BRCA2关键结构域突变与卵巢癌新辅助化疗获得性铂类耐药的相关性研究

发布时间：2018-08-31 16:15

【摘要】：目的：本研究旨在通过检测卵巢癌病人中BRCA2(breast cancer 2)关键结构域的突变情况,分析BRCA2关键结构域的突变与卵巢癌新辅助化疗后获得性铂类耐药之间的相关性,为卵巢癌的临床治疗策略提供新的指导依据。方法：1、DNA抽提试剂盒提取石蜡包埋卵巢癌组织DNA；2、采用巢式PCR (Nested-PCR)技术和第一代DNA测序技术检测64例III-IV期浆液性卵巢癌(30例接受初次肿瘤细胞减灭术、34例接受新辅助化疗-间歇性手术)中BRCA2关键结构域突变情况；3、收集患者临床病理资料,回顾性分析BRCA2关键结构域突变与铂类的治疗应答的关系,分析两组患者BRCA2突变的差异与两组卵巢癌患者无进展生存期(progression-free survival,PFS)和总生存期(overall survival, OS)差异之间的关系,推测BRCA2关键结构域的突变与卵巢癌新辅助化疗后获得性铂类耐药的相关性,分析卵巢癌临床病理特征、BRCA2关键结构域突变与预后之间的关系。结果：1、64例卵巢癌中28例患者发生BRCA2关键结构域突变,按突变改变氨基酸分类,同义突变(氨基酸不改变)4例,错义突变(氨基酸置换改变)19例、无义突变(碱基插入或缺失或置换造成氨基酸编码提前终止—导致蛋白截短)5例。2、直接手术治疗组(primary debulking surgery, PDS)总突变率为53.33%(同义突变1例,错义突变10例,无义突变5例)；新辅助化疗-间歇性手术组(neoadjuvant chemotherapy interval debulking surgery, NACT-IDS)总突变率为35.29%(同义突变3例,错义突变9例,无义突变0例)；3、BRCA2关键结构域不同突变与铂类治疗应答的相关(P=0.02),BRCA2无义突变与卵巢癌新辅助化疗后较短的无进展生存期相关(P=0.0367),BRCA2关键结构域突变与卵巢癌的预后密切相关,生存分析显示BRCA2无义突变是影响卵巢癌PFS的独立有利因素(P=0.023)。结论：检测BRCA2关键结构域的突变可为卵巢癌临床化疗方案的决策和判断预后提供重要的参考依据,相信随着BRCA2与卵巢癌铂类耐药相关机制的深入研究,卵巢癌的治疗效果定能得到明显改善。
[Abstract]:Objective: to investigate the relationship between mutation of BRCA2 (breast cancer 2 key domain in ovarian cancer patients and acquired platinum resistance after neoadjuvant chemotherapy. To provide a new guidance for the clinical treatment strategy of ovarian cancer. Methods DNA; from paraffin embedded ovarian cancer tissue was extracted with a DNA extraction kit of 1: 1. (2) nested PCR (Nested-PCR) technique and first-generation DNA sequencing technique were used to detect the mutation of BRCA2 key domain in 64 cases of III-IV stage serous ovarian carcinoma (30 cases of primary tumor cell reduction and 34 cases of neoadjuvant chemotherapy-intermittent operation). 3. The clinicopathological data of the patients were collected, and the relationship between the mutation of the key domain of BRCA2 and the therapeutic response of platinum was analyzed retrospectively. The relationship between BRCA2 mutation and progressive survival (progression-free survival,PFS) and total survival (overall survival, OS) in patients with ovarian cancer was analyzed. The relationship between the mutation of BRCA2 key domain and the acquired platinum resistance after neoadjuvant chemotherapy was speculated. To analyze the clinicopathological features of ovarian cancer and the relationship between BRCA 2 domain mutation and prognosis. Results among 64 cases of ovarian cancer, 28 cases had mutations of BRCA2 key domain, including 4 cases of synonymous mutation (amino acid change), 19 cases of missense mutation (amino acid replacement change), according to mutation change amino acid classification, and 4 cases of synonymous mutation (no change of amino acid), 19 cases of missense mutation (amino acid replacement). The total mutation rate of (primary debulking surgery, PDS) in direct operation group was 53.33% (1 case of synonymous mutation, 10 cases of missense mutation, 5 cases of nonsense mutation). The total mutation rate of (neoadjuvant chemotherapy interval debulking surgery, NACT-IDS in neoadjuvant chemotherapy-intermittent operation group was 35.29% (3 cases of synonymous mutation, 9 cases of missense mutation and 0 case of nonsense mutation). (3) different mutations in key domains of BRCA2 are correlated with the significance of platinum-like therapeutic response (P0. 02) and the short progression free survival (P0. 0367) of neoadjuvant chemotherapy in ovarian cancer. The mutation of the key domain of BRCA2 is closely related to the prognosis of ovarian cancer. Survival analysis showed that BRCA2 nonsense mutation was an independent and favorable factor affecting ovarian cancer PFS (P0. 023). Conclusion: detection of mutations in key domains of BRCA2 may provide an important reference for the decision of chemotherapy regimen and prognosis of ovarian cancer. It is believed that with the further study of the mechanism of BRCA2 and platinum resistance in ovarian cancer. The therapeutic effect of ovarian cancer can be significantly improved.
【学位授予单位】：广西医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R737.31

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