Article Database

Identifying disparities in germline and somatic testing in patients with ovarian cancer in a university health system

Abstract:

Objective: Germline mutations are present in approximately 25% of patients with epithelial ovarian cancers, and testing is recommended for these patients. Somatic mutations have been estimated to be 5–7%. Our objective was to assess the disparities in germline and somatic testing for patients treated at a comprehensive cancer center and a safety net hospital.

Identifying disparities in germline and somatic testing for ovarian cancer

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Identification of abrogated pathways in fallopian tube epithelium from BRCA1 mutation carriers

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The discovery of occult invasive and intra‐epithelial tubal carcinomas in BRCA1 mutation carriers undergoing prophylactic surgery has implicated the fallopian tube epithelium as the source of serous cancer. However, little is known of the early molecular events of serous oncogenesis, or why cancers in BRCA1 mutation carriers are found preferentially in tissues which are responsive to reproductive hormones. We hypothesize that molecular alterations present in morphologically normal tubal epithelium from BRCA1 heterozygotes reflect the earliest events in serous carcinogenesis and may be markers of increased cancer risk as well as targets for risk reduction. Genetic profiling of microdissected tubal epithelium from histologically normal BRCA1 mutation carriers and controls was performed. We sought to define a signature which differentiated BRCA1 mutant tubal epithelium from women with low risk of developing ovarian cancer. Molecular differences between the follicular and luteal phases were prominent and, by using filtering techniques and a two‐way ANOVA without a False Discovery Rate correction, we identified 440 probe sets with a more than two‐fold change in gene expression related to BRCA1 mutation status. Using gene ontology and known associations to cancer pathways, we selected five genes for further analysis by qPCR and immunohistochemistry, and were able to demonstrate statistically significant differentiation of BRCA1 and control cases in an independent set of cases. The altered expression profiles in histologically normal tubal epithelium from BRCA1 heterozygotes suggest that these cells may respond differently to microenvironmental stresses.

Human Papillomavirus Distribution Across the African Diaspora: A Cross-Sectional Analysis

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Not available at this time

Hormonal receptor expression and clinical outcome in ovarian high-grade serous carcinoma

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Objective: Ovarian high-grade serous carcinoma (HGSC) is genetically unstable and rapidly growing and diagnosed at advanced stages. Immunohistochemical profiles have demonstrated differential expression of estrogen receptor alpha (ER) and progesterone receptor (PR) in HGSC. Our objective was to investigate the ER and PR in HGSC and its precursor lesions and to assess the influence of ER/PR subtype on OS and ER/PR-driven pathogenesis in HGSC.

Functional immobilization of signaling proteins enables control of stem cell fate

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Fallopian tube cells from high-risk women have altered adipokine signaling

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Objective: Recent evidence has implicated the fallopian tube epithelium (FTE) as the major site of origin for high-grade serous ovarian cancer (HGSC). Adipose tissue secretes inflammatory cytokines, fatty acids, glucose, and hormones, creating an environment that promotes cancer invasion and metastasis. The objective was to understand the role of adipokines in DNA damage in ovarian cancer pathogenesis.

Exploring racial disparities of actionable mutations in gynecologic cancers

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Endometrial cancer outcomes among non-Hispanic US born and Caribbean born black women

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Purpose: Data on endometrial cancer outcomes among immigrant women in the USA are lacking. The objective was to determine the effect of Caribbean nativity on outcomes in black women with endometrial cancer compared with women born in the USA, with attention paid to the effects of tumor grade, sociodemographic factors, and treatment approaches.

Methods: A review of the institutional cancer registry was performed to identify black, non-Hispanic women with known nativity and treated for endometrial cancer between 2001 and 2017. Sociodemographic, treatment, and outcomes data were collected. Analyses were done using the χ² test, Cox proportional hazards models, and the Kaplan-Meier method, with significance set at P<0.05.

Results: 195 women were included in the analysis. High grade histologies were present in a large proportion of both US born (64.5%) and Caribbean born (72.2%) patients. Compared with US born women, those of Caribbean nativity were more likely to be non-smokers (P=0.01) and be uninsured (P=0.03). Caribbean born women had more cases of stage III disease (27.8% versus 12.5%, P<0.01), while carcinosarcoma was more common in US born black women (23.6% versus 10.6%, P=0.05). Caribbean nativity trended towards improvement in overall survival (hazard ratio (HR) 0.65 (0.40-1.07)). Radiation (HR 0.53 (0.29-1.00)) was associated with improved survival while advanced stage (HR 3.81 (2.20-6.57)) and high grade histology (HR 2.34 (1.17-4.72)) were predictive of worse survival.

Conclusions: The prevalence of high grade endometrial cancer histologies among black women of Caribbean nativity is higher than previously reported. Caribbean nativity may be associated with improved overall survival although additional study is warranted.

Embryonic Stem Cell Technologies for Understanding the Complexity of VEGF Function

Abstract:

Newly established F1 hybrid Embryonic Stem cells allow the production of ES cell-derived animals at a high enough efficiency to directly make ES cell based genetics feasible. An F1 hybrid ES cell line, G4 was used to generate transgenic over-expressing cell lines. The consequence of the expression of a panel of transgenes was assessed directly from ES cell-derived embryos produced by the tetraploid complementation assay. The generation of ES cell-derived embryos/animals was very efficient. A sufficient number of mutants for initial phenotypic analyses was derived only a few weeks after the establishment of the cell lines. The genes used in the study had either angiogenic/vasculogenic, anti-angiogenic or unknown properties. Of these transgenic mouse lines VEGF-A and Flt-Fc were used to further elucidate the effects of altered VEGF signaling on cell fate decisions in embryonic development and ES differentiation in two experimental systems. A. Early but transient Flk-1 activation led to enhanced generation of blood progenitors, whereas continuous activation of Flk-1 abolished this effect and enhanced endothelial cell generation. Ex vivo analysis of cells derived from E7.5 embryos demonstrated that sFlt-1-mediated control of Flk-1 activity also impacted the fate of hematopoietic and endothelial cells. The Flt-1-Fc transgenic mouse model was used to alter Flk-1 activation in vivo and show the relevance of the in vitro observations. These results demonstrate that sFlt-1 regulates Flk-1 activation in an oxygen responsive manner. Inhibition of Flk-1 activation by sFlt-1 increases the specification of hemangioblasts to blood cells consistent with a VEGF-independent default mechanism. B. Ubiquitous over-expression of VEGF164 isoform led to E8.75 embryonic lethality. The primary cause of lethality was the failure to form an organized cardiovascular system, which was manifested in three ways: the absence of yolk sac blood vessels, the lack of embryonic-maternal circulation due to the failure of allantochorionic fusion and improper cardiac function. The described phenotypes suggest that VEGF does not inhibit embryonic or extra-embryonic mesoderm formation at gastrulation but perturbs the balance amongst the mesodermal components.