Methylomic and transcriptomic differences in treatment-naïve profiles among black and non-Hispanic white (NHW) women [Methylation]
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ABSTRACT: Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy, with the high-grade serous ovarian cancer subtype (HGSOC) accounting for a significant proportion of cases. Despite platinum-based chemotherapies being the primary treatment for EOC, HGSOC displays high resistance to these therapies. Black women have the highest mortality/incidence ratio of all ethnic groups, and recent studies suggest significant genetic and epigenetic differences between black and non-Hispanic white women who are treatment naïve. This study aims to explore immunogenic differences and hypermethylation phenotype in black women that may contribute to poorer outcomes within this patient group. We collected primary tumor samples from 36 black and 31 non-Hispanic white (NHW) treatment-naïve patients via biopsy and performed methylomic and transcriptomic analyses. Our analysis revealed significant differences in gene expression and methylation between black and NHW patients. Among the differentially expressed genes, we found significant pathway enrichment within p53/apoptosis signaling pathway and cholesterol/lipid modulation. Additionally, we observed mild hypermethylation in black patients vs. the NHW cohort. Furthermore, we discovered differences in the proportion of important immune cell types between the two groups, with CD8+ T-cells and CD4+ memory-resting T-cells being significantly higher proportionally in black patients. In conclusion, our study identified significant differential expression between black and NHW patient groups, as well as mild hypermethylation and differences in the proportion of important immune cell types. These findings provide further insights into the biological mechanisms underlying the disparities in outcomes between black and NHW patients with EOC. Further exploration of the contribution of these differences to clinical outcomes and treatment response in black women is warranted.
Project description:Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy, with the high-grade serous ovarian cancer subtype (HGSOC) accounting for a significant proportion of cases. Despite platinum-based chemotherapies being the primary treatment for EOC, HGSOC displays high resistance to these therapies. Black women have the highest mortality/incidence ratio of all ethnic groups, and recent studies suggest significant genetic and epigenetic differences between black and non-Hispanic white women who are treatment naïve. This study aims to explore immunogenic differences and hypermethylation phenotype in black women that may contribute to poorer outcomes within this patient group. We collected primary tumor samples from 36 black and 31 non-Hispanic white (NHW) treatment-naïve patients via biopsy and performed methylomic and transcriptomic analyses. Our analysis revealed significant differences in gene expression and methylation between black and NHW patients. Among the differentially expressed genes, we found significant pathway enrichment within p53/apoptosis signaling pathway and cholesterol/lipid modulation. Additionally, we observed mild hypermethylation in black patients vs. the NHW cohort. Furthermore, we discovered differences in the proportion of important immune cell types between the two groups, with CD8+ T-cells and CD4+ memory-resting T-cells being significantly higher proportionally in black patients. In conclusion, our study identified significant differential expression between black and NHW patient groups, as well as mild hypermethylation and differences in the proportion of important immune cell types. These findings provide further insights into the biological mechanisms underlying the disparities in outcomes between black and NHW patients with EOC. Further exploration of the contribution of these differences to clinical outcomes and treatment response in black women is warranted.
