Chornokur, Ganna

Abstract 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.

ABSTRACTEpithelial‐mesenchymal transition (EMT) is a process whereby epithelial cells assume mesenchymal characteristics to facilitate cancer metastasis. However, EMT also contributes to the initiation and development of primary tumors. Prior studies that explored the hypothesis that EMT gene variants contribute to epithelial ovarian carcinoma (EOC) risk have been based on small sample sizes and none have sought replication in an independent population. We screened 15,816 single‐nucleotide polymorphisms (SNPs) in 296 genes in a discovery phase using data from a genome‐wide association study of EOC among women of European ancestry (1,947 cases and 2,009 controls) and identified 793 variants in 278 EMT‐related genes that were nominally (P < 0.05) associated with invasive EOC. These SNPs were then genotyped in a larger study of 14,525 invasive‐cancer patients and 23,447 controls. A P‐value <0.05 and a false discovery rate (FDR) <0.2 were considered statistically significant. In the larger dataset, GPC6/GPC5 rs17702471 was associated with the endometrioid subtype among Caucasians (odds ratio (OR) = 1.16, 95% CI = 1.07–1.25, P = 0.0003, FDR = 0.19), whereas F8 rs7053448 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), F8 rs7058826 (OR = 1.69, 95% CI = 1.27–2.24, P = 0.0003, FDR = 0.12), and CAPN13 rs1983383 (OR = 0.79, 95% CI = 0.69–0.90, P = 0.0005, FDR = 0.12) were associated with combined invasive EOC among Asians. In silico functional analyses revealed that GPC6/GPC5 rs17702471 coincided with DNA regulatory elements. These results suggest that EMT gene variants do not appear to play a significant role in the susceptibility to EOC.

Abstract Background. Transmembrane transport (GO:0055085) is the process whereby a solute/hormone/ion/iron is transported from one side of a membrane to the other. Disruption of these processes leads to defects in homeostasis which contributes to cancer risk. We hypothesized that germline single nucleotide polymorphisms (SNPs) in the cellular transport genes are associated with EOC risk and histopathology subtype. Methods. We genotyped 305 SNPs from 120 cellular transport related genes in 14,525 cases and 23,448 controls of European ancestry, 387 African, and 2,388 Asian ancestries from 43 studies in the Ovarian Cancer Association Consortium (OCAC). A custom Illumina iSelect designed for the Collaborative Oncological Gene-environment Study (COGS) was used. For women of European ancestry, both invasive cancers combined and the four main histological subtypes (serous (n=8,369), mucinous (n=943), endometroid (n=2,067) and clear cell (n=1,024) carcinoma) were analyzed, while for women of African and Asian ancestry only the serous subtype was analyzed adjusting for study site and first 5 principal components. Odds ratios and 95% confidence intervals were calculated using unconditional logistic regression. We fitted a log-additive genetic model. Results. In women of European ancestry, the strongest evidence of an association for all invasive EOCs was the iron transport gene, HEPH rs17216603 (OR=0.85, 95%CI=0.78-0.93, P=2.8x10−4), which was also the most significant association for serous histological subtype (OR=0.81, 95%CI=0.73-0.91, P=2.0x10−4). For endometrioid EOC, the strongest association was observed in the glucuronidation gene, UGT1A5 rs11563251 (OR=0.82, 95%CI=0.73-0.92, P=6.6x10−4). For clear cell and mucinous EOC, the thyroid hormone transport protein, SERPINA7 rs1804495 showed the strongest associations (OR=1.06, 95%CI=1.06-1.38, P=0.0041) and (OR=0.85, 95%CI=0.73-0.98, P=0.0407), respectively. For women of African ancestry, the strongest association for serous EOC was the glutathione conjugation gene, MGST rs6488840 (OR=0.55, 95%CI=0.37-0.82, P=0.0035). This SNP was not significant in women of European or Asian ancestry. In women of Asian ancestry, the HEPH rs17216603 (OR=1.45, 95%CI=1.15-1.83, P=0.0019) demonstrated the strongest association, although the directionality of risk was reversed compared to European women. Conclusions. Our results suggest that variation in transmembrane transport genes may influence EOC risk and histopathologic subtype in women of European, African and Asian ancestries, highlighting the differences in the disease etiology across populations. Additional epidemiological and functional studies are warranted to elucidate translational and clinical utility of these associations. Citation Format: Ganna Chornokur, Jonathan Tyrer, Hui-Yi Lin, Gang Han, Xiaotao Qu, Chen Zhihua, Ya-Yu Tsai, Ellen L. Goode, Julie M. Cunningham, Edwin Iversen, Susan J. Ramus, Andrew Berchuk, Joellen M. Schildkraut, Alvaro Monteiro, Simon A. Gayther, Steven A. Narod, Paul Pharoah, Thomas A. Sellers, Catherine M. Phelan. Variation in transmembrane transport genes influence epithelial ovarian cancer risk and histopathologic subtype. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3644. doi:10.1158/1538-7445.AM2013-3644