Germline Variants in DNA Damage Repair Genes: An Emerging Role in the Era of Precision Medicine in Pancreatic Adenocarcinoma

More knowledge is needed around the role and importance of specific genes in germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. In this study, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out an ancestry-matched case-control analysis to screen for enrichment of pathogenic germline variants in 141 established cancer predisposition genes in 1138 individuals with pediatric sarcoma diagnoses (222 Ewing sarcoma cases) relative to identically processed cancer-free controls. Findings in Ewing sarcoma were validated with an additional cohort of 425 individuals, and 301 Ewing sarcoma parent-proband trios were analyzed for inheritance patterns of identified pathogenic variants. A distinct pattern of pathogenic germline variants was seen in Ewing sarcoma relative to other sarcoma subtypes. FANCC was the only gene with an enrichment signal for heterozygous pathogenic variants in the discovery Ewing sarcoma cohort (OR 14.4, 95% CI 3.5 - 51.2, p = 0.002, FDR = 0.28). This enrichment in FANCC heterozygous pathogenic variants was seen again in the Ewing sarcoma validation cohort (OR 5.1, 95% CI 1.2 - 18.5, p = 0.03, single hypothesis), representing a broader importance of genes involved in DNA damage repair, which were also nominally enriched in Ewing sarcoma cases. Pathogenic variants in DNA damage repair genes were acquired through autosomal inheritance. Our study provides new insight into germline risk factors contributing to Ewing sarcoma pathogenesis.

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P57.04 Mutations of DNA Damage Repair Genes in Lung Adenocarcinoma and Their Association with Actionable Alterations

Journal of Thoracic Oncology ◽

10.1016/j.jtho.2021.01.948 ◽

2021 ◽

Vol 16 (3) ◽

pp. S534-S535

Author(s):

Z. Yu ◽

S. Dang ◽

J. Zhang ◽

J. Duan ◽

S. Chen ◽

...

Keyword(s):

Dna Damage ◽

Lung Adenocarcinoma ◽

Dna Damage Repair ◽

Damage Repair ◽

Repair Genes

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DISTRIBUTION OF DNA DAMAGE REPAIR GENE POLYMORPHISM hOGG1, XRCC1 and p53 AMONG SICKLE CELL DISEASE PATIENTS IN INDIA

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2015.046 ◽

2015 ◽

Vol 7 ◽

pp. e2015046 ◽

Cited By ~ 1

Author(s):

Sudhansu Sekhar Nishank

Keyword(s):

Oxidative Stress ◽

Dna Damage ◽

Sickle Cell Disease ◽

Gene Polymorphisms ◽

Clinical Effect ◽

Dna Damage Repair ◽

Cell Disease ◽

Repair Gene ◽

Damage Repair ◽

Repair Genes

Background– Defect in DNA damage repair genes due to oxidative stress predispose the humans to malignancies. There are many cases of association of malignancies with sickle cell disease patients (SCD) throughout the world, the molecular cause of which has never been investigated. DNA damage repair genes such as hOGG1, XRCC1 and p53 play significant role in repair of DNA damage during oxidative stress but the distribution and clinical effect of these genes are not known till date in SCD patients who are associated with oxidative stress related clinical complications. Objective – The aim of the study was to characterize the distribution and clinical effect of DNA damage gene polymorphisms p53 (codon 72 Arg> Pro), hOGG1 (codon 326 Ser>Cyst) and XRCC1 (codons 194 Arg>Trp, codon 280 Arg> His, codon 399 Arg> Gln) among SCD patients of central India. Methods- A case control study of 250 SCD patients and 250 normal individuals were investigated by PCR-RFLP techniques. Result- The prevalence of mutant alleles of hOGG1 gene, XRCC1 codon 280 Arg>His were found to be significantly high among SCD patients as compared to controls. However, SCD patients did not show clinical association with any of these DNA repair gene polymorphisms. Conclusion- This indicates that hOGG1, p53 and XRCC1 gene polymorphisms may not have any clinical impact among SCD patients in India.

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Antitumor Activity of a Novel Tyrosine Kinase Inhibitor AIU2001 Due to Abrogation of the DNA Damage Repair in Non-Small Cell Lung Cancer Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20194728 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4728 ◽

Cited By ~ 2

Author(s):

Hwani Ryu ◽

Hyun-Kyung Choi ◽

Hyo Jeong Kim ◽

Ah-Young Kim ◽

Jie-Young Song ◽

...

