Erratum: Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions

Zámborszky, J; Szikriszt, Bernadett; Gervai, Judit; Pipek, Orsolya; Póti, Ádám; Krzystanek, Marcin; Ribli, Dezső; Szalai-Gindl, János M.; Csabai, István; Szállási, Zoltán; Swanton, C; Richardson, A L; Szüts, Dávid

doi:10.1038/onc.2017.213

Cited by 30 publications

(16 citation statements)

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“…Analysis of the mutational spectra of nucleotide triplets in tumor specimens found that a signature characterized by a flat mutational spectrum (Signature 3) was connected to HRD; thus, the relative contribution of the corresponding mutational process might be used as an estimator for the deficiency. The relative proportion of deletions caused by microhomology-mediated end joining can also be used as a robust estimator for HRD [ 12 ]. All these mutational signatures together with the so-called rearrangement signatures were combined into a robust logistic-regression model, called HRDetect [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors

et al. 2018

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BackgroundBased on its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Therefore, identification of tumor types with increased HRD is important for the optimal use of this class of therapeutic agents. HRD levels can be estimated using various mutational signatures from next generation sequencing data and we used this approach to determine whether breast cancer brain metastases show altered levels of HRD scores relative to their corresponding primary tumor.Patients and methodsWe used a previously published next generation sequencing dataset of 21 matched primary breast cancer/brain metastasis pairs to derive the various mutational signatures/HRD scores strongly associated with HRD. We also carried out the myChoice HRD analysis on an independent cohort of 17 breast cancer patients with matched primary/brain metastasis pairs.ResultsAll of the mutational signatures indicative of HRD showed a significant increase in the brain metastases relative to their matched primary tumor in the previously published whole exome sequencing dataset. In the independent validation cohort, the myChoice HRD assay showed an increased level in 87.5% of the brain metastases relative to the primary tumor, with 56% of brain metastases being HRD positive according to the myChoice criteria.ConclusionsThe consistent observation that brain metastases of breast cancer tend to have higher HRD measures may raise the possibility that brain metastases may be more sensitive to PARP inhibitor treatment. This observation warrants further investigation to assess whether this increase is common to other metastatic sites as well, and whether clinical trials should adjust their strategy in the application of HRD measures for the prioritization of patients for PARP inhibitor therapy.

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Section: Introductionmentioning

confidence: 99%

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors

et al. 2018

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“…Several groups have identified a "BRCAness" signature that is associated with HR-deficient cancers, commonly referred to as Signature 3 in the Catalog of Somatic Mutations in Cancer (COSMIC). Signature 3 is characterized by an elevated number of base substitutions, deletions, and insertions > 3 bp with microhomologies located at the suspected breakpoint junctions, characteristic of alt-EJ repair [114].…”

Section: Error-prone Repair Contributes To Genome Evolution In Cancermentioning

confidence: 99%

Regulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution

Hanscom

McVey

2020

Cells

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Double-strand breaks are one of the most deleterious DNA lesions. Their repair via error-prone mechanisms can promote mutagenesis, loss of genetic information, and deregulation of the genome. These detrimental outcomes are significant drivers of human diseases, including many cancers. Mutagenic double-strand break repair also facilitates heritable genetic changes that drive organismal adaptation and evolution. In this review, we discuss the mechanisms of various error-prone DNA double-strand break repair processes and the cellular conditions that regulate them, with a focus on alternative end joining. We provide examples that illustrate how mutagenic double-strand break repair drives genome diversity and evolution. Finally, we discuss how error-prone break repair can be crucial to the induction and progression of diseases such as cancer.

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“…Germline mutations in the BRCA1 gene occurring in breast cancer cases often result in a complete loss of function of BRCA1 [134,135]. In turn, BRCA1 loss is synthetically viable with the loss of tumor protein p53-binding protein 1 (TP53BP1) [136].…”

Section: Critical Role Of Brca1 and Tp53bp1 In Vd3 Signaling In Triplmentioning

confidence: 99%

Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy

Błasiak

Pawłowska

Chojnacki

et al. 2020

IJMS

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Several studies show that triple-negative breast cancer (TNBC) patients have the lowest vitamin D concentration among all breast cancer types, suggesting that this vitamin may induce a protective effect against TNBC. This effect of the active metabolite of vitamin D, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D), can be attributed to its potential to modulate proliferation, differentiation, apoptosis, inflammation, angiogenesis, invasion and metastasis and is supported by many in vitro and animal studies, but its exact mechanism is poorly known. In a fraction of TNBCs that harbor mutations that cause the loss of function of the DNA repair-associated breast cancer type 1 susceptibility (BRCA1) gene, 1,25(OH)2D may induce protective effects by activating its receptor and inactivating cathepsin L-mediated degradation of tumor protein P53 binding protein 1 (TP53BP1), preventing deficiency in DNA double-strand break repair and contributing to genome stability. Similar effects can be induced by the interaction of 1,25(OH)2D with proteins of the growth arrest and DNA damage-inducible 45 (GADD45) family. Further studies on TNBC cell lines with exact molecular characteristics and clinical trials with well-defined cases are needed to determine the mechanism of action of vitamin D in TNBC to assess its preventive and therapeutic potential.

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Erratum: Loss of BRCA1 or BRCA2 markedly increases the rate of base substitution mutagenesis and has distinct effects on genomic deletions

Cited by 30 publications

References 0 publications

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors

Breast cancer brain metastases show increased levels of genomic aberration-based homologous recombination deficiency scores relative to their corresponding primary tumors

Regulation of Error-Prone DNA Double-Strand Break Repair and Its Impact on Genome Evolution

Vitamin D in Triple-Negative and BRCA1-Deficient Breast Cancer—Implications for Pathogenesis and Therapy

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