1. Functional genetic variants of GEN1 predict overall survival of Chinese epithelial ovarian cancer patients.
- Author
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Li, Haoran, Wu, Jiao, Xu, Qing, Pang, Yangyang, Gu, Yanzi, Wang, Mengyun, and Cheng, Xi
- Subjects
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OVARIAN epithelial cancer , *GENETIC variation , *OVERALL survival , *MYELOID-derived suppressor cells , *CANCER patients , *MYELOID differentiation factor 88 , *CELL migration inhibition - Abstract
Background: Inherited variations in DNA double-strand break (DSB) repair pathway are known to influence ovarian cancer occurrence, progression and treatment response. Despite its significance, survival-associated genetic variants within the DSB pathway remain underexplored. Methods: In the present study, we performed a two-phase analysis of 19,290 single-nucleotide polymorphisms (SNPs) in 199 genes in the DSB repair pathway from a genome-wide association study (GWAS) dataset and explored their associations with overall survival (OS) in 1039 Han Chinese epithelial ovarian carcinoma (EOC) patients. After utilizing multivariate Cox regression analysis with bayesian false-discovery probability for multiple test correction, significant genetic variations were identified and subsequently underwent functional prediction and validation. Results: We discovered a significant association between poor overall survival and the functional variant GEN1 rs56070363 C > T (CT + TT vs. TT, adjusted hazard ratio (HR) = 2.50, P < 0.001). And the impact of GEN1 rs56070363 C > T on survival was attributed to its reduced binding affinity to hsa-miR-1287-5p and the resultant upregulation of GEN1 mRNA expression. Overexpression of GEN1 aggregated EOC cell proliferation, invasion and migration presumably by influencing the expression of immune inhibitory factors, thereby elevating the proportion of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and then constructing an immunosuppressive tumor microenvironment. Conclusions: In conclusion, GEN1 rs56070363 variant could serve as a potential predictive biomarker and chemotherapeutic target for improving the survival of EOC patients. Highlights: Inherited variations in DSB repair pathway are known to influence ovarian cancer occurrence, progression and treatment response. In the present study, we performed a two-phase analysis of 19,290 SNPs in 199 genes in the DSB repair pathway among 1,039 ovarian cancer patients. Ultimately, we identified that the poor overall survival was significantly associated with functional variant GEN1 rs56070363 C > T. Further investigations revealed the mechanism underlying this association: the C > T transition resulted in decreased binding affinity to hsa-miR-1287-5p and subsequent upregulation of GEN1 mRNA expression. Overexpression of GEN1 aggregated EOC cell proliferation, invasion and migration presumably by influencing the expression immune inhibitory factors, thereby elevating the proportion of PMN-MDSCs and then constructing an immunosuppressive tumor microenvironment. Our findings thus provide novel molecular targets and a theoretical basis for individualized treatment approaches in ovarian cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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