Abstract 6068: Methylomic, transcriptomic and immune profiles of high grade serous ovarian cancer among Black and non-Hispanic White women

Abstract

Abstract Background: Ovarian cancer (OC) is the most lethal gynecological malignancy. There remains a significant difference in outcomes among black women, whose mortality/incidence ratio is 0.68 - the highest among all ethnic groups. Little is known about racially-defined biological key determinants of OC disparity. We recently characterized transcriptomic and methylomic profiles of high grade serous ovarian tumors (HGSOC) from black vs. non-Hispanic white women (NHW) to understand the observed disparity in survival. Methods: Nucleic acids were extracted from treatment-naïve HGSOC specimens (30 black and 26 NHW) and used for DNA methylation (EPIC array) and RNA-sequencing. Differential expression was performed using EBseq; pathway enrichment was performed using Enrichr. TIMER was used to deconvolute immune cell infiltration based on RNA-seq results, and multiplex immunohistochemistry (mIHC) was used for validation. Top differentially expressed genes (DEGs) were validated by qRT-PCR and studied functionally. Results: 191 and 825 genes were up- and down-regulated, respectively, in HGSOC tumors from black vs. NHW women (FDR-adjusted p-value < 0.10). Significantly enriched pathways among these DEGs included multiple classes of GPCRs - Class A, Monoamine GPCRs, and Peptide GPCRs. Among DEGs, calmodulin like-5 gene CALML5, involved in GPCR signaling, was significantly downregulated in tumors from black patients (0.086 fold-change). CALML5 downregulation in tumors from black vs. NHW women was validated by qRT-PCR. CALML5 knockdown by using shRNA disrupted colony and tumor sphere formation (p<0.05). Analysis using TIMER predicted that CD8+ and CD4+ memory-resting T-cells were enriched in tumors from black patients. mIHC validated increased infiltration by CD3+CD4+ and CD4+FOXP3+ lymphocytes in humors from black women, as well as increased expression of PD-L1, supporting an immunosuppressive phenotype. Global, modest hypermethylation was discovered in tumors from black vs. NHW patients: 47 CpGs were hypermethylated (FDR-adjusted p-value < 0.10) and 19 regions were differentially methylated between the two groups. Conclusions: We identified significant transcriptomic and modest methylation differences in HGSOC tumors from black and NHW patients. Pathway enrichment within GPCR-signaling was observed and an immunosuppressive phenotype was identified. Further exploration of the contribution of these differences to clinical outcomes and treatment response in black women is needed. Citation Format: Hao Huang, Russell Keathley, Ping Xie, JianJun Wei, Ernst Lengyel, Bin Zhang, Daniela Matei. Methylomic, transcriptomic and immune profiles of high grade serous ovarian cancer among Black and non-Hispanic White women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6068.