Clarifying the role of EMSY in DNA repair in ovarian cancer

Kondrashova, Olga; Scott, Clare L.

doi:10.1002/cncr.32135

Cited by 8 publications

(6 citation statements)

References 25 publications

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“…Mutations in BRCA1/2 genes result in homologous recombination (HR) deficiency which may be utilized in the treatment of OC with platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors [6,[8][9][10]. Other mechanisms of HR deficiency, which lead to phenotype described as BRCAness, include germline and somatic mutations in other HR-related genes, epigenetic modifications (e.g., BRCA1, RAD51C promoter hypermethylation) [11][12][13], and EMSY amplification/ overexpression [14,15]. Even up to 50% of OC exhibit HR deficiency (most commonly high-grade serous OC), therefore a substantial fraction of OC patients may benefit from therapeutic approaches based on PARP inhibitors [16].…”

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confidence: 99%

BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases

2020

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Background: It is estimated that more than 20% of ovarian cancer cases are associated with a genetic predisposition that is only partially explained by germline mutations in the BRCA1 and BRCA2 genes. Recently, several pieces of evidence showed that mutations in three genes involved in the homologous recombination DNA repair pathway, i.e., BRIP1, RAD51C, and RAD51D, are associated with a high risk of ovarian cancer. To more precisely estimate the ovarian cancer risk attributed to BRIP1, RAD51C, and RAD51D mutations, we performed a meta-analysis based on a comparison of a total of~29,400 ovarian cancer patients from 63 studies and a total of~116,000 controls from the gnomAD database. Results: The analysis allowed precise estimation of ovarian cancer risks attributed to mutations in BRIP1, RAD51C, and RAD51D, confirming that all three genes are ovarian cancer high-risk genes (odds ratio (OR) = 4.94, 95%CIs:4.07-6.00, p < 0.0001; OR = 5.59, 95%CIs:4.42-7.07, p < 0.0001; and OR = 6.94, 95%CIs:5.10-9.44, p < 0.0001, respectively). In the present report, we show, for the first time, a mutation-specific risk analysis associated with distinct, recurrent, mutations in the genes. Conclusions: The meta-analysis provides evidence supporting the pathogenicity of BRIP1, RAD51C, and RAD51D mutations in relation to ovarian cancer. The level of ovarian cancer risk conferred by these mutations is relatively high, indicating that after BRCA1 and BRCA2, the BRIP1, RAD51C, and RAD51D genes are the most important ovarian cancer risk genes, cumulatively contributing to~2% of ovarian cancer cases. The inclusion of the genes into routine diagnostic tests may influence both the prevention and the potential treatment of ovarian cancer.

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confidence: 99%

BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases

2020

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“…The EMSY gene was amplified along with CCND1 , PAK1 , and RSF1 most likely due to these genes’ grouped location within the 11q13 amplicon region. 6 Although the genes amplified, like CCND1 , PAK1 , and RSF1 , they have been implicated as potential oncogenes, EMSY and CCND1, have been proposed as the most likely drivers of oncogenesis. 6 , 7 Due to the amplification of other potential oncogenes, we cannot confirm that the EMSY gene amplification is the response marker for PARPi in this report.…”

Section: Discussionmentioning

confidence: 99%

“… 6 Although the genes amplified, like CCND1 , PAK1 , and RSF1 , they have been implicated as potential oncogenes, EMSY and CCND1, have been proposed as the most likely drivers of oncogenesis. 6 , 7 Due to the amplification of other potential oncogenes, we cannot confirm that the EMSY gene amplification is the response marker for PARPi in this report. However, its putative activity within the HR-DDR pathway and its interaction with the BRCA2 gene, an already established marker for PARPi response, argues for its viability as a predictor for response.…”

Section: Discussionmentioning

confidence: 99%

Poly (ADP-Ribose) Polymerase inhibitors (PARPi) therapy response in an acral melanoma patient with EMSY gene amplification

Nassief,

Butt,

Zhou

et al. 2024

JAAD Case Reports

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“…Further, there are patients with “BRCA mutated-like” ovarian carcinomas and impaired HR (i.e: with amplification/overexpression of EMSY [ 44 , 45 ]; with structural variances/hypermethylation in BRCA1/2 [ 46 , 47 ] and with mutation in genes involved in HR [ 5 , 48 ]). These patients could potentially also benefit from treatment with IAP inhibitors although this requires further study to confirm.…”

Section: Discussionmentioning

confidence: 99%

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

et al. 2022

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Background We tested the hypothesis that inhibitor of apoptosis family (IAP) proteins may be altered in BRCA1-mutated ovarian cancers and that could affect the sensitivity to IAP inhibitors. Methods The levels of IAP proteins were evaluated in human cancers and cell lines. Cell lines were used to determine the effects of IAP inhibitors. The in vivo effects of treatments were evaluated in PDX mouse models. Results Expression of X-linked inhibitor of apoptosis (XIAP) is increased in BRCA1-mutated cancers and high levels are associated with improved patient outcomes after platinum chemotherapy. XIAP overexpression is mediated by NF-kB activation and is associated with an optimisation of PARP. BRCA1-mutated cell lines are particularly sensitive to IAP inhibitors due to an inhibitory effect on PARP. Both a BRCA1-mutated cell line with acquired resistance to PARP inhibitors and one with restored BRCA1 remain sensitive to IAP inhibitors. Treatment with IAP inhibitors restores the efficacy of PARP inhibition in these cell lines. The IAP inhibitor LCL161 alone and in combination with a PARP inhibitor, exhibited antitumour effects in PDX mouse models of resistant BRCA2 and 1-mutated ovarian cancer, respectively. Conclusion A clinical trial may be justified to further investigate the utility of IAP inhibitors.

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Clarifying the role of EMSY in DNA repair in ovarian cancer

Cited by 8 publications

References 25 publications

BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases

BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases

Poly (ADP-Ribose) Polymerase inhibitors (PARPi) therapy response in an acral melanoma patient with EMSY gene amplification

BRCA mutations lead to XIAP overexpression and sensitise ovarian cancer to inhibitor of apoptosis (IAP) family inhibitors

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