The high methylation level of a novel 151-bp CpG island in the ESR1 gene promoter is associated with a poor breast cancer prognosis

Abstract Background The ESR1 gene suffers methylation changes in many types of cancers, including breast cancer (BC), the most frequently diagnosed cancer in women that is also present in men. Methylation at promoter A of ESR1 is the worse prognosis in terms of overall survival; thus, the early detection, prognostic, and prediction of therapy involve some methylation biomarkers. Methods Therefore, our study aimed to examine the methylation levels at the ESR1 gene in samples from Mexican BC patients and its possible association with menopausal status. Results We identified a novel 151-bp CpG island in the promoter A of the ESR1 gene. Interestingly, methylation levels at this CpG island in positive ERα tumors were approximately 50% less than negative ERα or control samples. Furthermore, methylation levels at ESR1 were associated with menopausal status. In postmenopausal patients, the methylation levels were 1.5-fold higher than in premenopausal patients. Finally, according to tumor malignancy, triple-negative cancer subtypes had higher ESR1 methylation levels than luminal/HER2+ or luminal A subtypes. Conclusions Our findings suggest that methylation at this novel CpG island might be a promising prognosis marker

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Breast cancer in togolese women: immunohistochemistry subtypes

BMC Women s Health ◽

10.1186/s12905-020-01130-2 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Ablavi Adani-Ifè ◽

Koffi Amégbor ◽

Kwamé Doh ◽

Tchin Darré

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Molecular Subtype ◽

Menopausal Status ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Histologic Subtype ◽

Cancer Subtypes ◽

Clinical Records

Abstract Background Molecular classification of breast cancer is an important factor for prognostic and clinical outcomes. There are no data regarding molecular breast cancer subtypes among Togolese women. The objective of this study was to evaluate the expression of ER, PR, HER2, and molecular subtypes of breast cancer receptors in Togolese patients and to establish the correlation between clinical and histological data and molecular types. Methods Clinicopathologic data of patients were collected from clinical records. Immunohistochemistry biomarkers (ER, PR, and HER2) were assessed in patients who have been diagnosed with invasive breast cancer from March 2016 to March 2020 in the department of oncology. The analysis of variance and the Chi-square Test was used to analyze the data. Results A total of 117 cases were collected. The mean age of patients was 52.05 ± 12.38 with an age range of 30 to 85 years. Half of the patients were over 50 years old and the majority (70.9%) was postmenopausal. More than half of patients (52.1%) presented with T3-T4tumors.The most common histologic subtype of breast cancer was invasive ductal carcinoma of no special type (95.7%). Tumors grade 2 were predominant (51.3%) followed by grade 3 (42.7%). Advanced carcinomas were found in 69 patients (59%). The percentage of ER+, PR+, and HER2 positive tumors was 54.7%, 41%, and 15.4% respectively. The predominant molecular subtype was Triple negative (37.6%), followed by Luminal A (30.8.7%), Luminal B subtype (23.9%), and HER2 enriched (7.7%). There was a significant association between stage and breast cancer subtypes (p 0.025), histologic grade, and subtype (p < 0.0001) but no correlation was found with age, menopausal status, and tumor size. Conclusion Breast carcinoma in our patients are high grade tumors and are diagnosed at an advanced stage. Triple negative and Luminal A are the two predominant breast cancer subtypes in Togolese women. Consequently, Receptor testing availability should be a priority to offer the best breast cancer treatment.

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Breast Cancer in Togolese Women: Immunohistochemistry Subtypes

10.21203/rs.3.rs-47507/v3 ◽

2020 ◽

Author(s):

Ablavi ADANI-IFE ◽

Koffi AMEGBOR ◽

Kwamé DOH ◽

Tchin DARRE

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Molecular Subtype ◽

Menopausal Status ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Histologic Subtype ◽

