卵巢上皮性癌TP53 K351N突变相关铂类耐药的分子机制及临床研究

Platinum resistance is a main contributor causing recurrence of patients with epithelial ovarian cancer (EOC) in a short-term interval. However, the molecular mechanisms of platinum resistance remain unclear. In patients who undergo neoadjuvant chemotherapy with interval debulking surgery (NACT-IDS) with IDS, 88.8% of the patients relapse within six months. TP53 K351N mutation in the tetramerization domain leading to loss of TP53 signal transduction and apoptosis activity is one of the causes related platinum resistance. Our previous studies showed for the first time that 50% of EOC patients who received NACT-ID relapsed within 6 months and emerged TP53K351N mutation. Our project will randomly divided the patients with advanced stage into NACT-IDS group and primary debulking surgery (PDS )group and detect TP53K351N in their tumor tissues using AS-PCR assay, and compare the outcome of treatment with different chemotherapy regimens. Also, EOC cell lines are transfected with TP53K351N plasmid and expressions of acetyl-TP53K351, MLH1 and DNA POL η are determined to clarify the molecular mechanisms of TP53K351N mutation and to circumvent the resistance mechanism for improvement of survival in EOC patients.

铂类耐药是导致晚期卵巢癌（EOC）近期复发的主要原因，但其耐药的分子机制仍不清楚。在EOC的新辅助化疗（NACT）后间歇性肿瘤细胞减灭术（IDS）中，有88.8%EOC患者在治疗后6个月内复发，可能与铂类化疗诱导的耐药有关。目前认为TP53K351N四聚体结构域突变造成TP53凋亡信号转导和功能的缺失是铂类耐药的原因之一。我们的前期研究证实，50% NACT-IDS治疗后6个月内复发者出现TP53K351N突变，为此，本研究收集晚期EOC患者，随机分组采取NACT-IDS和直接手术组，AS-PCR检测TP53K351N突变情况，并据此制定不同的化疗方案，分析比较治疗效果；同时通过转染TP53K351N到卵巢癌细胞，检测TP53K351蛋白乙酰化水平及相关蛋白MLH1和DNA聚合酶 POL η的表达，探索TP53K351N突变的分子机制。规避铂类耐药对疗效的影响，达到提高患者生存的目的。