ABSTRACT
INTRODUCTION: Homologous recombination (HR) is a crucial DNA-repair mechanism, and its disruption can lead to the accumulation of mutations that initiate and promote cancer formation. The key HR genes, BRCA1 and BRCA2, are particularly significant as their germline pathogenic variants are associated with a hereditary predisposition to breast and/or ovarian cancer. MATERIALS AND METHODS: The study was performed on 45 FFPE breast cancer tissues obtained from 24 and 21 patients, with and without the germline BRCA1/2 mutation, respectively. The expression of 11 genes: BRCA1, BRCA2, ATM, BARD1, FANCA, FANCB, FANCI, RAD50, RAD51D, BRIP1, and CHEK2 was assessed using Custom RT2 PCR Array (Qiagen), and results were analysed using R. RESULTS: Cancer tissues from patients with BRCA1 or BRCA2 germline mutations displayed no significant differences in the expression of the selected HR genes compared to BRCA1 or BRCA2 wild-type cancer tissues. In BRCA1mut cancer tissues, BRCA1 expression was significantly higher than in BRCA2mut and BRCA wild-type cancer tissues. CONCLUSIONS: In cancer tissues harbouring either BRCA1 or BRCA2 germline mutations, no significant differences in expression were observed at the mRNA level of any tested HR genes, except BRCA1. However, the significant differences observed in BRCA1 expression between germline BRCA1mut, germline BRCA2mut and BRCA1/2wt tissues may indicate a compensatory mechanism at the mRNA level to mitigate the loss of BRCA1 function in the cells.
ABSTRACT
Neoadjuvant chemotherapy is the foundation treatment for triple-negative breast cancer (TNBC) and frequently results in pathological complete response (pCR). However, there are large differences in clinical response and survival after neoadjuvant chemotherapy of TNBC patients. The aim was to identify genes whose expression significantly associates with the efficacy of neoadjuvant chemotherapy in patients with TNBC. Transcriptomes of 46 formalin-fixed paraffin-embedded (FFPE) tumor samples from TNBC patients were analyzed by RNA-seq by comparing 26 TNBCs with pCR versus 20 TNBCs with pathological partial remission (pPR). Subsequently, we narrowed down the list of genes to those that strongly correlated with drug sensitivity of 63 breast cancer cell lines based on Dependency Map Consortium data re-analysis. Furthermore, the list of genes was limited to those presenting specific expression in breast tumor cells as revealed in three large published single-cell RNA-seq breast cancer datasets. Finally, we analyzed which of the selected genes were significantly associated with overall survival (OS) in TNBC TCGA dataset. A total of 105 genes were significantly differentially expressed in comparison between pPR versus pCR. As revealed by PLSR analysis in breast cancer cell lines, out of 105 deregulated genes, 42 were associated with sensitivity to docetaxel, doxorubicin, paclitaxel, and/or cyclophosphamide. We found that 24 out of 42 sensitivity-associated genes displayed intermediate or strong expression in breast malignant cells using single-cell RNAseq re-analysis. Finally, 10 out of 24 genes were significantly associated with overall survival in TNBC TCGA dataset. Our RNA-seq-based findings suggest that there might be transcriptomic signature consisted of 24 genes specifically expressed in tumor malignant cells for predicting neoadjuvant response in FFPE samples from TNBC patients prior to treatment initiation. Additionally, nine out of 24 genes were potential survival predictors in TNBC. This group of 24 genes should be further investigated for its potential to be translated into a predictive test(s).
ABSTRACT
For many years, the age of the patient, the condition of axillar lymph nodes, the size of the tumour, histological traits (in particular histological grade of malignancy and invasion of lymphatic vessels), condition of hormonal receptors and HER2 represented principal factors used for the stratification of breast cancer patients for the purposes of evaluating the prognosis and determining the appropriate strategy of treatment. Although the variables are useful for the prognostic evaluation of individual groups of breast cancer patients, their role in determining the individual risk level of the patient and in the selection of supplementary treatment is quite restricted. This article shows the prognostic value of additional parameters, whose expression is associated with chemioresistance (MRP2, BCRP, YB1) or individual assessment of the dynamics of tumor progression (S100P, BUBR1). In addition, it describes the role of an online database of "The Kaplan-Meier plotter" which contains the assessment of the effects of expression of various genes on the clinical outcome of patients with breast cancer.
