Background
Breast cancer survival is improving due to early detection and treatment advances. However, racial/ethnic differences in tumor biology, stage, and mortality remain. The objective of this ...study was to analyze presumed disparities at a local level.
Methods
Breast cancer patients at a county hospital and private hospital from 2010 to 2012 were retrospectively reviewed. Demographic, clinical, pathologic, and surgical data were collected. Comparisons were made between hospital cohorts and between racial/ethnic groups from both hospitals combined.
Results
754 patients were included (322 from county hospital and 432 from private hospital). All patients were female. The median age was 54 years at county hospital and 60 years at private hospital (P < .0001). Racial/ethnic minorities comprised 85% of county hospital patients vs. 12% of private hospital patients (P < .0001). County hospital patients had a higher grade, clinical/pathologic stage, HER2-positive rate, and mastectomy rate. Compared to other racial/ethnic groups, non-Hispanic white women were more likely to have lower grade and ER-positive tumors. Hispanic/Latina women were younger and were more likely to have HER2-positive tumors. Both Hispanic/Latina and non-Hispanic black women presented at higher clinical stages and were more likely to undergo neoadjuvant chemotherapy and mastectomy.
Discussion
At county hospital compared to private hospital, the proportion of racial/ethnic minorities was higher, and patients presented at younger ages with more aggressive tumors and more advanced disease. The racial/ethnic disparities that were identified locally are largely consistent with those identified in national database studies. These marked differences at hospitals within a diverse city highlight the need for further research into the disparities.
Esophageal squamous cell carcinoma (ESCC) is a cancer of variable outcomes with limited effective treatments resulting in poor overall survival (OS). Epigenetic alterations contributing to this ...deadly cancer type that can be used as novel therapeutic or diagnostic targets are still poorly understood.
We explored genome-wide DNA methylation data from The Cancer Genome Atlas project and identified a panel of tumor-related genes hypermethylated in ESCC. The methylation statuses of RASSF1, RARB, CDKN2A (p16INK4a, p14ARF), APC, and RUNX3 genes and long interspersed nucleotide element-1 (LINE-1) were validated in a large cohort (n = 140) of clinically well-annotated ESCC specimens and esophageal normal mucosa (n = 28) using a quantitative methylation-specific polymerase chain reaction.
Hypermethylation of RARB, p16INK4a, RASSF1, APC, RUNX3, and p14ARF were observed in 55%, 24%, 20%, 19%, 14%, and 8% of specimens, respectively. Hypermethylation of APC was significantly associated with tumor depth (p = 0.02) and American Joint Committee on Cancer stage (p = 0.03). Global DNA methylation level, assessed by LINE-1, was significantly lower in ESCC than in normal mucosa (p < 0.0001), and lower in greater than or equal to T2 (n = 69) than T1 tumors (n = 45; p = 0.03). There was a significant inverse correlation between LINE-1 and RARB methylation (p = 0.008). Importantly, hypermethylation of RASSF1 and APC genes was significantly associated with overall survival (OS; p = 0.006 and p = 0.007, respectively). In addition, patients with tumors containing a higher number of methylated genes (greater than two genes) presented worse OS (p = 0.003).
This study demonstrates that epigenetic alterations of a panel of tumor-related genes and the noncoding region LINE-1 can be used as prognostic indicators and help in clinical management of ESCC patients.
In an ongoing effort to identify molecular determinants regulating melanoma brain metastasis, we previously identified Angiopoietin-like 4 (ANGPTL4) as a component of the molecular signature of such ...metastases. The aim of this study was to determine the functional significance of ANGPTL4 in the shaping of melanoma malignancy phenotype, especially in the establishment of brain metastasis. We confirmed that ANGPTL4 expression is significantly higher in cells metastasizing to the brain than in cells from the cutaneous (local) tumor from the same melanoma in a nude mouse xenograft model, and also in paired clinical specimens of melanoma metastases than in primary melanomas from the same patients. In vitro experiments indicated that brain-derived soluble factors and transforming growth factor β1 (TGFβ1) up-regulated ANGPTL4 expression by melanoma cells. Forced over-expression of ANGPTL4 in cutaneous melanoma cells promoted their ability to adhere and transmigrate brain endothelial cells. Over-expressing ANGPTL4 in cells derived from brain metastases resulted in the opposite effects. In vivo data indicated that forced overexpression of ANGPTL4 promoted the tumorigenicity of cutaneous melanoma cells but did not increase their ability to form brain metastasis. This finding can be explained by inhibitory activities of brain-derived soluble factors. Taken together these findings indicate that ANGPTL4 promotes the malignancy phenotype of primary melanomas of risk to metastasize to the brain.