Cancer Subtypes ◽

Clinical Records

Abstract Background: Molecular classification of breast cancer is an important factor for prognostic and clinical outcomes. There are no data regarding molecular breast cancer subtypes among Togolese women. The objective of this study was to evaluate the expression of ER, PR, HER2, and molecular subtypes of breast cancer receptors in Togolese patients and to establish the correlation between clinical and histological data and molecular types. Methods: Clinicopathologic data of patients were collected from clinical records. Immunohistochemistry biomarkers (ER, PR, and HER2) were assessed in patients who have been diagnosed with invasive breast cancer from March 2016 to March 2020 in the department of oncology. The analysis of variance and the Chi-square Test was used to analyze the data. Results: A total of 117 cases were collected. The mean age of patients was 52.05±12.38 with an age range of 30 to 85 years. Half of the patients were over 50 years old and the majority (70.9%) was postmenopausal. More than half of patients (52.1%) presented with T3-T4tumors.The most common histologic subtype of breast cancer was invasive ductal carcinoma of no special type (95.7%). Tumors grade 2 were predominant (51.3%) followed by grade 3 (42.7%). Advanced carcinomas were found in 69 patients (59%). The percentage of ER+, PR+, and HER2 positive tumors was 54.7%, 41%, and 15.4% respectively. The predominant molecular subtype was Triple negative (37.6%), followed by Luminal A (30.8.7%), Luminal B subtype (23.9%), and HER2 enriched (7.7%). There was a significant association between stage and breast cancer subtypes (p 0.025), histologic grade, and subtype (p<0.0001) but no correlation was found with age, menopausal status, and tumor size. Conclusion: Breast carcinoma in our patients are high grade tumors and are diagnosed at an advanced stage. Triple negative and Luminal A are the two predominant breast cancer subtypes in Togolese women. Consequently, Receptor testing availability should be a priority to offer the best breast cancer treatment.

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Methylation RE in serum of patients with breast cancer and relation with molecular phenotype and worse prognostic factors.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.27_suppl.224 ◽

2011 ◽

Vol 29 (27_suppl) ◽

pp. 224-224

Author(s):

J. Martínez-Galan ◽

B. Torres-Torres ◽

R. Del Moral ◽

M. I. Núñez ◽

S. Ríos ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Gene Promoter ◽

Therapy Resistance ◽

Her2 Status ◽

Molecular Phenotype ◽

Luminal A ◽

Cancer Subtypes ◽

Luminal B

224 Background: To determine whether Estrogen Receptor (ESR1) (+) and ESR1(-) status relates to epigenetic changes in breast cancer-related genes and to correlate with molecular breast cancer subtypes. Methods: Since January/02 to June/05, we quantified methylation levels ERS1 gene in serum of 92 pts breast cancer. A PCR quantitative technique was used to analyze levels of methylation gene. We also examined and correlationed the expression of ESR1 in tumors by immunohistochemistry with molecular phenotype. Results: Median age was 58 years (32-88); 69% were postmenopausal women. Nodal involvement (N0; 63%, N1; 30%, N2; 7%), tumor size (T1; 58%, T2; 35%, T3; 4%, T4; 4%) and grade (G1; 20%, G2; 37%, G3; 30%). Of the cases, 37 pts (40%) were Luminal A (LA), 32 pts (33%) Luminal B (LB), 14 pts (15%) Triple-negative (TN) and 9pts (10%) HER2+. The methylated ESR1 in serum was significantly associated with ESR1(-) in breast tumors >80% (p=0.0179). Methylation ESR1 was preferably associated with TN (80%) and HER2+ (60%) subtype. Nevertheless unmethylation ESR1 was found more frequently in LA (71%) and LB (59%) phenotype. With a median follow up of 5 years, we found worse overall survival (OS) with more frequent ESR1 methylation gene (p>0.05), Luminal A; ESR1 Methylation OS at 5 years 81% vs 93% when was ESR1 Unmethylation. Luminal B; ESR1 Methylation 86% SG at 5 years vs 92% in Unmethylation ESR1. Triple negative; ESR1 Methylation SG at 5 years 75% vs 80% in unmethylation ESR1. HER2; ESR1 Methylation SG at 5 years was 66.7% vs 75% unmethylation ESR1. Conclusions: Gene promoter region hypermethylation is a significant event in primary breast cancer. However, its impact on tumor progression and potential predictive implications remain relatively unknown. Our study identifies the presence of variations in global levels of methylation promoters ESR1 genes in breast cancer with different phenotype classes and shows that these differences have clinical significance. Although numerous issues remain to be resolved, quantitative measurement of circulating methylated DNA may be of significance in the assessment and search of targeted therapy resistance related to ESR1 and HER2 status by epigenetic or transcriptional cancer therapy.

