Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

Zhang, Min; Liu, Guoyan; Xue, Fengxia; Edwards, Robert P.; Sood, Anil K.; Zhang, Wei; Yang, Da

doi:10.1016/j.ygyno.2016.01.004

Cited by 39 publications

(34 citation statements)

References 36 publications

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“…RAD50 is a key DNA repair gene and is involved in the homologous recombination pathway . A recent study suggested that downregulation of RAD50 expression in ovarian cancer cells led to an increased response to cisplatin and olaparib . Therefore, RAD50 mutation carriers may be potential candidates for treatment with PARP inhibitors.…”

Section: Discussionmentioning

confidence: 99%

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Fan

Zhang

Ouyang

et al. 2018

Intl Journal of Cancer

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RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n = 6 cases; K994fs, n = 5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p = 0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p = 0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.

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Section: Discussionmentioning

confidence: 99%

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Fan

Zhang

Ouyang

et al. 2018

Intl Journal of Cancer

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“…Recent studies showed that PARPi sensitivity is not restricted to familial BRCA-mutated cancers and that all tumors incapable of the error-free DSB repair, i.e., tumors with a defect in the HR repair pathway, can benefit from PARPi treatment [152]. Zhang et al identified the copy number deletion of RAD50 as a candidate marker for survival and response to PARPi in BRCA-wildtype OvCa tumors [156]. Lee et al developed a multiparameter flow cytometry assay to measure γH2AX and MRE11, indicators of double-strand breaks and DBS-repair, in PBMCs [157].…”

Section: Biomarkers Predicting Responses To Biotherapies In Ovcamentioning

confidence: 99%

Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

Szajnik

Czystowska-Kuźmicz

Elishaev

et al. 2016

Expert Review of Molecular Diagnostics

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Introduction Ovarian cancer (OvCa) is among the most common types of cancer and is the leading cause of death from gynecological malignancies in western countries. Cancer biomarkers have a potential for improving the management of OvCa patients at every point from screening and detection, diagnosis, prognosis, follow up, response to therapy and outcome. Areas covered The literature search has indicated a number of candidate biomarkers have recently emerged that could facilitate the molecular definition of OvCa, providing information about prognosis and predicting response to therapy. These potentially promising biomarkers include immune cells and their products, tumor-derived exosomes, nucleic acids and epigenetic biomarkers. Expert commentary Although most of the biomarkers available today require prospective validation, the development of noninvasive liquid biopsy-based monitoring promises to improve their utility for evaluations of prognosis, response to therapy and outcome in OvCa.

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“…In addition, the mutation of RAD50 has an adverse effect on the prognosis of prostate cancer patients [7]. Increased RAD50 expression has been found in multiple tumours, including breast cancer, ovarian cancer, lung cancer and rectal cancer [8][9][10][11]. For example, RAD50 increases in colorectal cancer patients have been shown to be positively related to tumour development and prognosis [12].…”

Section: Introductionmentioning

confidence: 99%

Elevated double-strand break repair protein RAD50 predicts poor prognosis in hepatitis B virus-related hepatocellular carcinoma: A study based on Chinese high-risk cohorts

Liu¹,

Xu²,

Chen³

et al. 2020

J. Cancer

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Objective: Increasing evidence indicates that RAD50, which is involved in the repair process of DNA double-strand break (DSB), is also involved in cancer outcomes. However, its role in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains unclear. This study was designed to investigate the expression of RAD50 and its prognostic value in HBV-related HCC patients. Methods: 107 and 100 patients with HBV-related HCC from the Affiliated Hospital of Youjiang Medical University of Nationalities (AHYMUN) and the Affiliated Hospital of Nantong University (AHNU), respectively, were enrolled in the study. The distribution of the categorical clinical-pathological data and the levels of RAD50 expression were compared with a χ 2 test. Immunohistochemistry (IHC) staining of RAD50 was performed. A partial likelihood test based on univariate and multivariate Cox regression analysis was developed to address the influence of independent factors on disease-free survival (DFS) and overall survival (OS). The Oncomine online database was used to analyse and validate the differential expression of RAD50. The Kaplan-Meier method and a log-rank test were performed to assess the influence of RAD50 on survival at different levels. Results: RAD50 was highly expressed in HCC tissues compared to normal tissues and was significantly correlated with OS in the Cancer Genome Atlas (TCGA) cohort. The validation analysis indicated that significantly increased levels of RAD50 were expressed in HCC tissues in the two independent cohorts. In addition, HCC patients with elevated RAD50 expression levels showed poor OS and DFS in the AHYMUN cohort and decreased OS and DFS in the AHNTU cohort. Conclusion: In conclusion, our study reveals that elevated RAD50 expression is significantly correlated with cancer progression and poor survival in HBV-related HCC patients. These data suggest that RAD50 may act as an oncogene and may serve as a promising target for the therapy of HBV-related HCC patients.

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Copy number deletion of RAD50 as predictive marker of BRCAness and PARP inhibitor response in BRCA wild type ovarian cancer

Cited by 39 publications

References 36 publications

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

RAD50 germline mutations are associated with poor survival in BRCA1/2–negative breast cancer patients

Biological markers of prognosis, response to therapy and outcome in ovarian carcinoma

Elevated double-strand break repair protein RAD50 predicts poor prognosis in hepatitis B virus-related hepatocellular carcinoma: A study based on Chinese high-risk cohorts

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