Project description:Background: Differences in breast cancer outcomes according to race/ethnicity have been reported. Hispanic/Latino (H/L) populations are a genetically admixed and heterogeneous group, with variable fractions of European, Indigenous American and African ancestries. Some studies suggest that breast cancer-specific mortality is higher in U.S. Hispanic/Latinas compared to non-Hispanic Whites (NHW) even after adjustment for socioeconomic status and education. The molecular profile of breast cancer has been widely described in NHWs but equivalent knowledge is lacking in Hispanic/Latinas. We have previously reported that the most prevalent breast cancer intrinsic subtype in Colombian H/L women was Luminal B as defined by surrogate St. Gallen 2013 criteria. In this study we explored ancestry-associated differences in molecular profiles of Luminal B tumors among these highly admixed women. Methods: We performed whole-transcriptome RNA-seq analysis in 42 Luminal tumors (21 Luminal A and 21 Luminal B) from Colombian women. Genetic ancestry was estimated from a panel of 80 ancestry-informative markers (AIM). We categorized patients according to Luminal subtype and to the proportion of European and Indigenous American ancestry and performed differential expression analysis comparing Luminal B against Luminal A tumors according to the assigned ancestry groups. Results: We found 5 genes potentially modulated by genetic ancestry: ERBB2 (Fold Change = 2.367, padj < 0.01), GRB7 (Fold Change = 2.327, padj < 0.01), GSDMB (Fold Change = 1.723, padj < 0.01, MIEN1 (Fold Change = 2.195, padj < 0.01 and ONECUT2 (Fold Change = 2.204, padj < 0.01). In the replication set we found a statistical significant association between European ancestry fraction and the expression levels of ERBB2 (p = 0.02, B = 2.49) and ONECUT2 (p = 0.04, B = -4.87). We also observed statistical significant associations for ERBB2 expression with Indigenous American ancestry (p < 0.001, B = 3.82). This association was not biased by the distribution of HER2+ tumors among the groups analyzed. Conclusions: Our results suggest that genetic ancestry in Hispanic/Latina women might modify ERBB2 gene expression in Luminal tumors. Further analyses are needed to confirm these findings and explore their prognostic value.
Project description:We conducted an epigenome-wide association study (EWAS) to evaluate global DNA methylation in EOC. In a retrospective cohort of 30 HGSOC subtype primary ovarian cancers, we observed that global DNA hypermethylation was preferentially associated with recurrent HGSOC. A total of 2,969 DMPs corresponding to 1,471 genes were involved in olfactory transduction, and calcium and cAMP signaling.
Project description:Hepatocellular carcinoma (HCC) is a highly fatal disease with mortality running parallel to its incidence. For HCC patients, there is a statistically significant increase in incidence and mortality and a decrease in 5-year survival rates in African American (AA)/Black patients compared to non-Hispanic (white) patients. There is a gap of knowledge in our understanding of the molecular mechanism underlying the HCC racial disparity between AA/Black and white patients. To address this issue, we analyzed existing RNA-sequencing (RNA-seq) data from HCC patients in the TCGA database, and performed RNA-seq in 14 white and 19 AA/Black HCC patients from Virginia Commonwealth University. In both analysis the only pathway which showed statistically significant activation in AA/Black patients, compared to white patients, was type I interferon (IFN-I) signaling. A four gene signature of IFN-I-stimulated genes (ISGs) showed increased expression in AA/Black HCC tumors compared to their white counterparts. HCC is a disease of chronic inflammation and IFN-I function as a pro-inflammatory and immunosuppressive cytokine. These findings suggest a potential role of IFN-I in conferring disparity in AA/Black HCC patients.
Project description:Analyzing the US Center for Disease Control’s National Health and Nutrition Examination Survey chemical biomarker data, we identified a suite of toxicants, including metals, pesticides, and personal care product compounds, to which non-Hispanic Black women are disproportionately exposed. To characterize the impact of these toxicants on breast cancer pathways, we performed high throughput transcriptomic analysis of toxicant exposed breast cells.
Project description:SUMMARY Non-Hispanic Black/African American (Black/AA) men in the United States have disproportionally higher incidence and mortality rates of lung cancer compared to non-Hispanic White (NHW) men. Biological factors are believed to play critical roles in driving the disparities. Nevertheless, large-scale genomic studies fail to identify significant somatic differences in lung cancer driver genes contributing to the disparities. Elevated expression of protein arginine methyltransferases (PRMTs) correlating with poorer prognosis is observed in many cancer types. Here, we observed a higher PRMT6 expression in lung cancer of Black/AA men compared to NHW men. PRMT6 formed a heteromer complex with PRMT1 to catalyze arginine methylation of interleukin enhancer-binding factor 2 essential for cell proliferation. Disrupting PRMT1/PRMT6 heteromer complex by a competitive peptide reduced cell proliferation in non-small cell lung cancer cell lines and lung cancer patient-derived organoids. This work implicates that PRMT1/PRMT6 heteromer complex contributes to poorer lung cancer outcomes in Black/AA men vs. NHW men that could serve as a target to eliminate cancer health disparities.
