Integrating cell cycle score for precise risk stratification in ovarian cancer

Background: Ovarian cancer (OC) is a highly heterogeneous disease, of which the mesenchymal subtype has the worst prognosis, is the most aggressive, and has the highest drug resistance. The cell cycle pathway plays a vital role in ovarian cancer development and progression. We aimed to screen the key cell cycle genes that regulated the mesenchymal subtype and construct a robust signature for ovarian cancer risk stratification. Methods: Network inference was conducted by integrating the differentially expressed cell cycle signature genes and target genes between the mesenchymal and non-mesenchymal subtypes of ovarian cancer and identifying the dominant cell cycle signature genes. Results: Network analysis revealed that two cell cycle signature genes (POLA2 and KIF20B) predominantly regulated the mesenchymal modalities of OC and used to construct a prognostic model, termed the Cell Cycle Prognostic Signature of Ovarian Cancer (CCPOC). The CCPOC-high patients showed an unfavorable prognosis in the GSE26712 cohort, consistent with the results in the seven public validation cohorts and one independent internal cohort (BL-OC cohort, qRT-PCR, n = 51). Functional analysis, drug-sensitive analysis, and survival analysis showed that CCPOC-low patients were related to strengthened tumor immunogenicity and sensitive to the anti-PD-1/PD-L1 response rate in pan-cancer (r = -0.47, OC excluded), which indicated that CCPOC-low patients may be more sensitive to anti-PD-1/PD-L1. Conclusion: We constructed and validated a subtype-specific, cell cycle-based prognostic signature for ovarian cancer, which has great potential for predicting the response of anti-PD-1/PD-L1.