Abstract
BackgroundGenomic instability caused by mutation of the checkpoint molecule TP53 may endow cancer cells with the ability to undergo genomic evolution to survive stress and treatment. We attempted to gain insight into the potential contribution of ovarian cancer genomic instability resulted from TP53 mutation to the aberrant expression of multidrug resistance gene MDR1.MethodsTP53 mutation status was assessed by performing nucleotide sequencing and immunohistochemistry. Ovarian cancer cell DNA ploidy was determined using Feulgen-stained smears or flow cytometry. DNA copy number was analyzed by performing fluorescence in situ hybridization (FISH).ResultsIn addition to performing nucleotide sequencing for 5 cases of ovarian cancer, TP53 mutations were analyzed via immunohistochemical staining for P53. Both intensive P53 immunohistochemical staining and complete absence of signal were associated with the occurrence of TP53 mutations. HE staining and the quantification of DNA content indicated a significantly higher proportion of polyploidy and aneuploidy cells in the TP53 mutant group than in the wild-type group (p < 0.05). Moreover, in 161 epithelial ovarian cancer patients, multivariate logistic analysis identified late FIGO (International Federation of Gynecology and Obstetrics) stage, serous histotype, G3 grade and TP53 mutation as independent risk factors for ovarian cancer recurrence. In relapse patients, the proportion of chemoresistant cases in the TP53 wild-type group was significantly lower than in the mutant group (63.6% vs. 91.8%, p < 0.05). FISH results revealed a higher percentage of cells with >6 MDR1 copies and chromosome 7 amplication in the TP53 mutant group than in the wild-type group [11.7 ± 2.3% vs. 3.0 ± 0.7% and 2.1 ± 0.7% vs. 0.3 ± 0.05%, (p < 0.05), respectively]. And we observed a specific increase of MDR1 and chromosome 7 copy numbers in the TP53 mutant group upon disease regression (p < 0.01).ConclusionsTP53 mutation-associated genomic instability may promote chromosome 7 accumulation and MDR1 amplification during ovarian cancer chemoresistance and recurrence. Our findings lay the foundation for the development of promising chemotherapeutic approaches to treat aggressive and recurrent ovarian cancer.
Highlights
Genomic instability caused by mutation of the checkpoint molecule Tumor protein P53 (TP53) may endow cancer cells with the ability to undergo genomic evolution to survive stress and treatment
During chemotherapy, cancer cells undergo genomic changes to adapt to chemotherapeutics, a phenomenon referred to as single- or multi-drug chemoresistance [5, 6]
The absence or mutation of TP53 promotes two types of genomic instability, chromosomal and amplification instability, resulting in daughter cells that exhibit large amount of aneuploidy or abnormal chromosomes [11, 12]. Other related genes, such as pyruvate kinase isoform M2 (PKM2), breast cancer 1 (BRCA1) and homolog of the Schizosaccharomyces pombe cell cycle checkpoint gene (RAD17), are affected by genomic instability caused by TP53 gene mutation, resulting in an improved microenvironment that facilitates the ability of a cell to endure [13, 14]
Summary
Genomic instability caused by mutation of the checkpoint molecule TP53 may endow cancer cells with the ability to undergo genomic evolution to survive stress and treatment. Genomic evolution is one of the basic features of human cancers and endows malignant cells with the ability to survive and tolerate rigorous microenvironments, such as anoxia, ischemia and starvation, as well as resist attacks from immune cells [1,2,3,4]. Other related genes, such as pyruvate kinase isoform M2 (PKM2), breast cancer 1 (BRCA1) and homolog of the Schizosaccharomyces pombe cell cycle checkpoint gene (RAD17), are affected by genomic instability caused by TP53 gene mutation, resulting in an improved microenvironment that facilitates the ability of a cell to endure [13, 14]. In a recent rigorous reassessement, 100% of high-grade serous ovarian cancers exhibited TP53 mutations [17]
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