EB病毒DNA载量和亚型及宿主遗传标记与乳腺癌相关性研究

A large number of related studies have been done, but only 50% of the causes of breast cancer have been found. Epstein Barr virus (EBV) has been discovered in breast cancer tissues and is a new potential risk factor of breast cancer. We have found that breast cancer is significantly associated with the positivity of EBV-IgA antibodies, which reflect reactivation of EBV, in a high-incidence area of nasopharyngeal carcinoma. Still, IgA is not a direct biomarker for EBV exists, but the DNA is. However, till now, there has been no study on the difference of EBV-DNA load between breast cancer patients and normal population. In addition, it has been suggested that EBV subtypes, environmental factors, and host susceptibility are also associated with EBV carcinogenesis. Therefore, in the present study, we will detect EBV-DNA load and subtypes in peripheral blood mononuclear cells as well as the polymorphisms of the host genes related to EBV infection or reactivation in our established population of a breast cancer case-control study (1200case and 1200 controls). Combined the above results with environmental factors which may be associated with EBV reactivation or breast cancer risk, we would systematically and comprehensively explore the joint effects of these factors on breast cancer risk, so as to clarify the association between EBV and breast cancer and obtain carcinogenic subtypes of EBV, susceptibility biomarkers, and the environmental factors related to EBV infection and reactivation. Moreover, these results may offer clues for the mechanisms of EBV carcinogenesis and for targeted control and prevention of breast cancer in population. .

现有的大量相关研究仅揭示了约50%的乳腺癌病因。EB病毒（EBV）是一种新的乳腺癌可疑危险因素，已在乳腺癌组织被发现；在EBV高度相关的鼻咽癌高发区，我们发现了反映EBV重激活的血清EBV-IgA抗体与乳腺癌显著相关。然而，此抗体并非反映EBV存在的直接指标，其DNA才是；乳腺癌与正常人群体内EBV-DNA载量差异是确定乳腺癌与EBV关系的重要证据，但未见报道。此外，EBV亚型、特定环境及机体易感性与具有致癌性的EBV激活过程也密切相关。故此，本项目将利用我们已建立的乳腺癌病例对照（各1200例）人群，检测其血液单个核细胞中EBV-DNA载量和亚型及宿主相关基因多态性，同时调查与EBV激活的相关环境因素，从而综合分析其交互作用对乳腺癌发生风险的影响，以明确EBV与乳腺癌的关联，获得致癌EBV亚型及其相关环境因素和易感标记物，为EBV致癌机制提供线索，也为针对性防控乳腺癌提供依据。

本项目收集了乳腺癌病例和对照人群各1600余例以及近3000例乳腺癌队列人群，获得了所有研究对象的流行病学信息和血尿等生物样品，并对2400余例病例人群进行了常规追踪随访；检测了血液单个核细胞（PBMC）中EBV-DNA载量及其两种EBV亚型和多种相关基因的遗传多态性，如EBV激活相关基因、甲基化基因、FGFR2通路基因等，并对多种可能与EBV激活等相关的环境因素进行了调查，如某些金属类金属水平、体育锻炼和睡眠等。结果显示，PBMC中EBV-DNA及其基因组中的 F/f亚型与乳腺癌风险无关联，但其D型显著增加乳腺癌发生风险；广州地区成年女性均存在EB 病毒既往感染，抗VCA-IgA阳性率随着年龄逐渐增高，而抗EBNA1-IgG OD 值则逐渐下降；EBV激活相关基因TSG101 rs2292179 变异等位基因与低BMI可协同降低乳腺癌发病风险，ATF2 rs3845744变异等位基因显著降低乳腺癌风险，尤其在绝经后女性；FGFR2 rs2981582与ER阳性但非阴性乳腺癌关联显著，FGF1 rs250108 和 RBFOX2 rs2051579则与阴性但非阳性乳腺癌显著相关，FGFR2 rs2981582与体育锻炼对乳腺癌风险具有效应修饰作用，FGFR2 rs2981582 和 MTHFR rs1801133两位点的变异等位基因也协同增加乳腺癌患病风险；甲基化相关基因及其多态性位点MTHFR rs1801133的变异等位基因可与低硒水平协同增加乳腺癌风险；等位基因不平衡基因MUC16 rs2591592 和SLAMF1 rs1061217与乳腺癌发病风险相关，而ZNF331 rs8109631 和 CHRAC1 rs10216653则与乳腺癌预后相关；另外，夜班可增加乳腺癌发生风险，午睡可降低其风险，睡眠时间过短和过长也均增加乳腺癌患病风险；值夜班和过长睡眠时间会协同增加乳腺癌风险。上述结果从另一个角度阐明了EBV与乳腺癌的关联，特别是提出了这种关联可能受宿主遗传因素和环境因素影响。本项目已达至原计划研究目标。