Mitochondrial dysfunction represents an important cellular stressor and when intense and persistent cells must unleash an adaptive response to prevent their extinction. Furthermore, mitochondria can ...induce nuclear transcriptional changes and DNA methylation can modulate cellular responses to stress. We hypothesized that mitochondrial dysfunction could trigger an epigenetically mediated adaptive response through a distinct DNA methylation patterning. We studied cellular stress responses (i.e., apoptosis and autophagy) in mitochondrial dysfunction models. In addition, we explored nuclear DNA methylation in response to this stressor and its relevance in cell survival. Experiments in cultured human myoblasts revealed that intense mitochondrial dysfunction triggered a methylation-dependent pro-survival response. Assays done on mitochondrial disease patient tissues showed increased autophagy and enhanced DNA methylation of tumor suppressor genes and pathways involved in cell survival regulation. In conclusion, mitochondrial dysfunction leads to a “pro-survival” adaptive state that seems to be triggered by the differential methylation of nuclear genes.
Background
Pathological response to neoadjuvant chemotherapy (NAC) is critical in prognosis and selection of systemic treatments for patients with triple-negative breast cancer (TNBC). The aim of ...this study is to identify gene expression-based markers to predict response to NAC.
Patients and Methods
A survey of 43 publicly available gene expression datasets was performed. We identified a cohort of TNBC patients treated with NAC (
n
= 708). Gene expression data from different studies were renormalized, and the differences between pretreatment (pre-NAC), on-treatment (post-C1), and surgical (Sx) specimens were evaluated. Euclidean statistical distances were calculated to estimate changes in gene expression patterns induced by NAC. Hierarchical clustering and pathway enrichment analyses were used to characterize relationships between differentially expressed genes and affected gene pathways. Machine learning was employed to refine a gene expression signature with the potential to predict response to NAC.
Results
Forty nine genes consistently affected by NAC were involved in enhanced regulation of wound response, chemokine release, cell division, and decreased programmed cell death in residual invasive disease. The statistical distances between pre-NAC and post-C1 significantly predicted pathological complete response area under the curve (AUC) = 0.75;
p
= 0.003; 95% confidence interval (CI) 0.58–0.92. Finally, the expression of
CCND1
, a cyclin that forms complexes with CDK4/6 to promote the cell cycle, was the most informative feature in pre-NAC biopsies to predict response to NAC.
Conclusions
The results of this study reveal significant transcriptomic changes induced by NAC and suggest that chemotherapy-induced gene expression changes observed early in therapy may be good predictors of response to NAC.
Immune checkpoint inhibitors (ICI) improve clinical outcomes in triple-negative breast cancer (TNBC) patients. However, a subset of patients does not respond to treatment. Biomarkers that show ICI ...predictive potential in other solid tumors, such as levels of PD-L1 and the tumor mutational burden, among others, show a modest predictive performance in patients with TNBC.
We built machine learning models based on pre-ICI treatment gene expression profiles to construct gene expression classifiers to identify primary TNBC ICI-responder patients. This study involved 188 ICI-naïve and 721 specimens treated with ICI plus chemotherapy, including TNBC tumors, HR+/HER2- breast tumors, and other solid non-breast tumors.
The 37-gene TNBC ICI predictive (TNBC-ICI) classifier performs well in predicting pathological complete response (pCR) to ICI plus chemotherapy on an independent TNBC validation cohort (AUC = 0.86). The TNBC-ICI classifier shows better performance than other molecular signatures, including PD-1 (PDCD1) and PD-L1 (CD274) gene expression (AUC = 0.67). Integrating TNBC-ICI with molecular signatures does not improve the efficiency of the classifier (AUC = 0.75). TNBC-ICI displays a modest accuracy in predicting ICI response in two different cohorts of patients with HR + /HER2- breast cancer (AUC = 0.72 to pembrolizumab and AUC = 0.75 to durvalumab). Evaluation of six cohorts of patients with non-breast solid tumors treated with ICI plus chemotherapy shows overall poor performance (median AUC = 0.67).
TNBC-ICI predicts pCR to ICI plus chemotherapy in patients with primary TNBC. The study provides a guide to implementing the TNBC-ICI classifier in clinical studies. Further validations will consolidate a novel predictive panel to improve the treatment decision-making for patients with TNBC.
Importance
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and appears to have disproportionately higher incidence and worse outcomes among younger African American ...females.
Objective
To investigate whether epigenetic differences exist in TNBCs of younger African American females that may explain clinical disparities seen in this patient group.
