Homologous recombination proficiency in ovarian and breast cancer patients

Creeden, Justin; Nanavaty, Nisha S.; Einloth, Katelyn; Gillman, Cassidy; Stanbery, Laura; Hamouda, Danae; Dworkin, Lance D.; Nemunaitis, John

doi:10.1186/s12885-021-08863-9

Cited by 41 publications

(28 citation statements)

References 136 publications

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“…In BRCA1 and BRCA2 , multiple mutation cluster regions have been observed and are associated with relatively different BC and OC risks [ 31 ]. In our cohort, five out of seven BRCA1 pathogenic mutations are located from c.5216 to c.5563, which has been described as a region associated with higher BC risk [ 10 ]. Deleterious mutation of BRCA2 were detected in the coding sequence region comprised between c.3187 and c.6450, which is consistent with the higher OC risk compared to BC risk associated to mutations in this cluster [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

“…In our cohort, five out of seven BRCA1 pathogenic mutations are located from c.5216 to c.5563, which has been described as a region associated with higher BC risk [ 10 ]. Deleterious mutation of BRCA2 were detected in the coding sequence region comprised between c.3187 and c.6450, which is consistent with the higher OC risk compared to BC risk associated to mutations in this cluster [ 10 ]. To our knowledge, no significance differences have been reported so far in the assessment of OC risk vs. BC risk in correlation with the distribution of the pathogenic variants along BRIP1 , RAD51C , and BARD1 coding sequences.…”

Section: Discussionmentioning

confidence: 99%

“…Genes such as BARD1 , BRIP1 , PALB2 , RAD51C , and RAD51D are all involved in the HR DNA repair mechanism interacting with both BRCA1 and BRCA2 . Briefly, BRCA1 binds the site of DSB where it coordinates the repair mechanisms downstream [ 10 ]. BARD1 and BRIP1 both directly interact with BRCA1 mediating its function [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

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Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Turchiano

Loconte

Nola

et al. 2022

Cancers

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Background: Pathogenic variants in homologous recombination repair (HRR) genes other than BRCA1/2 have been associated with a high risk of ovarian cancer (OC). In current clinical practice, genetic testing is generally limited to BRCA1/2. Herein, we investigated the mutational status of both BRCA1/2 and 5 HRR genes in 69 unselected OC, evaluating the advantage of multigene panel testing in everyday clinical practice. Methods: We analyzed 69 epithelial OC samples using an NGS custom multigene panel of the 5 HRR pathways genes, beyond the genetic screening routine of BRCA1/2 testing. Results: Overall, 19 pathogenic variants (27.5%) were detected. The majority (21.7%) of patients displayed a deleterious mutation in BRCA1/2, whereas 5.8% harbored a pathogenic variant in one of the HRR genes. Additionally, there were 14 (20.3%) uncertain significant variants (VUS). The assessment of germline mutational status showed that a small number of variants (five) were not detected in the corresponding blood sample. Notably, we detected one BRIP1 and four BRCA1/2 deleterious variants in the low-grade serous and endometrioid histology OC, respectively. Conclusion: We demonstrate that using a multigene panel beyond BRCA1/2 improves the diagnostic yield in OC testing, and it could produce clinically relevant results.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Turchiano

Loconte

Nola

et al. 2022

Cancers

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“…This repair pathway is active throughout the cell cycle, particularly in the G0/G1 phase when sister chromatids are absent. Contrastingly, HR is the main pathway used strictly in late S or G2 phase cells and can accurately repair the damage using intact homologous sister chromatids as a sequence homologous template for the DNA repair reaction [9,27] (Figure 3a).…”

Section: • Hr Repairmentioning

confidence: 99%

Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

Yoshimura

Imoto

Iwata

2022

IJMS

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Approximately 5–10% of all breast cancer (BC) cases are caused by germline pathogenic variants (GPVs) in various cancer predisposition genes (CPGs). The most common contributors to hereditary BC are BRCA1 and BRCA2, which are associated with hereditary breast and ovarian cancer (HBOC). ATM, BARD1, CHEK2, PALB2, RAD51C, and RAD51D have also been recognized as CPGs with a high to moderate risk of BC. Primary and secondary cancer prevention strategies have been established for HBOC patients; however, optimal preventive strategies for most hereditary BCs have not yet been established. Most BC-associated CPGs participate in DNA damage repair pathways and cell cycle checkpoint mechanisms, and function jointly in such cascades; therefore, a fundamental understanding of the disease drivers in such cascades can facilitate the accurate estimation of the genetic risk of developing BC and the selection of appropriate preventive and therapeutic strategies to manage hereditary BCs. Herein, we review the functions of key BC-associated CPGs and strategies for the clinical management in individuals harboring the GPVs of such genes.

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“…The breast cancer 1, early onset (BRCA1) germline and somatic mutation rates are ~11.5% and 7%, respectively, in ovarian cancer (OC) [ 1 – 4 ]. BRCA1 mutations cause loss of BRCA1 protein function and, as a result, DNA repair by homologous recombination (HR) is defective [ 5 ]. This renders OC cells with BRCA1 mutations specifically sensitive to cytotoxicity by platinum-based chemotherapy drugs [ 6 ], and by Poly (ADP-ribose) polymerase (PARP) inhibitors [ 6 ].…”

Section: Introductionmentioning

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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Homologous recombination proficiency in ovarian and breast cancer patients

Cited by 41 publications

References 136 publications

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Beyond BRCA1/2: Homologous Recombination Repair Genetic Profile in a Large Cohort of Apulian Ovarian Cancers

Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

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

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