Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Gynecol Oncol. 2013 Sep;130(3):565-9. doi: 10.1016/j.ygyno.2013.06.016. Epub 2013 Jun 22.
The objective of this study is to investigate whether wild-type TP53 status in high-grade serous ovarian carcinoma is associated with poorer survival.
Clinical and genomic data of 316 sequenced samples from The Cancer Genome Atlas (TCGA) ovarian high-grade serous carcinoma study were downloaded from TCGA data portal. Association between wild-type TP53 and survival was analyzed with Kaplan Meier method and Cox regression. The diagnosis of high-grade serous carcinomas was evaluated by reviewing pathological reports and high-resolution hematoxylin and eosin (H&E) images from frozen sections. The authenticity of wild-type TP53 in these tumor samples was assessed by analyzing SNP array data with ASCAT algorithm, reverse phase protein array (RPPA) data and RNAseq data.
Fifteen patients with high grade serous ovarian carcinomas were identified to have wild-type TP53, which had significantly shorter survival and higher chemoresistance than those with mutated TP53. The authenticity of wild-type TP53 status in these fifteen patients was supported by SNP array, RPPA, and RNAseq data. Except four cases with mixed histology, the classification as high grade serous carcinomas was supported by pathological reports and H&E images. Using RNAseq data, it was found that EDA2R gene, a direct target of wild-type TP53, was highly up-regulated in samples with wild-type TP53 in comparison to samples with either nonsense or missense TP53 mutations.
Although patients with wild-type TP53 ovarian cancer were rare in the TCGA high grade ovarian serous carcinomas cohort, these patients appeared to have a poorer survival and were more chemoresistant than those with mutated TP53. Differentially expressed genes in these TP53 wild-type tumors may provide insight in the molecular mechanism in chemotherapy resistance.
本研究旨在探讨高级别浆液性卵巢癌中野生型 TP53 的状态是否与生存率降低有关。
从 TCGA 卵巢高级别浆液性癌研究的 TCGA 数据门户下载了 316 个测序样本的临床和基因组数据。采用 Kaplan-Meier 法和 Cox 回归分析野生型 TP53 与生存的相关性。通过复习病理报告和来自冷冻切片的高分辨率苏木精和伊红（H&E）图像，评估高级别浆液性癌的诊断。通过分析 SNP 阵列数据、反相蛋白阵列（RPPA）数据和 RNAseq 数据，使用 ASCAT 算法评估这些肿瘤样本中野生型 TP53 的真实性。
鉴定出 15 例高级别浆液性卵巢癌患者存在野生型 TP53，与突变型 TP53 相比，其生存时间明显缩短，化疗耐药性更高。这些 15 例患者的野生型 TP53 状态的真实性得到了 SNP 阵列、RPPA 和 RNAseq 数据的支持。除了 4 例混合组织学病例外，病理报告和 H&E 图像支持高级别浆液性癌的分类。使用 RNAseq 数据发现，野生型 TP53 的直接靶基因 EDA2R 基因在野生型 TP53 样本中高度上调，与具有无意义或错义 TP53 突变的样本相比。
尽管在 TCGA 高级别卵巢浆液性癌队列中，野生型 TP53 卵巢癌患者很少见，但与突变型 TP53 患者相比，这些患者的生存率似乎较低，且对化疗的耐药性更强。这些 TP53 野生型肿瘤中的差异表达基因可能为化疗耐药的分子机制提供了新的认识。
