The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

In the era of precision medicine, analyzing the transcriptomic profile of patients is essential to tailor the appropriate therapy. In this study, we explored transcriptional differences between two invasive breast cancer subtypes; infiltrating ductal carcinoma (IDC) and lobular carcinoma (LC) using RNA-Seq data deposited in the TCGA-BRCA project. We revealed 3854 differentially expressed genes between normal ductal tissues and IDC. In addition, IDC to LC comparison resulted in 663 differentially expressed genes. We then focused on DNA repair genes because of their known effects on patients’ response to therapy and resistance. We here report that 36 DNA repair genes are overexpressed in a significant number of both IDC and LC patients’ samples. Despite the upregulation in a significant number of samples, we observed a noticeable variation in the expression levels of the repair genes across patients of the same cancer subtype. The same trend is valid for the expression of miRNAs, where remarkable variations between patients’ samples of the same cancer subtype are also observed. These individual variations could lie behind the differential response of patients to treatment. The future of cancer diagnostics and therapy will inevitably depend on high-throughput genomic and transcriptomic data analysis. However, we propose that performing analysis on individual patients rather than a big set of patients’ samples will be necessary to ensure that the best treatment is determined, and therapy resistance is reduced.

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Homologous recombination deficiency (HRD) in patients with pancreatic cancer (PC) and response to chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.317 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 317-317 ◽

Cited By ~ 3

Author(s):

Safi Shahda ◽

Kirsten Timms ◽

Ashley Ibrahim ◽

Julia E. Reid ◽

Harvey M Cramer ◽

...

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Locally Advanced ◽

Response To Therapy ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Response To Chemotherapy ◽

Mutation Data ◽

Repair Genes

317 Background: Mutations or copy number abnormalities of genes involved in homologous recombination occur in PC. DNA-based measures of HRD have been developed and may help identify tumors with better response to DNA damaging agents. This study aimed to describe the mutation and HRD status of PC and determine their association with treatment response and outcome. Methods: This was a retrospective analysis of tumor samples from patients treated at Indiana University for locally advanced or metastatic PC. Patients were included if they received gemcitabine/nab-paclitaxel or FOLFIRINOX and had adequate follow up to assess survival and response to therapy. Tumor analysis generated a 3-biomarker (LOH, TAI, LST) HRD score and mutation data for 45 genes. Results: Ninety-one samples met inclusion criteria, 78 (15 FFPE and 63 FNA) generated mutation data. HRD analysis was successful for 57; the primary cause of failure low tumor %. The final analysis set consisted of 78 samples with mutation status, including 57 with HRD scores (range= 5 -61 (median=18,)). Six BRCA1/ 2 mutations were detected, 5 had high HRD scores, with 4 in the top decile (p=0.011). Other DNA repair gene mutations ( ATM=3, ATR=1, BRIP1=1 and FANCI=1) were detected, but most retained one functional allele and were not associated with HRD score. There was no statistically significant correlation between HRD score and response to FOLFIRINOX (OR per interquartile range = 1.40, p=0.32 adjusted for treatment). HRD score was not associated with PFS or OS. For FOLFIRINOX, median survival times for low vs. high HRD (dichotomized at the median) were 5.3 vs. 9.4 months PFS (p=0.049) and OS 12.3 vs. 11.3 months (p=0.89). For gemcitabine/nab-paclitaxel, mPFS was 6.1 vs. 4.6 months (p=0.88), and mOS was 14.4 vs. 11.4 months (p=0.29). Conclusions: Mutations in DNA repair genes occur in PC, and HRD scores can be generated in the majority of cases. HRD score was not significantly associated with higher response rate or prolonged survival in relation to FOLFIRINOX in this small non-randomized retrospective cohort. Larger studies to examine the association of mutations in DNA repair genes and HRD may be needed to detect significant associations.

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Truncating variants in DNA-repair genes and their effect on AAO of hereditary breast cancer

10.1055/s-0038-1651801 ◽

2018 ◽

Author(s):

I Sepahi ◽

U Faust ◽

M Sturm ◽

K Bosse ◽

M Kehrer ◽

...