Project description:Ovarian cancer is one of the most common gynecologic malignancies globally, which is a significant cause of morbidity and mortality, accounting for 207,252 new deaths each year. The 5-year survival rate of this cancer is reported to be 26-42% and is often diagnosed in an advanced stage. Epithelial ovarian cancer (EOC) is a heterogeneous disease that comprises various histological subtypes. Of them, high-grade serous ovarian cancer (HGSOC) is the most common cancer subtype (70-80%), which is highly aggressive and grows rapidly. Despite the initial success observed with cytoreductive surgery and platinum-based chemotherapy, over 75% of HGSOC patients experience relapse following completion of first-line therapy. The challenge of tailoring therapeutic interventions to control progressive disease is compounded by the inherent cellular heterogeneity and genomic instability characteristic of HGSOC. While platinum chemotherapy remains the cornerstone of contemporary treatment, the grim reality persists that a majority of EOC patients develop chemotherapy resistance, resulting in a five-year survival rate of less than 50%. Numerous ovarian cancer studies have underscored the prognostic significance of factors such as age at diagnosis, disease stage, grade, histology, residual disease post-surgery, and disease recurrence. The genetic predisposition towards EOC indicates that high-grade HGSC exhibits significant chromosomal instability and carries mutations in the tumor protein 53 (TP53) gene, as well as mutations in the breast cancer genes BRCA1/2. Molecular markers like BRCA1/2 mutations and homologous repair deficiency in HGSOC have been validated as predictive of response to platinum therapy and poly-ADP polymerase (PARP) inhibitors. Furthermore, recent research has shed light on the prognostic potential of immune cell populations infiltrating ovarian tumor tissue. The Cancer Genome Atlas (TCGA) and other genomic studies of HGSOC have conducted extensive genomic and transcriptomic analyses of HGSOC to delineate its genomic landscape and facilitate the development of targeted therapies for this highly lethal malignancy. Key findings from previous studies include the prevalent mutation of TP53 genes, frequent and widespread DNA copy number alterations, identification of transcriptional signatures associated with clinical outcome and molecular subtype, and diverse mechanisms of BRCA1/2 inactivation. However, most studies have focused on HGSOC of white populations, and there is limited comprehensive molecular characterization of East Asian HGSOC, including those from Korea. In this study, we aimed to discern clinical and molecular factors distinguishing 123 HGSOC patients from the Korean population through an integrated analysis of clinical features, germline variants, somatic genomic alterations, and the tumor immune microenvironment.
Project description:Epithelial ovarian cancer (EOC) is the most lethal gynecological tumor in developed countries and is characterized by high biological and molecular heterogeneity. High-grade serous ovarian carcinoma (HGSOC) is the most frequent and intractable form of the disease, mainly due to its rapid dissemination into the abdominal cavity, a process that is tightly linked to peritoneal ascites. Despite several studies provided insights into the genetic and epigenetic alterations relevant in EOC, the precise molecular alterations involved in tumor onset and progression remain largely unknown. Here we provide an experimental framework to perform a comprehensive investigation of molecular alterations relevant in HGSOC and ovarian cancer stem cells (OCSC) biology. We relied on a well characterized experimental set derived from human HGSOC-associated ascites and consisting of primary tumor cells, OCSC-enriched spheroids and serially propagated patient-derived xenografts, in order to define genetic and transcriptional signatures associated to specific HGSOC evolutionary trajectories. Such signatures exhibited prognostic value in a large cohort of HGSOC patients and allowed to define PI3K signaling as a novel vulnerability in OCSCs. Thus, our approach proved effective for the identification of druggable targets in HGSOC ascites, which is a major player in relapse and poor prognosis.