染色体6q26-q27区域遗传变异对结直肠癌发生发展的影响及其机制研究

Genetic variation, characterized by existing heterogeneity in different populations, is an important factor for the differences between individual susceptibility and clinical progression of colorectal cancer (CRC). A genome-wide association studies (GWAS) based on Japanese population reported that chromosome 6q26-q27 region was closely related with CRC risk. We replicated in Chinese population and found that there may be novel polymorphism loci related to CRC in this region. Moreover, our previous study showed that SLC22A3 and LPAL2, which located in 6q26-q27 region, were both over-expressed in CRC samples. However, the genuine causal site in this region has not yet been proven. Therefore, we plan to use case-control study to investigate the relationship between chromosome 6q26-q27 region and the CRC risk comprehensively, search the genuine causative loci, and explore the relationship between genetic variants and clinical progression, as well as prognosis of CRC. We will also clarify the biological functions of the associated loci and the two genes by molecular biology assay. Finally, our study will contribute to screening of high-risk populations, early prevention and individualized treatment of CRC.

遗传变异是导致结直肠癌易感性和临床进展存在个体间差异的重要原因，其特征在不同人群间存在异质性。基于日本人群结直肠癌全基因组关联性研究（GWAS）中发现的染色体6q26-q27区域与结直肠癌发生风险关系密切，本课题组前期对此区域进行了同为亚裔的中国人群结直肠癌的验证性研究，发现该区域可能存在中国人群结直肠癌发生相关的新位点；而且，在此区域中存在两个在结直肠癌组织中高表达的基因SLC22A3和LPAL2。然而，该区域内真正的致病位点目前尚未探明。据此，本课题拟在前期研究基础上，通过病例-对照研究方法，对该染色体6q26-q27区域与结直肠癌发生风险的关系进行全面系统的分析，寻找出结直肠癌真正的致病位点，并探讨其与结直肠癌临床进展及预后之间的关系，进而应用分子生物学手段阐明该位点和两个功能基因的生物学作用，为未来结直肠癌高危人群筛查、早期干预及临床个体化治疗提供理论依据。

结直肠癌（CRC）是最常见的消化系统恶性肿瘤之一。其发生发展的机制仍未完全阐明，环境和遗传因素共同参与。遗传因素中，单核苷酸多态性是最为常见的类型。日本人群结直肠癌GWAS研究中发现的染色体 6q26-q27 区域rs7758229与肠癌发生风险相关，多个课题组对此位点在中国人群中验证，结果与日本人群不一致。但我们前期工作发现此区域中的基因SLC22A3在结直肠癌组织中显著高表达，研究报道其与结直肠癌、肝癌、前列腺癌相关。因而本课题组推论由于不同种族遗传背景差异，中国人群中该区域内真正的致病位点目前尚未探明。.本研究首先通过病例-对照研究，寻找出染色体 6q26-q27 区域与结直肠癌易感性相关的位点。运用表达数量性状基因座（eQTL）分析和荧光素酶报告基因实验探讨该相关位点对所在基因SLC22A3的调控。并探索SLC22A3对肠癌细胞生物学行为的影响。.在病例对照研究中，发现rs420038与中国人群结直肠癌的发生风险明显相关， AA/AG基因型个体较GG型个体结直肠癌发生率显著降低（调整OR = 0.79，95% CI = 0.67-0.94，P = 0.007）。SLC22A3在肠癌中呈高表达（P < 0.001），其表达量与rs420038不同基因型呈线性相关（P = 0.040）。且携带A等位基因较携带G等位基因的肠癌细胞的SLC22A3启动子活性明显降低。干扰SLC22A3后，发现肠癌细胞的增殖、迁移及侵袭能力有显著的抑制作用，凋亡增多，G1期细胞数增加，S期细胞数减少。.rs420038 AA型能够降低结直肠癌发病风险。rs420038可能在转录水平通过调控SLC22A3启动子活性进而影响其表达量。 SLC22A3在肠癌中显著高表达，且与肠癌细胞恶性生物学行为相关。本研究结果可为进一步探讨SLC22A3在肠癌发生发展中深入机制研究及临床应用提供线索。