 1367 controls in a Chinese population. Single-variant association analysis was conducted on 63 373 SNPs, and the promising variants were then confirmed by a two-stage validation with 1875 SCCHN cases and 4637 controls. Bioinformatics analysis and functional assays were applied to uncover the potential pathogenic mechanism of the promising variants and genes associated with SCCHN. Results We first identified three novel genetic variants significantly associated with the risk of SCCHN (p=7.45x10(-7) for rs2517611 at 6p22.1, p=1.76x10(-9) for rs2524182 at 6p21.33 and p=2.17x10(-10) for rs3131018 at 6p21.33). Further analysis and biochemical assays showed that rs3094187, which was in a region in high linkage disequilibrium with rs3131018, could modify TCF19 expression by regulating the binding affinity of the transcription factor SREBF1 to the promoter of TCF19. In addition, experiments revealed that the inhibition of TCF19 may affect several important pathways involved in tumourigenesis and attenuate the cell proliferation and migration of SCCHN. Conclusion These findings offer important evidence that functional genetic variants could contribute to development of SCCHN and that TCF19 may function as a putative susceptibility gene for SCCHN.