Keyword(s):

Lung Cancer ◽

Dna Damage ◽

Tyrosine Kinase ◽

Small Molecule ◽

Parp Inhibitor ◽

Dna Damage Repair ◽

Class Iii ◽

Damage Repair ◽

Repair Genes

Class III receptor tyrosine kinase (RTK) inhibitors targeting mainly FLT3 or c-KIT have not been well studied in lung cancer. To identify a small molecule potentially targeting class III RTK, we synthesized novel small molecule compounds and identified 5-(4-bromophenyl)-N-(naphthalen-1-yl) oxazol-2-amine (AIU2001) as a novel class III RKT inhibitor. In an in vitro kinase profiling assay, AIU2001 inhibited the activities of FLT3, mutated FLT3, FLT4, and c-KIT of class III RTK, and the proliferation of NSCLC cells in vitro and in vivo. AIU2001 induced DNA damage, reactive oxygen species (ROS) generation, and cell cycle arrest in the G2/M phase. Furthermore, AIU2001 suppressed the DNA damage repair genes, resulting in the ‘BRCAness’/‘DNA-PKness’ phenotype. The mRNA expression level of STAT5 was downregulated by AIU2001 treatment and knockdown of STAT5 inhibited the DNA repair genes. Our results show that compared to either drug alone, the combination of AIU2001 with a poly (ADP-ribose) polymerase (PARP) inhibitor olaparib or irradiation showed synergistic efficacy in H1299 and A549 cells. Hence, our findings demonstrate that AIU2001 is a candidate therapeutic agent for NSCLC and combination therapies with AIU2001 and a PARP inhibitor or radiotherapy may be used to increase the therapeutic efficacy of AIU2001 due to inhibition of DNA damage repair.

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Changes in DNA Damage Repair Gene Expression and Cell Cycle Gene Expression Do Not Explain Radioresistance in Tamoxifen-Resistant Breast Cancer

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15555794826018 ◽

2020 ◽

Vol 28 (1) ◽

pp. 33-40 ◽

Cited By ~ 3

Author(s):

Annemarie E. M. Post ◽

Johan Bussink ◽

Fred C. G. J. Sweep ◽

Paul N. Span

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Dna Damage ◽

Dna Damage Repair ◽

Cross Resistance ◽

Damage Repair ◽

Breast Cancer Cohort ◽

Tamoxifen Resistant ◽

Repair Genes

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

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Altered expression of DNA damage repair genes in the brain tissue of mice conceived by in vitro fertilization

MHR Basic science of reproductive medicine ◽

10.1093/molehr/gaaa010 ◽

2020 ◽

Vol 26 (3) ◽

pp. 141-153

Author(s):

Minhao Hu ◽

Yiyun Lou ◽

Shuyuan Liu ◽

Yuchan Mao ◽

Fang Le ◽

...

Keyword(s):

Dna Methylation ◽

Dna Damage ◽

Brain Tissue ◽

Dna Damage Repair ◽

Damage Repair ◽

Gene And Protein Expression ◽

The Brain ◽

Repair Genes

Abstract Our previous study revealed a higher incidence of gene dynamic mutation in newborns conceived by IVF, highlighting that IVF may be disruptive to the DNA stability of IVF offspring. However, the underlying mechanisms remain unclear. The DNA damage repair system plays an essential role in gene dynamic mutation and neurodegenerative disease. To evaluate the long-term impact of IVF on DNA damage repair genes, we established an IVF mouse model and analyzed gene and protein expression levels of MSH2, MSH3, MSH6, MLH1, PMS2, OGG1, APEX1, XPA and RPA1 and also the amount of H2AX phosphorylation of serine 139 which is highly suggestive of DNA double-strand break (γH2AX expression level) in the brain tissue of IVF conceived mice and their DNA methylation status using quantitative real-time PCR, western blotting and pyrosequencing. Furthermore, we assessed the capacity of two specific non-physiological factors in IVF procedures during preimplantation development. The results demonstrated that the expression and methylation levels of some DNA damage repair genes in the brain tissue of IVF mice were significantly changed at 3 weeks, 10 weeks and 1.5 years of age, when compared with the in vivo control group. In support of mouse model findings, oxygen concentration of in vitro culture environment was shown to have the capacity to modulate gene expression and DNA methylation levels of some DNA damage repair genes. In summary, our study indicated that IVF could bring about long-term alterations of gene and protein expression and DNA methylation levels of some DNA damage repair genes in the brain tissue and these alterations might be resulted from the different oxygen concentration of culture environment, providing valuable perspectives to improve the safety and efficiency of IVF at early embryonic stage and also throughout different life stages.

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