全基因外显子组测序联合功能基因组学探索子宫内膜异位症恶变的驱动基因

Malignant changes of endometriosis (EM) are considered having causal relationship with ovarian clear cell carcinoma (OCCC), and EM is proposed as the precursor lesion of OCCC. However, there is little known about the genetic landscape of malignant changes of EM during OCCC development. In this study, we intend to utilize the samples obtained from the endometriosis-associated ovarian clear cell carcinoma (EAOCCC) patients with the previous surgical history of endometriotic cyscetomy to generate the first the whole-exome mutation profiles of EM and concomitant OCCC. Our study fulfills two important objectives of significance vis-a-vis EM malignant changing pathogenesis: first, it tends to establish these informative allelic mutations with specific cutting points along time series, so as to obtain the progressively changes of EM during the process of malignant transformation. These samples are the very suitable candidate subjects for this study. Second, our study intends to indentify the target mutation alleles as novel cancerous related genes in EM by applying whole-exome sequencing and Sequenom MassARRAY genotype. The protein encoded by the mutation gene will be measured as a key landscape of high risk or low risk of turning cancerous for patients with EM. Furthermore, using ShRNA knockout endomtriotic cell line and functional assay, we plan to explore the consequences of inactivating gene function on the neoplastic phenotype.

子宫内膜异位症（内异症）是最常见的妇科疾病之一。内异症恶变与卵巢透明细胞癌存在密切联系，甚至被认为是后者的癌前病变。本研究拟利用全外显子测序技术筛选内异症恶变的关键突变基因，并对突变基因进行功能学研究。本研究的创新之处主要为两方面：一、选用既往有良性内异症手术标本的内异症相关性卵巢癌患者，由此能获得内异症随时间可能发生的基因突变的累积，是研究恶变发生机制极佳的研究对象，标本非常珍贵。二、利用全外显子测序及Sequenom MassARRAY分型，筛选恶变相关目标基因突变，研究目标突变基因编码蛋白在不同组织中表达情况，并对突变基因利用ShRNA敲除细胞转染技术构建相应基因沉默细胞株，从细胞增殖、凋亡、侵袭转移、克隆形成等方面对其进行功能测定。旨在利用高通量基因测序分型技术筛选内异症恶变相关基因突变，为临床筛选内异症恶变高危人群、预测疾病进展、进行疾病分子分型和个体化治疗提供重要基础理论依据。

子宫内膜异位症（内异症）是最常见的妇科疾病之一。内异症恶变与卵巢透明细胞癌存在密切联系，甚至被认为是后者的癌前病变。本研究拟利用全外显子测序技术筛选内异症恶变的关键突变基因，并对突变基因进行功能学研究。旨在利用高通量基因测序分型技术筛选内异症恶变相关基因突变，为临床筛选内异症恶变高危人群、预测疾病进展、进行疾病分子分型和个体化治疗提供重要基础理论依据。本研究发现，45岁以上的卵巢内异症患者，绝经后、卵巢包块≥8 cm、合并子宫内膜异常的患者发生EAOC的风险明显增加，提示需要严密随诊并积极干预。对于指导临床对于此类患者的病情监测、降低恶变患者的漏诊、误诊，同时减少诊断性手术干预，有重要意义。基础研究结果提示，全外显子组测序证实良性内异症、不典型内异症和卵巢透明细胞癌间存在突变累积，不典型内异症和卵巢透明细胞癌间存在相同突变位点，其中PAPBC3可能是内异症至透明细胞癌过程的潜在驱动基因。关键基因PAPBC3有可能成为内异症恶变的预测、恶变高危患者的早期诊断及筛查的分子标志物。本研究目前发表论文共9篇，6篇SCI收录，影响因子共12.942分；中文核心期刊共3篇。本研究产出的4篇论文参加子宫内膜异位症领域最具影响力的国际学术会议——世界内异症大会交流，其中1篇大会发言，3篇壁报交流；4篇论文参加国内最具影响力的内异症学术会议——中国内异症大会交流，均为大会发言。