Abstract A50: Mitochondrial metabolism gene variants are associated with risk and survival in epithelial ovarian cancer (EOC)
2016
Abstracts: AACR Special Conference: Metabolism and Cancer; June 7-10, 2015; Bellevue, WA
Background: Epithelial Ovarian Cancer (EOC) is a lethal gynecologic malignancy. Mitochondria are cellular organelles that regulate energy metabolism and are the primary source of reactive oxygen species (ROS), which damage both the nuclear and mitochondria DNA (mtDNA), contributing to the pathogenesis of EOC. Previously, we identified statistically significant EOC risk associations with 54 single nucleotide polymorphisms (SNPs) from 11 mitochondria-related genes in a study of 1815 EOC cases and 1900 controls. In this replication study we expand our investigation of mitochondrial metabolism genetic variants and associations with EOC risk and overall survival (OS).
Methods: In a discovery set of 3761 EOC cases and 2722 controls, we investigated risk associations in 4200 SNPs from 130 mitochondrial metabolism genes. We genotyped 431 of the most significant SNPs from 86 genes in 14,525 EOC cases and 23,447 controls (of European ancestry) from 43 studies in OCAC using an Illumina Infinium iSelect BeadChip. Risk analyses were conducted using unconditional logistic regression under a log-additive model and adjusted for study site and the first five principal components of population substructure. Both invasive cancers combined and the four main histological subtypes were analyzed. Survival analyses were conducted on the same SNPs using Cox hazards models to estimate hazard ratios (HRs) and 95% CIs considering overall survival in 10,084 cases from 28 OCAC studies. We adjusted for multiple tests using False Discovery Rate q<20%.
Results: The strongest evidence of an association for risk of invasive cancers combined and the serous subtype was SNP rs3096 in the pyridoxamine 5'-phosphate oxidase (PNPO) gene (OR=1.08, p=2.8x10-6). In clear cell carcinoma, the strongest association was a missense coding SNP rs28379632 (Ile421Met) in the MT-CYB gene (OR=4.0, p=0.003). For endometrioid cancer rs9330440 in the UNQ6494 gene was most significant (OR=0.89, p=0.001) while rs10267797 in the dihydrolipoamide dehydrogenase (DLD) gene was most significant in the mucinous subtype (OR=1.15, p=0.004). The strongest association with overall survival was mitochondrial transcription termination factor 1 (MTERF) rs2540571 (HR=0.92, p= 0.00011).
Conclusion: These results suggest that mitochondrial metabolism gene variants appear to be associated with EOC risk and survival.
Citation Format: Ganna Chornokur, Hui-Yi Lin, Alvaro Monteiro, Joellen Schildkraut, Ellen L. Goode, Paul DP Pharoah, Simon A. Gayther, Susan Ramus, Thomas A. Sellers, Catherine M. Phelan. Mitochondrial metabolism gene variants are associated with risk and survival in epithelial ovarian cancer (EOC). [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A50.
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