Keyword(s):

Breast Cancer ◽

Dna Repair ◽

Hereditary Breast Cancer ◽

Dna Repair Genes ◽

Repair Genes

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Comprehensive Analyses of Copy Number Variations In DNA Repair Genes Reveal the Role of Poly(ADP-Ribose) Polymerase in Longevity in Trees

SSRN Electronic Journal ◽

10.2139/ssrn.3751787 ◽

2020 ◽

Author(s):

Yuta Aoyagi Blue ◽

Junko Kusumi ◽

Akiko Satake

Keyword(s):

Dna Repair ◽

Copy Number ◽

Copy Number Variations ◽

Dna Repair Genes ◽

Repair Genes

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Copy number analyses of DNA repair genes reveal the role of poly(ADP-ribose) polymerase (PARP) in tree longevity

iScience ◽

10.1016/j.isci.2021.102779 ◽

2021 ◽

pp. 102779

Author(s):

Yuta Aoyagi Blue ◽

Junko Kusumi ◽

Akiko Satake

Keyword(s):

Dna Repair ◽

Copy Number ◽

Dna Repair Genes ◽

Repair Genes

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Coexistence of SOS-Dependent and SOS-Independent Regulation of DNA Repair Genes in Radiation-Resistant Deinococcus Bacteria

Cells ◽

10.3390/cells10040924 ◽

2021 ◽

Vol 10 (4) ◽

pp. 924

Author(s):

Laurence Blanchard ◽

Arjan de Groot

Keyword(s):

Dna Repair ◽

Deinococcus Radiodurans ◽

Dna Repair Genes ◽

Lesion Bypass ◽

Radiation Resistant ◽

Radiation Induced ◽

Induced Mutagenesis ◽

High Doses ◽

Translesion Polymerases ◽

Repair Genes

Deinococcus bacteria are extremely resistant to radiation and able to repair a shattered genome in an essentially error-free manner after exposure to high doses of radiation or prolonged desiccation. An efficient, SOS-independent response mechanism to induce various DNA repair genes such as recA is essential for radiation resistance. This pathway, called radiation/desiccation response, is controlled by metallopeptidase IrrE and repressor DdrO that are highly conserved in Deinococcus. Among various Deinococcus species, Deinococcus radiodurans has been studied most extensively. Its genome encodes classical DNA repair proteins for error-free repair but no error-prone translesion DNA polymerases, which may suggest that absence of mutagenic lesion bypass is crucial for error-free repair of massive DNA damage. However, many other radiation-resistant Deinococcus species do possess translesion polymerases, and radiation-induced mutagenesis has been demonstrated. At least dozens of Deinococcus species contain a mutagenesis cassette, and some even two cassettes, encoding error-prone translesion polymerase DnaE2 and two other proteins, ImuY and ImuB-C, that are probable accessory factors required for DnaE2 activity. Expression of this mutagenesis cassette is under control of the SOS regulators RecA and LexA. In this paper, we review both the RecA/LexA-controlled mutagenesis and the IrrE/DdrO-controlled radiation/desiccation response in Deinococcus.

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Patients with Systemic Sclerosis Present Increased DNA Damage Differentially Associated with DNA Repair Gene Polymorphisms

The Journal of Rheumatology ◽

10.3899/jrheum.130376 ◽

2014 ◽

Vol 41 (3) ◽

pp. 458-465 ◽

Cited By ~ 11

Author(s):

Gustavo Martelli Palomino ◽

Carmen L. Bassi ◽

Isabela J. Wastowski ◽

Danilo J. Xavier ◽

Yara M. Lucisano-Valim ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Systemic Sclerosis ◽

Blood Cells ◽

Gene Polymorphisms ◽

Peripheral Blood Cells ◽

Dna Repair Genes ◽

Repair Gene ◽

Dna Repair Gene ◽

Repair Genes

Objective.Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1Arg399Gln andXRCC4Ile401Thr) in patients with SSc.Methods.A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay.Results.Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage.XRCC1(rs: 25487) andXRCC4(rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, theXRCC1Arg399Gln allele was associated with increased DNA damage only in healthy controls and theXRCC4Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, theXRCC1Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc.Conclusion.These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of theXRCC1andXRCC4DNA repair genes may differentially influence DNA damage and the development of autoantibodies.

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