Transcriptome profiling may be a powerful and effective method for searching for new molecular biomarkers of cancer prognosis, risk of progression, cancer-free survival, and other clinical features. Recent studies confirmed that a high homologous recombination deficiency (HRD) score is associated with poor survival among BC, prostate cancer, glioma, and head and neck squamous cell carcinoma (HNSCC) patients [21,22,23,24,25]. Hence, HRD, resulting from the loss of function of HR genes, including BRCA1/2, has been approved as an independent predictive biomarker of sensitivity to PARPi therapy [15, 16, 26]. Moreover, recent studies suggest a potential predictive value of HRD status in platinum-based chemotherapy in breast [27] and ovarian cancer (OC) patients [28].

Our study assessed the expression of the selected main HR pathway genes in cancer tissue to check whether their mRNA levels are altered in the BRCA1/2mut BC. The rationale for this research was based on the extensive interconnections among HR proteins, where deregulation of a single but critical gene’s expression could potentially impact the expression of others.

The only statistically significant differences were observed for BRCA1, as its mRNA level was elevated in BRCA1-mutated tissues compared to BRCA2-mutated and BRCA1/2 wild-type tissues.

Our results are consistent with those published by Wang et al., who proved that BRCA1 and BRCA2 gene expression is upregulated in breast and ovarian cancer (OC) tissues. Moreover, these authors observed an increased expression of NF1 and SYCP2 genes, interacting with BRCA1/2 genes in the regulation of the cell cycle. Therefore, they suggested the importance of functional interrelations among the BRCA1/2 with the other genes involved in BC and OC development and progression, thus, influencing the clinical course of disease and treatment outcomes [29].

In their recent study on 38 ovarian cancer vs 11 fallopian tube tissues, Custódio et al. showed that BRCA1/2 mRNA expression varied between individual samples. Moreover, in tissues characterised by downregulated BRCA1/2 expression, the other 12 genes involved in the HR pathway also exhibited low mRNA levels. The analysis of 299 ovarian cancer samples from The Cancer Genome Atlas (TCGA) confirmed these findings [30]. It is important to emphasise that our study’s findings on BRCAmut breast cancer tissues differ, as we observed elevated mRNA levels for BRCA1. This discrepancy may arise from the varying schemes and methodologies employed in the studies: 1) the cancer type (BC vs OC) or 2) different HR genes studied (ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, EXO1, FAN1, FANCA, FANCB, FANCC vs ATM, BARD1, FANCA, FANCB, FANCI, RAD50, RAD51D, BRIP1, CHEK2), 3) different BRCA1/2 mutational status (17/40 (42.5%) samples with BRCA1/2 pathogenic or likely pathogenic variant vs 24/45 (53%)), and finally, the most importantly 4) different laboratory methods (very sensitive and accurate NanoString Technology and droplet digital PCR (ddPCR) vs real-time PCR).

Another study on 96 fresh frozen ovarian cancer tissues obtained from chemotherapy-naïve patients and patients after neoadjuvant chemotherapy was performed using a tailored NanoString-based Pancancer Pathway Panel of 19 HR genes and showed a correlation between over-expression of C11osf30, NBN, FANCF, FANCC, FANCB, RAD50 and improved outcome in chemotherapy-naïve patients. Moreover, a correlation has been observed between over-expression of BRCA2, TP53, FANCB, and RAD51 and worse outcomes in chemotherapy-treated patients. When adding the extent of debulking as a covariate, the expression of NBN, FANCF, RAD50, and RAD51 was significant, respectively [31].

Also, in the bladder cancer cell lines, the expression of four DNA damage repair genes, including two MR genes, was evaluated respectively before and after chemotherapy. The authors of this study revealed that the increase of BRCA1 and RBBP8 expression induced by chemotherapy correlates with worse sensitivity to treatment in non-basal and non-luminal cell lines. In contrast, no significant differences in the basal-cell lines most sensitive to chemo and radiotherapy were observed. This observation revealed the high diversity of HR genes expression, which correlates with the histopathological characteristics of tumours [32]. Moreover, in 413 bladder cancer samples (data derived from TCGA), a significantly higher expression level of four genes, RAD21, RAD51, BARD1, and ERBB2, was observed in ERBB-low as compared to ERBB-high tumours. Also, the combined expression of two out of four tested genes has been shown to correlate with chosen clinical features. This confirms the interconnections among the expression of different HR pathway genes [33].

In sporadic gastric cancer patients after receiving postoperative adjuvant chemotherapy, BRCA1/BRCA2 expression assessed using IHC and mRNA tests displayed a correlation between BRCA2-elevated expression with advanced tumour stage but not disease-free and overall survival [34].

These findings indicate that the investigation should encompass not only the alterations in individual HR genes but also their interrelations, considering the clinical course of the disease alongside histopathological and biochemical variables characterising the studied cancer.