Abstract
To investigate the expressions of key markers in the homologous recombination (HR) pathway and the correlation with clinicopathological parameters in serous ovarian cancer (SOC). We analyzed the protein expression of MRE11, MDC1, ATM, ATR and BRCA1 by immunohistochemistry (IHC) in 97 SOC samples, and correlated with clinical parameters including age, tumor grades, clinical stage, status of menstruation and chemotherapy. Low expression of MRE11 and MDC1 was detected in 14.4 % and 3.1 % of the patient samples, and negative expression of ATM, ATR and BRCA1 was found in 11.3 %, 6.3 % and 29.9 % of the patient samples, respectively. ATR deficiency was significantly associated with menopause (P = 0.025), strong expression of ATM (P = 0.017) and MRE11 (P = 0.040) with pre-menopausal SOC, strong expression of MRE11 (P = 0.016) with low tumor grade, and strong expression of BRCA1 (P = 0.015) with early clinical stage. In addition, low expression of MRE11 was strongly associated with negativity of ATR (P < 0.001) and BRCA1 (P = 0.004) Furthermore, ATR deficiency was associated with low expression of ATM (P = 0.028) and loss expression of BRCA1 (P = 0.009). Our results suggest that reduced expression or loss of proteins in HR pathway is associated with SOC development. Abnormality of MRE11 and BRCA1 are strongly associated with late clinical stage in SOC patients.
Highlights
DNA double-strand breaks (DSBs) are hazardous to the cell since they cause base pair mismatch,[1] which is strongly associated with cancer susceptibility
In our serous ovarian cancer (SOC) samples, negative expression (IHC score ‘0’) of homologous recombination (HR) pathway proteins was at the following rates; Ataxia telangiectasia mutated (ATM) 11.3 % (11/97), ATR 6.3 % (6/96), and Breast cancer susceptibility gene 1 (BRCA1) 29.9 % (29/97)
Platinum-based chemotherapy regimens are widely used to treat Ovarian cancer (OC) patients, these are nonspecific treatment modalities which can lead to severe side effects and poor tolerance due to effects on normal tissues
Summary
DNA double-strand breaks (DSBs) are hazardous to the cell since they cause base pair mismatch,[1] which is strongly associated with cancer susceptibility. Three mechanisms exist to repair DSBs: non-homologous end joining (NHEJ), microhomologymediated end joining (MMEJ), and homologous recombination (HR).[2] HR-mediated repair requires one homologous sequence to accurately repair breaks. MMEJ requires a 5–25 base pair microhomologous sequence, whilst NHEJ can function to directly religate broken ends in the absence of a homologous template. HR repairs DSBs in the late S and G2 phases of the cell cycle when sister chromatids are readily available,[3] as opposed to MMEJ which occurs in S phase and NHEJ in the G0/ G1 and early S phases. Sister chromatids are ideal templates for repair as they provide identical copies of the same chromosome. HR plays an important role in the fidelity of DNA replication,[4] which is vital to the integrity and stability of the genome
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