Functional genetic variants of GEN1 predict overall survival of Chinese epithelial ovarian cancer patients.

Autor: Li H; Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China., Wu J; Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China., Xu Q; Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China., Pang Y; Department of Urology, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, China., Gu Y; Department of Biobank, Fudan University Shanghai Cancer Center, Shanghai, China., Wang M; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China. wangmengyun@fudan.edu.cn.; Cancer Institute, Fudan University Shanghai Cancer Center, 270 Dong'an Road, Shanghai, 200032, China. wangmengyun@fudan.edu.cn., Cheng X; Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. cheng_xi1@hotmail.com.; Department of Oncology, Shanghai Medical College, Fudan University, 270 Dong'an Road, Shanghai, 200032, China. cheng_xi1@hotmail.com.; Department of Gynecological Oncology, Minhang Branch, Fudan University Shanghai Cancer Center, Shanghai, China. cheng_xi1@hotmail.com.
Jazyk: angličtina
Zdroj: Journal of translational medicine [J Transl Med] 2024 Jun 18; Vol. 22 (1), pp. 577. Date of Electronic Publication: 2024 Jun 18.
DOI: 10.1186/s12967-024-05236-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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