Dataset Information

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients.

ABSTRACT:

Background

African American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined for The Cancer Genome Atlas (TCGA) breast cancer patient cohort.

Methods

The systematic differential analysis of mRNA expression integrated with the analysis of clinical outcomes was performed for 1055 samples from the breast invasive carcinoma TCGA PanCancer cohorts. A deep learning fully-convolutional model was used to determine the association between gene expression and tumor features based on breast cancer patient histopathological images.

Results

We found that more than 30% of all protein-coding genes are differentially expressed in White and African American breast cancer patients. We have determined a set of 32 genes whose overexpression in African American patients strongly correlates with decreased survival of African American but not White breast cancer patients. Among those genes, the overexpression of mitogen-activated protein kinase kinase 3 (MKK3) has one of the most dramatic and race-specific negative impacts on the survival of African American patients, specifically with triple-negative breast cancer. We found that MKK3 can promote the TNBC tumorigenesis in African American patients in part by activating of the epithelial-to-mesenchymal transition induced by master regulator MYC.

Conclusions

The poor clinical outcomes in African American women with breast cancer can be associated with the abnormal elevation of individual gene expression. Such genes, including those identified and prioritized in this study, could represent new targets for therapeutic intervention. A strong correlation between MKK3 overexpression, activation of its binding partner and major oncogene MYC, and worsened clinical outcomes suggests the MKK3-MYC protein-protein interaction as a new promising target to reduce racial disparity in breast cancer survival.

SUBMITTER: Yang X

PROVIDER: S-EPMC7465409 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients.

Yang Xuan X Amgad Mohamed M Cooper Lee A D LAD Du Yuhong Y Fu Haian H Ivanov Andrey A AA

Journal of translational medicine 20200901 1

<h4>Background</h4>African American women experience a twofold higher incidence of triple-negative breast cancer (TNBC) and are 40% more likely to die from breast cancer than women of other ethnicities. However, the molecular bases for the survival disparity in breast cancer remain unclear, and no race-specific therapeutic targets have been proposed. To address this knowledge gap, we performed a systematic analysis of the relationship between gene mRNA expression and clinical outcomes determined ...[more]

PMID: 32873298

Similar Datasets

Project description:Although miR-99b is a known suppressive microRNA (miRNA) in several cancers, its role in breast cancer has not been elucidated. In this study, we examined the clinical relevance of miR-99b expression in breast cancer. We analyzed miRNA and mRNA expression and their relationships with clinical parameters in 1,961 breast cancer samples from two independent large cohorts, the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA). Several algorithms, including gene set enrichment analysis (GSEA) and xCell, have been used to investigate biological functions and the tumor microenvironment. High miR-99b expression significantly enriched the mTORC1 signaling gene set in breast cancer (NES = 1.63, FDR = 0.03, and NES = 1.58, FDR = 0.10, in METABRIC and TCGA, respectively). No other mechanisms, including the epithelial mesenchymal transition, NFκB, and TGF-β signaling, were consistently enriched in both cohorts. MiR-99b-high breast cancer was associated with high homologous recombination deficiencies, intratumor heterogeneity, and high rates of mutation and neoantigens. In agreement, miR-99b-high breast cancer was associated with increased cell proliferation, correlating with Nottingham histological grade, and significant enrichment of E2F targets, G2/M checkpoint, and mitotic spindle gene sets consistently in both cohorts (P = 0.01, P < 0.001). High miR-99b levels were also associated with low stromal cell fractions in the tumor microenvironment, including adipocytes, keratinocytes, and lymphatic endothelial cells (P < 0.001). However, in both cohorts, miR-99b expression was not associated with significant infiltration of immune cells, except dendritic cells (P = 0.006, 0.020). Finally, in both cohorts, breast cancer with high miR-99b expression was significantly associated with worse disease-free survival (DSS) and overall survival (OS), particularly in estrogen receptor (ER)-positive/human epidermal growth factor (HER)2-negative breast cancer (DSS hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10-1.51, P < 0.001 in the METABRIC cohort and HR 1.82, 95% CI 1.12-2.98, P = 0.017 in the TCGA cohort). In conclusion, breast cancer with high miR-99b expression was significantly associated with mTORC1 signaling, cell proliferation, and decreased patient survival, particularly in the ER-positive/HER2-negative subtype.

Project description:PIEZO1 plays a crucial role in the human body as a mechanosensory ion channel. It has been demonstrated that PIEZO1 is important in tissue development and regulating many essential physiological processes. Studies have suggested that the PIEZO1 ion channel plays a role in invasion and progression in cancer; elevated levels of PIEZO1 have been correlated with increased migration in breast cancer cells, chemo-resistance and invasion in gastric cancer cells, and increased invasion of osteosarcoma cells. In addition, high PIEZO1 expression levels were correlated with a worse prognosis in glioma patients. On the other hand, studies in lung cancer have attributed high PIEZO1 levels to better patient outcomes. However, the clinical impact of PIEZO1 in breast cancer is not well characterized. Therefore, our goal was to determine the clinical relevance of PIEZO1 in breast cancer. An analysis of breast cancer data from The Cancer Genome Atlas (TCGA) was conducted to investigate PIEZO1 expression levels and correlation to survival, followed by validation in an independent dataset, GSE3494. We also performed gene set enrichment analysis (GSEA) and pathway enrichment analysis. We also analyzed the immune cell composition in breast tumors from TCGA through a CIBERSORT algorithm. Our results demonstrated that the PIEZO1 expression levels are higher in hormone-receptor (HR)-negative than in HR-positive cohorts. High PIEZO1 expression is correlated with a significant decrease in survival in HR-negative cohorts, especially in triple-negative breast cancer (TNBC), suggesting that PIEZO1 could be utilized as a prognostic biomarker in HR-negative breast cancer. GSEA showed that various signaling pathways associated with more invasive phenotypes and resistance to treatments, including epithelial-mesenchymal transition (EMT), hypoxia, and multiple signaling pathways, are enriched in high-PIEZO1 HR-negative tumors. Our results also demonstrated a decrease in CD8+ and CD4+ T cell infiltration in high-PIEZO1 HR-negative tumors. Further investigations are necessary to elucidate the mechanistic roles of PIEZO1 in HR-negative breast cancer.

