A potential mutation-defined POLE/MMR/TP53 group classifications to stratify BRCA wild type epithelial ovarian cancer

BACKGROUND: TCGA molecular classification has prognostic value in endometrial cancer, but its application in epithelial ovarian cancer is not clear. METHODS: We investigated the somatic mutations of POLE, MMR (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2) and TP53, in 181 BRCA wild type EOC patients. RESULTS: The patterns were different in histology [ serous vs. endometrioid vs. clear cell (POLEmut: 0% vs. 2.8% vs. 0%, MMRmut: 6.4% vs. 22.2% vs. 11.9%, TP53mut: 75.7% vs. 16.7% vs. 4.5%, NSMP: 17.9% vs. 58.3% vs. 83.6%, p < 0.001)]; FIGO stage [early vs. advanced (POLEmut: 1.4% vs. 0%, MMRmut: 11.3% vs. 11.8%, TP53mut: 9.8% vs. 55.5%, NSMP: 77.5% vs. 32.7%, p < 0.001)]; tumor grade [low vs. high (POLEmut: 3.8% vs. 0%, MMRmut: 19.2% vs. 10.3%, TP53mut: 11.5% vs. 41.9%, NSMP: 65.5% vs. 47.8%, p = 0.002)]; tumor recurrence [no vs. yes (POLEmut: 1.4% vs. 0%, MMRmut: 11.3% vs. 11.9%, TP53mut: 21.1% vs. 47.7%, NSMP: 66.2% vs. 40.4%, p = 0.002)] and tumor-related death [no vs. yes (POLEmut: 1.0% vs. 0%, MMRmut: 9.2% vs. 14.5%, TP53mut: 25.5% vs. 51.8%, NSMP: 64.3% vs. 33.7%, p < 0.001)]. There was difference in median disease-free survival [months (POLEmut: not reached, MMRmut: 12.5, TP53mut: 8.5, NSMP: 36.5; p = 0.002)] and overall survival [months (POLEmut: not reached, MMRmut: 41, TP53mut: 47, NSMP: not reached; p = 0.008)]. In multivariate regression analysis, R0 resection (HR: 0.54 [0.32-0.90], p < 0.001) was important prognostic factor of tumor recurrence. Platinum partial sensitive response (HR: 9.27 [3.73-23.01], p < 0.001) and platinum resistant response (HR: 26.29 [11.75-58.82], p < 0.001) were important prognostic factors of tumor-related death. CONCLUSIONS: The pattern of mutation-defined POLE/MMR/TP53 group classifications varied in histological subtypes, FIGO stage and clinical outcomes in BRCA wild type EOC. BRCA wild type EOC patients with POLEmut or NSMP had favorable survival than those with MMRmut or TP53mut. The panel could be a potential marker for EOC patients.