Design, Setting, and Participants
This cross-sectional study used clinical, demographic, DNA methylation (HumanMethylation450; Illumina), and gene expression (RNA sequencing) data for US patient populations from publicly available data repositories (The Cancer Genome Atlas TCGA, 2006-2012, and Gene Expression Omnibus GEO, 2004-2013) accessed on April 13, 2021. White and African American females with TNBC identified in TCGA (69 patients) and a validation cohort of 210 African American patients from GEO (
GSE142102
) were included. Patients without available race or age data were excluded. Data were analyzed from September 2022 through April 2023.
Main Outcomes and Measures
DNA methylation and gene expression profiles of TNBC tumors by race (self-reported) and age were assessed. Age was considered a dichotomous variable using age 50 years as the cutoff (younger <50 years vs older ≥50 years).
Results
A total of 69 female patients (34 African American 49.3% and 35 White 50.7%; mean SD; range age, 55.7 11.6; 29-82 years) with TNBC were included in the DNA methylation analysis; these patients and 210 patients in the validation cohort were included in the gene expression analysis (279 patients). There were 1115 differentially methylated sites among younger African American females. The DNA methylation landscape on TNBC tumors in this population had increased odds of enrichment of hormone (odds ratio OR, 1.82; 95% CI, 1.21 to 2.67;
P
= .003), muscle (OR, 1.85; 95% CI, 1.44 to 2.36;
P
< .001), and proliferation (OR, 3.14; 95% CI, 2.71 to 3.64;
P
< .001) pathways vs other groups (older African American females and all White females). Alterations in regulators of these molecular features in TNBCs of younger African American females were identified involving hormone modulation (downregulation of androgen receptor: fold change FC = −2.93; 95% CI, −4.76 to −2.11;
P
< .001) and upregulation of estrogen-related receptor α (FC = 0.86; 95% CI, 0.34 to 1.38;
P
= .002), muscle metabolism (upregulation of
FOXC1
: FC = 1.33; 95% CI, 0.62 to 2.03;
P
< .001), and proliferation mediators (upregulation of
NOTCH1
: FC = 0.71; 95% CI, 0.23 to 1.19;
P
= .004 and
MYC
(FC = 0.81; 95% CI, 0.18 to 1.45;
P
= .01).
Conclusions and Relevance
These findings suggest that TNBC of younger African American females may represent a distinct epigenetic entity and offer novel insight into molecular alterations associated with TNBCs of this population. Understanding these epigenetic differences may lead to the development of more effective therapies for younger African American females, who have the highest incidence and worst outcomes from TNBC of any patient group.
Breast cancer is a heterogeneous disease characterized by the accumulation of genetic and epigenetic alterations that contribute to the development of regional and distant metastases. Lymph node ...metastasis (LNM) status is the single most important prognostic factor. Metastatic cancer cells share common molecular alterations with those of the primary tumor, but in addition, they develop distinct changes that allow the cancer to progress. There is an urgent need for molecular studies which focus on identifying genomic and epigenomic markers that can predict the progression to metastasis. The objective of this study was to identify epigenetic similarities and differences between paired primary breast tumor (PBT) and LNM. We employed Methylation-Specific-MLPA (Multiplex ligation-dependent probe amplification) to assess the methylation status of 33 cancer-related genes in a cohort of 50 paired PBT and LNM specimens. We found that the methylation index, which represents the degree of aberrantly methylated genes in a specimen, was maintained during the progression to LNM. However, some genes presented differential methylation profiles. Interestingly,
PAX6
presented a significant negative correlation between paired PBT and LNM (
p
= 0.03), which indicated a switch from methylated to unmethylated status in the progression from PBT to LNM. We further identified that the methylation status of
PAX6
on the identified CpG site functionally affected the expression of
PAX6
at the mRNA level. Our study unraveled significant epigenetic changes during the progression from PBT to LNM, which may contribute to improved prognosis, prediction and therapeutic management of metastatic breast cancer patients.
Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their ...role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCOR
CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.
To investigate the integrated epigenetic regulation of acquired drug resistance in cancer.
Our gene expression data of five induced drug-tolerant cell models, one resistant cell line and one publicly ...available drug-resistant dataset were integrated to identify common differentially expressed genes and pathways. ChIP-seq and DNA methylation by HM450K beadchip were used to study the epigenetic profile of differential expressed genes.
Integrated transcriptomic analysis identified a common ‘viral mimicry’ related gene signature in induced drug-tolerant cells and the resistant state. Analysis of the epigenetic regulation revealed a common set of down-regulated genes, which are marked and regulated by a concomitant loss of H3K4me3, gain of H3K9me3 and increment of regional DNA methylation levels associated with tumor suppressor genes and apoptotic signaling.
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