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Breast Cancer in Togolese Women: Immunohistochemistry Subtypes

10.21203/rs.3.rs-47507/v1 ◽

2020 ◽

Author(s):

Ablavi ADANI-IFE ◽

Koffi AMEGBOR ◽

Kwamé DOH ◽

Tchin DARRE

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Molecular Subtype ◽

Menopausal Status ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Histologic Subtype ◽

Cancer Subtypes ◽

Clinical Records

Abstract Background Molecular classification of breast cancer is an important factor for prognostic and clinical outcome. There are no data regarding molecular breast cancer subtypes among Togolese women. The objective of this study was to evaluate the expression of ER, PR, HER2 and molecular subtypes of breast cancer receptor in Togolese patients and to establish the correlation between clinical and histological data and molecular types. Methods Clinicopathologic data of patients were collected from clinical records. Immunohistochemistry biomarkers (ER, PR and HER2) were assessed in patients who have been diagnosed with invasive breast cancer from March 2016 to March 2020 in the department of oncology. The analysis of variance and the Chi-square Test were used to analyze the data. Results A total of 117 cases were collected. Mean age of patients was 52.05 ± 12.38 with an age range of 30 to 85 years. Half of patients were over 50 years old and majority (70.9%) was postmenopausal. More than half of patients (52.1%) presented with T3-T4tumors.The most common histologic subtype of breast cancer was invasive ductal carcinoma of no special type (95.7%). Tumors grade 2 were predominant (51.3%) followed by grade 3 (42.7%). Advanced carcinomas were found in 69 patients (59%). The percentage of ER+, PR + and HER2 positive tumors was 50.4%, 37.6% and 15.4% respectively. The predominant molecular subtype was Luminal A (42.7%) followed by Triple negative (41.9%), Luminal B subtype (9.4%) and HER2 enriched (6%). There was significant association between tumor size and breast cancer subtypes (p = 0.026) but no correlation was found with age, stage, menopausal status and histologic grade. Conclusion Breast carcinoma in our patients are high grade tumors and are diagnosed at advanced stage. Luminal A and triple negative are the two predominant breast cancer subtypes in Togolese women. Consequently, Receptor testing availability should be a priority in order to offer the best breast cancer treatment.

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Breast Cancer In Togolese Women: Immunohistochemistry Subtypes

10.21203/rs.3.rs-47507/v2 ◽

2020 ◽

Author(s):

Ablavi ADANI-IFE ◽

Koffi AMEGBOR ◽

Kwamé DOH ◽

Tchin DARRE

Keyword(s):

Breast Cancer ◽

Triple Negative ◽

Ductal Carcinoma ◽

Molecular Subtype ◽

Menopausal Status ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Histologic Subtype ◽

Cancer Subtypes ◽

Clinical Records

Abstract Background: Molecular classification of breast cancer is an important factor for prognostic and clinical outcomes. There are no data regarding molecular breast cancer subtypes among Togolese women. The objective of this study was to evaluate the expression of ER, PR, HER2, and molecular subtypes of breast cancer receptors in Togolese patients and to establish the correlation between clinical and histological data and molecular types.Methods: Clinicopathologic data of patients were collected from clinical records. Immunohistochemistry biomarkers (ER, PR, and HER2) were assessed in patients who have been diagnosed with invasive breast cancer from March 2016 to March 2020 in the department of oncology. The analysis of variance and the Chi-square Test was used to analyze the data.Results: A total of 117 cases were collected. The mean age of patients was 52.05±12.38 with an age range of 30 to 85 years. Half of the patients were over 50 years old and the majority (70.9%) was postmenopausal. More than half of patients (52.1%) presented with T3-T4tumors.The most common histologic subtype of breast cancer was invasive ductal carcinoma of no special type (95.7%). Tumors grade 2 were predominant (51.3%) followed by grade 3 (42.7%). Advanced carcinomas were found in 69 patients (59%). The percentage of ER+, PR+, and HER2 positive tumors was 54.7%, 41%, and 15.4% respectively. The predominant molecular subtype was Triple negative (37.6%), followed by Luminal A (30.8.7%), Luminal B subtype (23.9%), and HER2 enriched (7.7%). There was a significant association between stage and breast cancer subtypes (p 0.025), histologic grade, and subtype (p<0.0001) but no correlation was found with age, menopausal status, and tumor size.Conclusion: Breast carcinoma in our patients are high grade tumors and are diagnosed at an advanced stage. Triple negative and Luminal A are the two predominant breast cancer subtypes in Togolese women. Consequently, Receptor testing availability should be a priority to offer the best breast cancer treatment.