Project description:People with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, COVID-19, can have neurological problems including headache, anosmia, dysgeusia, altered mental status (AMS), ischemic stroke with or without large vessel occlusion, and Guillen-Barre Syndrome. Louisiana was one of the states hit hardest by the pandemic with just over 57,000 laboratory-confirmed cases of COVID-19 by the end of June 2020. We reviewed the electronic medical records (EMR) of patients hospitalized during the peak of the pandemic, March 1st through March 31st, to document the type and frequency of neurological problems seen in patients with COVID-19 at presentation to the emergency room. Secondary aims were to determine: 1) the frequency of neurological complaints during the hospital stay; 2) whether the presence of any neurological complaint at presentation or any of the individual types of neurological complaints at admission predicted three separate outcomes: death, length of hospital stay, or the need for intubation; and 3) if the presence of any neurological complaint or any of the individual types of neurological complaints developed during hospital stay predicted the previous three outcomes. A large proportion of our sample (80 %) was African American and had hypertension (79 %). Out of 250 patients, 56 (22 %) patients died, and 72 (29 %) patients required intubation. Thirty-four (14 %) had a neurological chief complaint at presentation; the most common neurological chief complaints in the entire sample were altered mental status (AMS) (8 %), headache (2 %), and syncope (2 %). We used a competing risk model to determine whether neurological symptoms at presentation or during hospital stay were predictors of prolonged hospital stay and death. To establish whether neurological symptoms were associated with higher odds of intubation, we used logistic regression. Age was the only significant demographic predictor of death and hospital stay. The HR (95 %CI) for remaining in the hospital for a ten-year increase in age was 1.2, (1.1, 1.3, p < 0.0001), and for death was 1.3, (1.1, 1.5, p < 0.01). There were no demographic characteristics, including age or comorbidities predictive of intubation. Adjusting for age, patients who at presentation had neurological issues as their chief complaint were at significantly increased risk for remaining in the hospital, HR = 1.7, (1.1,2.5, p = 0.0001), and dying, HR = 2.1(1.1,3.8, p = 0.02), compared to patients without any neurological complaint. Of the individual admission complaints, AMS was associated with a significantly prolonged hospital stay, HR = 1.8, (1.0-3.3, p = 0.05). Patients that required dialysis or intubation or had AMS during hospitalization had more extended hospital stays. After adjusting for age, dialysis, and intubation, patients with AMS during hospital stay had a HR of 1.6, (1.1, 2.5, p = 0.01) for remaining in the hospital. Patients who had statistically significant higher odds of requiring intubation were those who presented with any neurological chief complaint, OR = 2.8 (1.3,5.8, p = 0.01), or with headaches OR = 13.3 (2.1,257.0, p = 0.008). Patients with AMS during the hospital stay, as well as those who had seizures, were more likely to need intubation. In the multivariate model, dialysis, OR = 4.9 (2.6,9.4, p < 0.0001), and AMS, OR = 8.8 (3.9,21.2, p < 0.0001), were the only independent predictors of intubation. Neurological complaints at presentation and during the hospital stay are associated with a higher risk of death, prolonged hospital stay, and intubation. More work is needed to determine whether the cause of the neurological complaints was direct CNS involvement by the virus or the other systemic complications of the virus.

Project description:ImportancePeripartum cardiomyopathy (PPCM) disproportionately affects women of African ancestry, but well-powered studies to explore differences in severity of disease and clinical outcomes are lacking.ObjectiveTo compare the clinical characteristics, presentation, and outcomes of PPCM between African American and non-African American women.Design, setting, and participantsThis retrospective cohort study using data from January 1, 1986, through December 31, 2016, performed at the University of Pennsylvania Health System, a tertiary referral center serving a population with a high proportion of African American individuals, included 220 women with PPCM.Main outcomes and measuresDemographic and clinical characteristics and echocardiographic findings at presentation, as well as clinical outcomes including cardiac recovery, time to recovery, cardiac transplant, persistent dysfunction, and death, were compared between African American and non-African American women with PPCM.ResultsA total of 220 women were studied (mean [SD] age at diagnosis, 29.5 [6.6] years). African American women were diagnosed with PPCM at a younger age (27.6 vs 31.7 years, P < .001), were diagnosed with PPCM later in the postpartum period, and were more likely to present with a left ventricular ejection fraction less than 30% compared with non-African American women (48 [56.5%] vs 30 [39.5%], P = .03). African American women were also more likely to worsen after initial diagnosis (30 [35.3%] vs 14 [18.4%], P = .02), were twice as likely to fail to recover (52 [43.0%] vs 24 [24.2%], P = .004), and, when they did recover, recovery took at least twice as long (median, 265 vs 125.5 days; P = .02) despite apparent adequate treatment.Conclusions and relevanceIn a large cohort of women with well-phenotyped PPCM, this study demonstrates a different profile of disease in African American vs non-African American women. Further work is needed to understand to what extent these differences stem from genetic or socioeconomic differences and how treatment of African American patients might be tailored to improve health outcomes.

Dataset Information

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients.

Background

Methods

Results

Conclusions

Publications

High expression of MKK3 is associated with worse clinical outcomes in African American breast cancer patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets