RESUMEN
BACKGROUND: In this study, we compared the contribution of pathogenic variants of the BRCA1/2 genes (5382insC, 185delAG, 6174delT, 4153delA, T300G) and hypermethylation of the BRCA1 gene promoter region to the risk of breast cancer and clinical features in women. METHODS: This study enrolled 74 women (tumor tissue, blood) with newly diagnosed breast cancer and 62 women (blood) without oncological pathology (control group). Molecular genetic testing of samples and determination of hypermethylation status were performed on freshly collected material with the addition of a preservative before the procedure of DNA isolation. RESULTS: Hypermethylation of the BRCA1 gene promoter in women is a risk breast cancer factor (χ2 = 19.10, p = 0.001, OR = 16.25 (3.67-71.92)) and is more common than major pathogenic variants in the BRCA1/2 genes. The patients with the BRCA1 gene promoter hypermethylation were more likely to be diagnosed with late-stage metastatic cancer (χ2 = 4.31, p = 0.038, OR = 4.04 (1.19-13.65)). Hypermethylation of the BRCA1 gene promoter was predominant in tumor tissue among BC patients without family history compared to patients with cancer in relatives. CONCLUSION: We proved that hypermethylation of the BRCA1 gene promoter is a risk factor for breast cancer and possibly an early biological marker of clinical onset, as its presence contributed to rapid disease progression with metastasis. The high frequency of hypermethylation in the examined breast cancer patients may be a consequence of environmental factors pressure on the risk of the disease development. Further large-scale studies are needed for the clinical application of the results.
Asunto(s)
Neoplasias de la Mama , Genes BRCA1 , Humanos , Femenino , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Regiones Promotoras Genéticas , Metilación de ADN , Factores de Riesgo , Biomarcadores , Proteína BRCA1/genéticaRESUMEN
PURPOSE: The gene BRCA1 plays a key role in DNA repair in breast and ovarian cell lines and this is considered one of target tumor suppressor genes in same line of cancers. The 5382insC mutation is among the most frequently detected in patients (Eastern Europe) with triple-negative breast cancer (TNBC). In Ukraine, there is not enough awareness of necessity to test patients with TNBC for BRCA1 mutations. That is why this group of patients is not well-studied, even through is known the mutation may affect the course of disease. METHODS: The biological samples of 408 female patients were analyzed of the 5382insC mutation in BRCA1. We compared the frequency of the 5382insC mutation in BRCA1 gene observed in Ukraine with known frequencies in other countries. RESULTS: For patients with TNBC, BRCA1 mutations frequency was 11.3%, while in patients with luminal types of breast cancers, the frequency was 2.8%. Prevalence of 5382insC among TNBC patients reported in this study was not different from those in Tunisia, Poland, Russia, and Bulgaria, but was higher than in Australia and Germany. CONCLUSION: The BRCA1 c.5382 mutation rate was recorded for the first time for TNBC patients in a Ukrainian population. The results presented in this study underscore the importance of this genetic testing of mutations in patients with TNBC. Our study supports BRCA1/2 genetic testing for all women diagnosed with TNBC, regardless of the age of onset or family history of cancer and not only for women diagnosed with TNBC at <60y.o., as guidelines recommend.
Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Neoplasias de la Mama Triple Negativas , Proteína BRCA1/genética , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Femenino , Genes BRCA1 , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Humanos , Mutación , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Neoplasias de la Mama Triple Negativas/epidemiología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Ucrania/epidemiologíaRESUMEN
OBJECTIVE: The aim: The purpose of this study is to investigate prognostic value of tumor stroma ratio in triple negative breast carcinomas. PATIENTS AND METHODS: Materials and methods: This cohort retrospective study included a total number of 232 previously untreated operational materials with primary stage I-III triple negative breast cancer. The median follow-up period was 3.8 years for overall survival and 3.2 years for disease-free survival. Tumor stroma ratio was evaluated by two pathologists (Kappa coefficient was 0.71 and 0.84, respectively). RESULTS: Results: Kaplan-Meier curves with logrank test statistically significantly showed relationship between tumor stroma ratio and both overall and disease-free survival. The Cox proportional hazards model showed tumor stroma ratio is a strong independent prognostic factor for triple negative breast carcinomas with hazard ratios of 2.11 (p=0.002) for overall survival and 1.83 (p=0.004) for disease-free survival in multivariate analysis. CONCLUSION: Conclusions: Triple negative breast tumors with high stroma ratio have worse overall and disease-free survival compared to low stroma ratio tumors. Investigation of tumor stroma ratio doesn't require any additional costs and slide preparation. It can be added to routine breast cancer investigation to expand knowledge about cancer prognosis.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Biomarcadores de Tumor , Neoplasias de la Mama/patología , Humanos , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Células del Estroma/patología , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Breast cancer is the second leading cause of cancer death among women worldwide and besides life style, age and genetic risk factors, exposure to ionizing radiation is known to increase the risk for breast cancer. Further, DNA copy number alterations (CNAs), which can result from radiation-induced double-strand breaks, are frequently occurring in breast cancer cells. We set out to identify a signature of CNAs discriminating breast cancers from radiation-exposed and non-exposed female patients. We analyzed resected breast cancer tissues from 68 exposed female Chernobyl clean-up workers and evacuees and 68 matched non-exposed control patients for CNAs by array comparative genomic hybridization analysis (aCGH). Using a stepwise forward-backward selection approach a non-complex CNA signature, that is, less than ten features, was identified in the training data set, which could be subsequently validated in the validation data set (p value < 0.05). The signature consisted of nine copy number regions located on chromosomal bands 7q11.22-11.23, 7q21.3, 16q24.3, 17q21.31, 20p11.23-11.21, 1p21.1, 2q35, 2q35, 6p22.2. The signature was independent of any clinical characteristics of the patients. In all, we identified a CNA signature that has the potential to allow identification of radiation-associated breast cancer at the individual level.
Asunto(s)
Neoplasias de la Mama/genética , Accidente Nuclear de Chernóbil , Variaciones en el Número de Copia de ADN , Neoplasias Inducidas por Radiación/genética , Exposición a la Radiación/efectos adversos , Adulto , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/patología , Estudios de Cohortes , Hibridación Genómica Comparativa , Femenino , Estudios de Seguimiento , Dosificación de Gen , Genómica , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Neoplasias Inducidas por Radiación/epidemiología , Neoplasias Inducidas por Radiación/patología , Pronóstico , Curva ROC , Ucrania/epidemiologíaRESUMEN
Ionizing radiation is a well-recognized risk factor for the development of breast cancer. However, it is unknown whether radiation-specific molecular oncogenic mechanisms exist. We investigated post-Chernobyl breast cancers from radiation-exposed female clean-up workers and nonexposed controls for molecular changes. Radiation-associated alterations identified in the discovery cohort (n = 38) were subsequently validated in a second cohort (n = 39). Increased expression of hsa-miR-26b-5p was associated with radiation exposure in both of the cohorts. Moreover, downregulation of the TRPS1 protein, which is a transcriptional target of hsa-miR-26b-5p, was associated with radiation exposure. As TRPS1 overexpression is common in sporadic breast cancer, its observed downregulation in radiation-associated breast cancer warrants clarification of the specific functional role of TRPS1 in the radiation context. For this purpose, the impact of TRPS1 on the transcriptome was characterized in two radiation-transformed breast cell culture models after siRNA-knockdown. Deregulated genes upon TRPS1 knockdown were associated with DNA-repair, cell cycle, mitosis, cell migration, angiogenesis and EMT pathways. Furthermore, we identified the interaction partners of TRPS1 from the transcriptomic correlation networks derived from gene expression data on radiation-transformed breast cell culture models and sporadic breast cancer tissues provided by the TCGA database. The genes correlating with TRPS1 in the radiation-transformed breast cell lines were primarily linked to DNA damage response and chromosome segregation, while the transcriptional interaction partners in the sporadic breast cancers were mostly associated with apoptosis. Thus, upregulation of hsa-miR-26b-5p and downregulation of TRPS1 in radiation-associated breast cancer tissue samples suggests these molecules representing radiation markers in breast cancer.