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Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer

Cancers ◽

10.3390/cancers13040833 ◽

2021 ◽

Vol 13 (4) ◽

pp. 833

Author(s):

Jesús Fuentes-Antrás ◽

Ana Lucía Alcaraz-Sanabria ◽

Esther Cabañas Morafraile ◽

María del Mar Noblejas-López ◽

Eva María Galán-Moya ◽

...

Keyword(s):

Breast Cancer ◽

Drug Development ◽

Gene Mutations ◽

Complete Response ◽

Breast Cancer Patients ◽

Clinical Value ◽

Luminal A ◽

Genomic Alterations ◽

Cancer Hallmarks ◽

Worse Prognosis

The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.

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Performance of a novel protease-activated fluorescent imaging system for intraoperative detection of residual breast cancer during breast conserving surgery

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06106-w ◽

2021 ◽

Vol 187 (1) ◽

pp. 145-153

Author(s):

Conor R. Lanahan ◽

Bridget N. Kelly ◽

Michele A. Gadd ◽

Michelle C. Specht ◽

Carson L. Brown ◽

...

Keyword(s):

Breast Cancer ◽

Real Time ◽

Imaging System ◽

Ex Vivo ◽

Menopausal Status ◽

Fluorescent Imaging ◽

Cancer Subtypes ◽

Surgical Workflow ◽

Tumor Types

Abstract Purpose Safe breast cancer lumpectomies require microscopically clear margins. Real-time margin assessment options are limited, and 20–40% of lumpectomies have positive margins requiring re-excision. The LUM Imaging System previously showed excellent sensitivity and specificity for tumor detection during lumpectomy surgery. We explored its impact on surgical workflow and performance across patient and tumor types. Methods We performed IRB-approved, prospective, non-randomized studies in breast cancer lumpectomy procedures. The LUM Imaging System uses LUM015, a protease-activated fluorescent imaging agent that identifies residual tumor in the surgical cavity walls. Fluorescent cavity images were collected in real-time and analyzed using system software. Results Cavity and specimen images were obtained in 55 patients injected with LUM015 at 0.5 or 1.0 mg/kg and in 5 patients who did not receive LUM015. All tumor types were distinguished from normal tissue, with mean tumor:normal (T:N) signal ratios of 3.81–5.69. T:N ratios were 4.45 in non-dense and 4.00 in dense breasts (p = 0.59) and 3.52 in premenopausal and 4.59 in postmenopausal women (p = 0.19). Histopathology and tumor receptor testing were not affected by LUM015. Falsely positive readings were more likely when tumor was present < 2 mm from the adjacent specimen margin. LUM015 signal was stable in vivo at least 6.5 h post injection, and ex vivo at least 4 h post excision. Conclusions Intraoperative use of the LUM Imaging System detected all breast cancer subtypes with robust performance independent of menopausal status and breast density. There was no significant impact on histopathology or receptor evaluation.

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The association of women’s birth size with risk of molecular breast cancer subtypes: a cohort study

BMC Cancer ◽

10.1186/s12885-021-08027-9 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Marie S. Sandvei ◽

Signe Opdahl ◽

Marit Valla ◽

Pagona Lagiou ◽

Ellen Veronika Vesterfjell ◽

...

