TP73 DNA methylation and upregulation of ΔNp73 are associated with an adverse prognosis in breast cancer

2017 ◽  
Vol 71 (1) ◽  
pp. 52-58 ◽  
Author(s):  
Laura C Gomez ◽  
Mayra L Sottile ◽  
Martin E Guerrero-Gimenez ◽  
Felipe C M Zoppino ◽  
Analia L Redondo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Histological Grade ◽  
Methylation Status ◽  
Prognostic Significance ◽  
Inverse Correlation ◽  
Positive Association ◽  
Immunohistochemical Analysis ◽  
Aberrant Methylation ◽  
Breast Cancer Patients

AimAccumulated evidence suggests that aberrant methylation of the TP73 gene and increased levels of ΔNp73 in primary tumours correlate with poor prognosis. However, little is known regarding the transcriptional and functional regulation of the TP73 gene in breast cancer. The aim of the present study was to determine the expression of the ΔNp73 isoform, its relationship with DNA methylation of TP73 and their clinical prognostic significance in breast cancer patients.MethodsTP73 gene methylation was studied in TCGA datasets and in 70 invasive ductal breast carcinomas (IDCs). The expression of p73 isoforms was evaluated by immunohistochemistry (IHC) and Western blot and correlated with clinicopathological variables and clinical outcome.ResultsWe observed that the methylation of diverse CpG islands of TP73 differed significantly between molecular subtypes. An inverse correlation was found between p73 protein expression and the methylation status of the TP73 gene. The expression of exon 3’ of p73 (only expressed in ΔNp73) was significantly higher in patients with wild-type p53. Immunohistochemical analysis revealed that all p73 isoforms were localised in both the nuclear and cytoplasmic compartments. We confirmed a positive association between the expression of ∆Np73 and high histological grade.ConclusionsOur findings suggest that high expression of ΔNp73 could be used to determine the aggressiveness of IDCs and could be incorporated in the pathologist’s report.

scholarly journals DNA Methylation Based Molecular Subtypes Predict Prognosis in Breast Cancer Patients

2021 ◽  
Vol 28 ◽  
pp. 107327482098851
Author(s):  
Zeng-Hong Wu ◽  
Yun Tang ◽  
Yan Zhou
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Molecular Subtypes ◽  
Methylation Status ◽  
The Cancer Genome Atlas ◽  
Training Dataset ◽  
Consensus Clustering ◽  
Breast Cancer Patients ◽  
Cancer Subtypes ◽  
Novel Biomarkers

Background: Epigenetic changes are tightly linked to tumorigenesis development and malignant transformation’ However, DNA methylation occurs earlier and is constant during tumorigenesis. It plays an important role in controlling gene expression in cancer cells. Methods: In this study, we determining the prognostic value of molecular subtypes based on DNA methylation status in breast cancer samples obtained from The Cancer Genome Atlas database (TCGA). Results: Seven clusters and 204 corresponding promoter genes were identified based on consensus clustering using 166 CpG sites that significantly influenced survival outcomes. The overall survival (OS) analysis showed a significant prognostic difference among the 7 groups (p<0.05). Finally, a prognostic model was used to estimate the results of patients on the testing set based on the classification findings of a training dataset DNA methylation subgroups. Conclusions: The model was found to be important in the identification of novel biomarkers and could be of help to patients with different breast cancer subtypes when predicting prognosis, clinical diagnosis and management.

scholarly journals A qualitative transcriptional signature to reclassify histological grade of ER-positive breast cancer patients

2020 ◽  
Author(s):  
Jing Li ◽  
Wenbin Jiang ◽  
Qirui Liang ◽  
Guanghao Liu ◽  
Yupeng Dai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Histological Grade ◽  
Objective Assessment ◽  
Prognostic Significance ◽  
Breast Cancer Patients ◽  
Transcriptional Signature ◽  
Gene Pairs ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Purpose Histological grade (HG) is commonly adopted as a prognostic factor for ER-positive breast cancer patients. However, HG evaluation methods, such as the pathological Nottingham grading system, are highly subjective with only 50%-85% inter-observer agreements. Specifically, the subjectivity in the pathological assignment of the intermediate grade (HG2) breast cancers, comprising of about half of breast cancer cases, results in uncertain disease outcomes prediction. Here, we developed a qualitative transcriptional signature, based on within-sample relative expression orderings (REOs) of gene pairs, to define HG1 and HG3 and reclassify pathologically-determined HG2 (denoted as pHG2) breast cancer patients.Results From the gene pairs with significantly stable REOs in pathologically-determined HG1 (denoted as pHG1) samples and reversely stable REOs in pathologically-determined HG3 (denoted as pHG3) samples, concordantly identified from seven datasets, we extracted a signature which could determine the HG state of samples through evaluating whether the within-sample REOs match with the patterns of the pHG1 REOs or pHG3 REOs. A sample was classified into the HG3 group if at least a half of the REOs of the 10 gene pairs signature within this sample voted for HG3; otherwise, HG1. Using four datasets including samples of early stage (I–II) ER-positive breast cancer patients who accepted surgery only, we validated that this signature was able to reclassify pHG2 patients into HG1 and HG3 groups with significantly different survival time. For the original pHG1 and pHG3 patients, the signature could also more accurately and objectively stratify them into distinct prognostic groups. And the up-regulated and down down-regulated genes in HG1 compared with HG3 involved in cell proliferation and extracellular signal transduction pathways respectively. By comparing with existing signatures, 10-GPS was with prognostic significance and was more aligned with survival of patients especially for pHG2 samples.Conclusions The transcriptional qualitative signature can provide an objective assessment of HG states of ER-positive breast cancer patients, especially for reclassifying patients with pHG2, to assist decision making on clinical therapy.

scholarly journals Association Between MGMT Promoter Methylation and Breast Cancer: a Meta-Analysis

2017 ◽  
Vol 42 (6) ◽  
pp. 2430-2440 ◽  
Author(s):  
Nairui An ◽  
Yu Shi ◽  
Peng Ye ◽  
Zhongya Pan ◽  
Xinghua Long
Keyword(s):  
Breast Cancer ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Histological Grade ◽  
Meta Analysis ◽  
Methylation Status ◽  
Mgmt Promoter Methylation ◽  
P Value ◽  
Breast Cancer Patients ◽  
Mgmt Promoter

Background/Aims: Numerous studies have suggested that the promoter methylation status of O6-methylguanine-DNA methyltransferase (MGMT) is significantly associated with breast cancer. However, these studies have not demonstrated consistent results. Methods: To obtain more accurate results for this possible association, we performed a meta-analysis-based study using the relevant data. A total of 14 articles were included in this meta-analysis. Results: Our study showed that the frequency of MGMT promoter methylation was significantly higher in patients with breast cancer than non-breast cancer subjects with an Odds Ratio (OR) of 4.47, a 95% Confidence Interval (CI) ranging between 1.95 - 10.25 and a P value of 0.0004. Moreover, MGMT methylation was significantly associated with the negative expression of the MGMT protein (OR = 4.65, 95%CI = 2.66 - 8.12, P < 0.00001), Oestrogen Receptor (ER)-negative tumours (OR = 1.79, 95%CI = 1.09 - 2.93, P = 0.02), postmenopausal status (OR =1.84, 95%CI = 1.18 - 2.87, P = 0.007) and histological grade III tumours (OR = 2.49, 95%CI = 1.53 - 4.07, P = 0.0003) in breast cancer patients. However, breast cancer was not significantly correlated with lymph node metastasis (OR = 1.19, 95%CI = 0.83 - 1.70, P = 0.35), Progesterone Receptor (PR) status (OR = 1.08, 95%CI = 0.58 - 2.00, P = 0.81), Human epidermal growth factor receptor - 2（HER-2/neu）status (OR = 1.01, 95%CI = 0.65 - 1.57, P = 0.97), P53 mutation (OR = 1.30, 95%CI = 0.76 - 2.21, P = 0.34) and age > 50 (OR = 1.07, 95%CI = 0.46 - 2.51, P = 0.88). Conclusions: Our study suggests that MGMT promoter methylation may be an early biomarker for the diagnosis of breast cancer.

scholarly journals Exploration of Euchromatin Cell-Free DNA Methylation in Breast Cancer

2020 ◽  
pp. 1-3
Author(s):  
Chen-Hsiung Yeh ◽  
Keyword(s):  
Breast Cancer ◽  
Dna Methylation ◽  
Genomic Dna ◽  
Methylation Status ◽  
Active Regions ◽  
Breast Cancer Patients ◽  
Plasma Dna ◽  
Cell Free Dna ◽  
Cancer Management ◽  
Free Dna

Circulating cell-Free DNA (cfDNA) is emerging as a non-invasive liquid biopsy biomarker for personalized and precision cancer management. While extensive tissue-based DNA methylation profiling at global and gene levels have been documented, studies regarding methylation status of cfDNA at the sub-genome scale as well as correlation with that of tissue-derived genomic DNA have yet to be explored. The ability to specifically interrogate DNA methylation status of the transcriptionally active regions within chromosomes, i.e., euchromatin, not only fulfills the knowledge gap but also provides a much needed longitudinal and real-time insight for early cancer detection and intervention. We have developed a proprietary technology for selective enrichment of euchromatin cfDNA and analyzed the 5-methylcytosine (5-mC) content in these circulating nucleocomplexes. Paired tissue and plasma DNA (n=28) were obtained from breast cancer patients at various stages with ages and genders matched to the control arm (n=21). Quantitative measurement of DNA methylation was determined by ELISA-based assays. Our results revealed significant lower methylation levels from breast cancer cohort as compared to the cancer-free group (P<0.01). Most importantly, the methylation quantification dataset from euchromatin cfDNA strongly correlated with that of tissue genomic DNA (R²=0.72). This is the first report on euchromatin cfDNA methylation and provides promising outcomes for its future clinical application

scholarly journals Epigenetic Alteration and its Association With Downregulated FOXP3 Gene in Indian Breast Cancer Patients

2021 ◽  
Vol 12 ◽  
Author(s):  
Sadaf ◽  
Naseem Akhter ◽  
Raed A. Alharbi ◽  
Abdulmajid A. A. Sindi ◽  
Mohammad Zeeshan Najm ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Expression ◽  
Cancer Patients ◽  
Promoter Methylation ◽  
Histological Grade ◽  
Mrna Level ◽  
Methylation Status ◽  
Positive Lymph Node ◽  
Breast Cancer Patients ◽  
Protein Loss

Background:FOXP3 gene, known to be a potential tumor suppressor, has been identified to interact with HER2 in mammary cancer. Moreover, the high expression of FOXP3 serves as a good predictor of the survival of patients in breast cancer, prostate cancer, and gastric cancer. The expression and epigenetic alterations were evaluated in female breast cancer patients.Material and Methods: Expression studies at the mRNA level and protein level were conducted in 140 breast cancer cases by real-time PCR and immunohistochemistry, respectively. Epigenetic studies were also conducted by analyzing the methylation status at the promoter region of the gene using MS-PCR.Results:FOXP3 mRNA expression and protein expression were downregulated in breast cancer patients. The absence of FOXP3 protein expression is significantly associated with promoter methylation, where 70 methylated cases exhibited protein loss (70/95, 73.6%). Statistically, we also found a significant correlation between FOXP3 protein expression and TNM stage, promoter methylation, and histological grade. The methylated FOXP3 cases that did not express protein were also significantly associated with positive lymph node metastasis and HER-2 status.Conclusion: The expression profile of FOXP3 may serve as a prognostic factor. In short, FOXP3 may stand in the most crucial list of biomarkers for breast cancer, bringing compelling results in terms of treatment and management of the disease.

scholarly journals A qualitative transcriptional signature to reclassify histological grade of ER-positive breast cancer patients

2020 ◽  
Author(s):  
Jing Li ◽  
Wenbin Jiang ◽  
Qirui Liang ◽  
Guanghao Liu ◽  
Yupeng Dai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Histological Grade ◽  
Objective Assessment ◽  
Prognostic Significance ◽  
Breast Cancer Patients ◽  
Transcriptional Signature ◽  
Gene Pairs ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Purpose Histological grade (HG) is commonly adopted as a prognostic factor for ER-positive breast cancer patients. However, HG evaluation methods, such as the pathological Nottingham grading system, are highly subjective with only 50%-85% inter-observer agreements. Specifically, the subjectivity in the pathological assignment of the intermediate grade (HG2) breast cancers, comprising of about half of breast cancer cases, results in uncertain disease outcomes prediction. Here, we developed a qualitative transcriptional signature, based on within-sample relative expression orderings (REOs) of gene pairs, to define HG1 and HG3 and reclassify pathologically-determined HG2 (denoted as pHG2) breast cancer patients.Results From the gene pairs with significantly stable REOs in pathologically-determined HG1 (denoted as pHG1) samples and reversely stable REOs in pathologically-determined HG3 (denoted as pHG3) samples, concordantly identified from seven datasets, we extracted a signature which could determine the HG state of samples through evaluating whether the within-sample REOs match with the patterns of the pHG1 REOs or pHG3 REOs. A sample was classified into the HG3 group if at least a half of the REOs of the 10 gene pairs signature within this sample voted for HG3; otherwise, HG1. Using four datasets including samples of early stage (I–II) ER-positive breast cancer patients who accepted surgery only, we validated that this signature was able to reclassify pHG2 patients into HG1 and HG3 groups with significantly different survival time. For the original pHG1 and pHG3 patients, the signature could also more accurately and objectively stratify them into distinct prognostic groups. And the up-regulated and down down-regulated genes in HG1 compared with HG3 involved in cell proliferation and extracellular signal transduction pathways respectively. By comparing with existing signatures, 10-GPS was with prognostic significance and was more aligned with survival of patients especially for pHG2 samples.Conclusions The transcriptional qualitative signature can provide an objective assessment of HG states of ER-positive breast cancer patients, especially for reclassifying patients with pHG2, to assist decision making on clinical therapy.

scholarly journals Apoptosis regulator Bcl-2 is an independent prognostic marker for worse overall survival in triple-negative breast cancer patients

2017 ◽  
Vol 33 (1) ◽  
pp. 109-115 ◽  
Author(s):  
Petar Ozretic ◽  
Ilija Alvir ◽  
Bozena Sarcevic ◽  
Zeljko Vujaskovic ◽  
Zrinka Rendic-Miocevic ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Histological Grade ◽  
Prognostic Significance ◽  
Clinical Variable ◽  
Breast Cancer Patients ◽  
Roc Curve Analysis ◽  
P53 Expression

Background: The objective of this study was to examine the prognostic significance of carbonic anhydrase IX (CAIX), an endogenous marker for tumor hypoxia; the cellular tumor antigen p53; and the apoptosis regulator Bcl-2, in triple-negative breast cancer (TNBC) patients. Methods: Immunohistochemically determined expression of CAIX, p53, Bcl-2 and proliferation factor Ki-67, analyzed in 64 paraffin-embedded TNBC tissue samples, was used to assess their relation to clinicopathological variables and prognostic implications for overall survival (OS). Results: Bcl-2 expression was negatively correlated with histological grade of tumor, while expression of p53 was positively correlated with the same clinical variable (p = 0.036 and p = 0.033, respectively). The p53 expression was also positively correlated with tumor size (p = 0.010). Survival analysis showed that patients with high Bcl-2 expression (above cutoff value determined by receiver operator characteristic [ROC] curve analysis) had shorter OS (p = 0.020). The same was observed for patients with tumors larger than 5 cm (p = 0.034) or positive lymph nodes (p = 0.004). Among all 3 examined markers, multivariate analysis showed that only Bcl-2 expression was a strong independent prognostic indicator for decreased OS (hazard ratio [HR] = 15.16, 95% confidence interval [95% CI], 2.881-79.727, p = 0.001). Conclusions: Elevated expression of Bcl-2 was an independent prognostic factor for poorer OS in TNBC and as such a significant marker for tumor aggressiveness.

scholarly journals Clinical impact of PTEN methylation status as a prognostic marker for breast cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Amal Ramadan ◽  
Maha Hashim ◽  
Amr Abouzid ◽  
Menha Swellam
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Tumor Markers ◽  
Prognostic Marker ◽  
Methylation Status ◽  
Clinical Impact ◽  
Breast Cancer Patients ◽  
Duct Carcinoma ◽  
Cancer Group ◽  
And Control

Abstract Background Aberrant DNA methylation of phosphatase and tensin homolog (PTEN) gene has been found in many cancers. The object of this study was to evaluate the clinical impact of PTEN methylation as a prognostic marker in breast cancer. The study includes 153 newly diagnosed females, and they were divided according to their clinical diagnosis into breast cancer patients (n = 112) and females with benign breast lesion (n = 41). A group of healthy individuals (n = 25) were recruited as control individuals. Breast cancer patients were categorized into early stage (0–I, n = 48) and late stage (II–III, n = 64), and graded into low grade (I–II, n = 42) and high grade (III, n = 70). Their pathological types were invasive duct carcinoma (IDC) (n = 66) and duct carcinoma in situ (DCI) (n = 46). Tumor markers (CEA and CA15.3) were detected using ELISA. DNA was taken away from the blood, and the PTEN promoter methylation level was evaluated using the EpiTect Methyl II PCR method. Results The findings revealed the superiority of PTEN methylation status as a good discriminator of the cancer group from the other two groups (benign and control) with its highest AUC and increased sensitivity (96.4%) and specificity (100%) over tumor markers (50% and 84% for CEA and 49.1% and 86.4% for CA15.3), respectively. The frequency of PTEN methylation was 96.4% of breast cancer patients and none of the benign and controls showed PTEN methylation and the means of PTEN methylation (87 ± 0.6) were significantly increased in blood samples of breast cancer group as compared to both benign and control groups (25 ± 0.7 and 12.6 ± 0.3), respectively. Methylation levels of PTEN were higher in the blood of patients with ER-positive than in patients with ER-negative cancers (P = 0.007) and in HER2 positive vs. HER2 negative tumors (P = 0.001). The Kaplan-Meier analysis recognizes PTEN methylation status as a significant forecaster of bad progression-free survival (PFS) and overall survival (OS), after 40 months follow-up. Conclusions PETN methylation could be supposed as one of the epigenetic aspects influencing the breast cancer prognosis that might foretell more aggressive actions and worse results in breast cancer patients.

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