Evidence that p53-Mediated Cell-Cycle-Arrest Inhibits Chemotherapeutic Treatment of Ovarian Carcinomas

Gene expression profiles of malignant tumors surgically removed from ovarian cancer patients pre-treated with chemotherapy (neo-adjuvant) prior to surgery group into two distinct clusters. One group clusters with carcinomas from patients not pre-treated with chemotherapy prior to surgery (C-L), while the other clusters with non-malignant adenomas (A-L). We show here that although the C-L cluster is preferentially associated with p53 loss-of-function (LOF) mutations, the C-L cluster cancer patients display a more favorable clinical response to chemotherapy as evidenced by enhanced long-term survivorships. Our results support a model whereby p53 mediated cell-cycle-arrest/DNA repair serves as a barrier to optimal chemotherapeutic treatment of ovarian and perhaps other carcinomas and suggest that inhibition of p53 during chemotherapy may enhance clinical outcome.本数据集包含来自接受术前新辅助化疗（neo-adjuvant）的卵巢癌患者术中切除的恶性肿瘤的基因表达谱，该类表达谱可分为两个截然不同的聚类：其中一个聚类与术前未接受化疗的癌组织（C-L）聚为一类，另一个聚类则与非恶性腺瘤（A-L）聚为一类。本研究发现，尽管C-L聚类显著富集p53功能缺失（loss-of-function, LOF）突变，但该聚类对应的卵巢癌患者对化疗展现出更优的临床应答，其长期生存率显著升高。本研究结果支持如下模型：p53介导的细胞周期阻滞/DNA修复过程会成为卵巢癌乃至其他实体癌最优化疗方案的阻碍，并提示在化疗期间抑制p53活性或可改善临床结局。