Keyword(s):

Breast Cancer ◽

Birth Weight ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Head Circumference ◽

Birth Length ◽

Birth Size ◽

Luminal A ◽

Cancer Subtypes ◽

Luminal B

Abstract Background Because birth size appears to be positively associated with breast cancer risk, we have studied whether this risk may differ according to molecular breast cancer subtypes. Methods A cohort of 22,931 women born 1920–1966 were followed up for breast cancer occurrence from 1961 to 2012, and 870 were diagnosed during follow-up. Archival diagnostic material from 537 patients was available to determine molecular breast cancer subtype, specified as Luminal A, Luminal B (human epidermal growth factor receptor 2 (HER2)-), Luminal B (HER2+), HER2 type, and Triple negative (TN) breast cancer. Information on the women’s birth weight, birth length and head circumference at birth was used to estimate hazard ratios (HR) with 95% confidence intervals (CI) for each molecular subtype, applying Cox regression, and stratified by maternal height. Results Birth length (per 2 cm increments) was positively associated with Luminal A (HR = 1.2, 95% CI, 1.0–1.3), Luminal B (HER2+) (HR = 1.3, 95% CI, 1.0–1.7), and TN breast cancer (HR = 1.4, 95% CI, 1.0–1.9). No clear association was found for birth weight and head circumference. The positive associations of birth length were restricted to women whose mothers were relatively tall (above population median). Conclusion We found a positive association of birth length with risk of Luminal A, Luminal B (HER2+) and TN breast cancer that appears to be restricted to women whose mothers were relatively tall. This may support the hypothesis that breast cancer risk is influenced by determinants of longitudinal growth and that this finding deserves further scrutiny.

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Comprehensive immunohistochemical analysis of RET, BCAR1, and BCAR3 expression in patients with Luminal A and B breast cancer subtypes

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06452-9 ◽

2022 ◽

Author(s):

Ana Carolina Pavanelli ◽

Flavia Rotea Mangone ◽

Piriya Yoganathan ◽

Simone Aparecida Bessa ◽

Suely Nonogaki ◽

...

Keyword(s):

Breast Cancer ◽

Immunohistochemical Analysis ◽

Breast Cancer Subtypes ◽

Luminal A ◽

Cancer Subtypes

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Identification of key genes unique to the luminal A and basal-like breast cancer subtypes via bioinformatic analysis

10.21203/rs.3.rs-28637/v1 ◽

2020 ◽

Author(s):

Rong Jia ◽

Zhongxian Li ◽

Wei Liang ◽

Yucheng Ji ◽

Yujie Weng ◽

...

Keyword(s):

Breast Cancer ◽

Differentially Expressed Genes ◽

Survival Data ◽

Breast Cancer Subtypes ◽

Differentially Expressed ◽

Expression Data ◽

Luminal A ◽

Cancer Subtypes ◽

Protein Protein Interaction ◽

Basal Like Breast Cancer

Abstract Background Breast cancer subtypes are statistically associated with prognosis. The search for markers of breast tumor heterogeneity and the development of precision medicine for patients are the current focuses of the field. Methods We used a bioinformatic approach to identify key disease-causing genes unique to the luminal A and basal-like subtypes of breast cancer. First, we retrieved gene expression data for luminal A breast cancer, basal-like breast cancer, and normal breast tissue samples from The Cancer Genome Atlas database. The differentially expressed genes unique to the 2 breast cancer subtypes were identified and subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We constructed protein–protein interaction networks of the differentially expressed genes. Finally, we analyzed the key modules of the networks, which we combined with survival data to identify the unique cancer genes associated with each breast cancer subtype. Results We identified 1,114 differentially expressed genes in luminal A breast cancer and 1,042 differentially expressed genes in basal-like breast cancer, of which the subtypes shared 500. We observed 614 and 542 differentially expressed genes unique to luminal A and basal-like breast cancer, respectively. Through enrichment analyses, protein–protein interaction network analysis, and module mining, we identified 8 key differentially expressed genes unique to each subtype. Analysis of the gene expression data in the context of the survival data revealed that high expression of NMUR1 and NCAM1 in luminal A breast cancer statistically correlated with poor prognosis, whereas the low expression levels of CDC7 , KIF18A , STIL , and CKS2 in basal-like breast cancer statistically correlated with poor prognosis. Conclusions NMUR1 and NCAM1 are novel key disease-causing genes for luminal A breast cancer, and STIL is a novel key disease-causing gene for basal-like breast cancer. These genes are potential targets for clinical treatment.

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