PMID- 28148293 OWN - NLM STAT- MEDLINE DCOM- 20170217 LR - 20230730 IS - 1746-1596 (Electronic) IS - 1746-1596 (Linking) VI - 12 IP - 1 DP - 2017 Feb 2 TI - TP53 mutation-mediated genomic instability induces the evolution of chemoresistance and recurrence in epithelial ovarian cancer. PG - 16 LID - 10.1186/s13000-017-0605-8 [doi] LID - 16 AB - BACKGROUND: 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. 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. METHODS: TP53 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). RESULTS: In 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). CONCLUSIONS: TP53 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. FAU - Zhang, Meiying AU - Zhang M AD - Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. AD - Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. FAU - Zhuang, Guanglei AU - Zhuang G AD - Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. AD - State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. FAU - Sun, Xiangjun AU - Sun X AD - Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. AD - Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. FAU - Shen, Yanying AU - Shen Y AD - Department of Pathology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. FAU - Wang, Wenjing AU - Wang W AD - Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. FAU - Li, Qing AU - Li Q AD - Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. FAU - Di, Wen AU - Di W AD - Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. diwen126@126.com. AD - Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127, China. diwen126@126.com. LA - eng GR - EP-C-14-005/EPA/EPA/United States PT - Journal Article DEP - 20170202 PL - England TA - Diagn Pathol JT - Diagnostic pathology JID - 101251558 RN - 0 (TP53 protein, human) RN - 0 (Tumor Suppressor Protein p53) SB - IM MH - Adult MH - Aged MH - Carcinoma, Ovarian Epithelial MH - DNA Mutational Analysis MH - Drug Resistance, Neoplasm/*genetics MH - Female MH - Flow Cytometry MH - Gene Dosage MH - *Genomic Instability MH - Humans MH - Immunohistochemistry MH - In Situ Hybridization, Fluorescence MH - Kaplan-Meier Estimate MH - Middle Aged MH - Mutation MH - Neoplasm Recurrence, Local/*genetics MH - Neoplasms, Glandular and Epithelial/*genetics/mortality/pathology MH - Ovarian Neoplasms/*genetics/mortality/pathology MH - Tumor Suppressor Protein p53/*genetics PMC - PMC5288946 OTO - NOTNLM OT - Epithelial ovarian cancer OT - Genomic instability OT - MDR1 copy number OT - Recurrence OT - TP53 mutation EDAT- 2017/02/06 06:00 MHDA- 2017/02/18 06:00 PMCR- 2017/02/02 CRDT- 2017/02/03 06:00 PHST- 2016/10/25 00:00 [received] PHST- 2017/01/17 00:00 [accepted] PHST- 2017/02/03 06:00 [entrez] PHST- 2017/02/06 06:00 [pubmed] PHST- 2017/02/18 06:00 [medline] PHST- 2017/02/02 00:00 [pmc-release] AID - 10.1186/s13000-017-0605-8 [pii] AID - 605 [pii] AID - 10.1186/s13000-017-0605-8 [doi] PST - epublish SO - Diagn Pathol. 2017 Feb 2;12(1):16. doi: 10.1186/s13000-017-0605-8.