dna repair gene
Recently Published Documents


TOTAL DOCUMENTS

843
(FIVE YEARS 173)

H-INDEX

62
(FIVE YEARS 9)

2022 ◽  
Author(s):  
Michael D Kessler ◽  
Amy Damask ◽  
Sean O'Keeffe ◽  
Michael Michael Van Meter ◽  
Nilanjana Banerjee ◽  
...  

Clonal hematopoiesis (CH) refers to the expansion of certain blood cell lineages and has been associated with aging and adverse health outcomes. Here, we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal hematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 27 loci (24 novel) where germline genetic variation influences CH/CHIP predisposition, including missense variants in the DNA-repair gene PARP1 and the lymphocytic antigen coding gene LY75 that are associated with reduced incidence of CH/CHIP. Analysis of 5,194 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID outcomes, cardiovascular disease, hematologic traits, malignancy, smoking, obesity, infection, and all-cause mortality. Longitudinal analyses revealed that one of the CHIP subtypes, DNMT3A-CHIP, is associated with the subsequent development of myeloid but not lymphoid leukemias, and with solid cancers including prostate and lung. Additionally, contrary to previous findings from the initial 50,000 UKB exomes, our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogenous phenotypes with shared and unique germline genetic causes and varied clinical implications.


Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6295
Author(s):  
Ymera Pignochino ◽  
Giovanni Crisafulli ◽  
Giorgia Giordano ◽  
Alessandra Merlini ◽  
Enrico Berrino ◽  
...  

Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively “immune-cold” tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation. Whole-exome and targeted panel sequencing data analyses revealed that three cycles of trabectedin and olaparib combination neither affected the mutational profiles, DNA repair gene status, or copy number alterations, nor increased TMB both in homologous recombinant-defective and proficient cells or in xenografts. Moreover, TMB was not increased in tumor specimens derived from trabectedin- and olaparib-treated patients (5–6 cycles) when compared to pre-treatment biopsies. Conversely, repeated treatments with temozolomide induced a massive TMB increase in the SJSA-1 osteosarcoma model. In conclusion, a trabectedin and olaparib combination did not show mutagenic effects and is unlikely to prime subsequent immune-therapeutic interventions based on TMB increase. On the other hand, these findings are reassuring in the increasing warning of treatment-induced hematologic malignancies correlated to PARP1 inhibitor use.


2021 ◽  
Vol 159 ◽  
pp. 52-55
Author(s):  
James R. Marthick ◽  
Kelsie Raspin ◽  
Georgea R. Foley ◽  
Nicholas B. Blackburn ◽  
Annette Banks ◽  
...  

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 212-212
Author(s):  
Biqi Zhou ◽  
Xinran Chu ◽  
Hong Tian ◽  
Tianhui Liu ◽  
Hong Liu ◽  
...  

Abstract Introduction Patients with E2A-PBX1 fusion are expected to have an aggressive disease course. Because of the rarity of this genotype (nearly 5% of pediatric and 3% of adult B-cell acute lymphoblastic leukemia (B-ALL) cases), a consensus on the clinical and prognostic characteristics of adult E2A-PBX1-positive B-ALL patients, especially in adult patients, has not yet been reached. Patients and Methods We retrospectively summarized our clinical findings from 137 B-ALL patients diagnosed with E2A-PBX at our centers from 2009 to 2019, including 56 adolescents/adults (≥15 years old) and 81 children (<15 years old). Genomic investigated analysis was performed on sufficient bone marrow at diagnosis, relapse and remission as well as matched hair follicle cells using somatic copy number variation detection (n=25), whole-exome sequencing (n=29), the next-generation sequencing pane (tumor only, n=14) and RNA sequencing (n=22). Results The proportions of E2A-PBX1-positive B-ALL in our centers were 5.3% (81/1526) in children, 4.6% (43/925) in AYA and 2.1% (15/713) in older adults. The complete remission rate among all E2A-PBX1-positive B-ALL patients in this study was 94.9% (129/136) after one course of induction chemotherapy. The 5-year overall survival (OS) and disease-free survival (DFS) rates of the whole cohort were 68.6% and 61.0%, respectively. Allo-HSCT at CR1 in adolescents/adults could dramatically improve the 5-year prognoses (OS: 80.8% vs. 25.7%, P<0.001; DFS: 73.3% vs. 15.5%, P<0.001; cumulative incidence of relapse (CIR): 20.0% vs. 80.5%, P<0.001) (Figure 1A). Haploidentical-HSCT decreased the CIR compared with HLA-matched-HSCT in adolescents/adults (12.5% vs 58.3%, P=0.017) (Figure 1B). A total of 12 patients received CD19-targeted CAR-T cell therapy for disease progression (Figure 1C), and 91.7% (11/12) of patients achieved remission. Two patients died of relapse, and 3 patients died of complications (One died of grade 4 CRS, one died of cerebral hemorrhage after transfusion, and the other one died of infection after 14 months). Three patients received CAR-T bridging to allo-HSCT, and all of them remained in remission within the follow-up period. Univariate and multivariate analysis showed that t(1;19)(q23;p13) only (OS: P=0.020, HR=0.387, 95% CI: 0.174-0.862; DFS: P=0.004, HR= 0.375, 95% CI: 0.193-0.729; CIR: P=0.009, HR= 0.400, 95% CI: 0.200-0.799), Age (DFS: P=0.037, HR=1.009, 95% CI: 1.001-1.018; CIR: P=0.005, HR=1.025, 95% CI: 1.008-1.044) and the level of minimal residual disease (MRD) after induction chemotherapy (OS: P=0.020, HR=2.971, 95% CI: 1.185-7.452; DFS: P=0.002, HR= 3.218, 95% CI: 1.510-6.861; CIR: P=0.006, HR= 3.190, 95% CI: 1.406-7.246) were independent risk factors in E2A-PBX1-positive B-ALL (Figure 1D). In the diagnosis samples, mutations in PBX1, PAX5, CTCF and SETD2, amplification of AKT3, and deletion of CDKN2A/B were common in the total cohort, while transcriptome differences were found in the cell cycle, NGF signaling pathway and transcriptional regulation by TP53 between adolescents/adults and children (Figure 2A,B). More DNA repair gene mutations were detected in the relapse samples (7.9% vs. 57.1%, P<0.001). The median number of subclones in E2A-PBX1-positive B-ALL at diagnosis was 2 (range 1-4). Patients with multiple subclones at diagnosis tended to have unfavorable 3-year prognoses (DFS: P=0.010; CIR: P=0.021). Leukemia clones with DNA repair gene mutations showed aggressive and treatment-refractory phenotypes in this subtype of ALL (Figure 2C). Conclusions Our study indicated that age, the level of MRD and DNA repair gene mutations were associated with E2A-PBX1-positive B-ALL outcomes. Allo-HSCT, especially haploidentical-HSCT, could improve the prognosis of adolescent/adult patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 25-25
Author(s):  
Liberalis Debraj Boila ◽  
Liqing Jin ◽  
Alex Murison ◽  
Subham K. Bandyopadhyay ◽  
Subhadeep Ghosh ◽  
...  

Abstract Acute myeloid leukemia (AML) is a heterogeneous, aggressive hematological malignancy with dismal prognosis where limited targeted therapies are currently available. Poly-(ADP-ribose)-polymerase (PARP) inhibition has emerged as an important therapeutic arsenal to target homologous recombination-deficient tumors. However, molecular understanding of PARP blockade in the context of epigenetic derangements and transcriptional plasticity in human elderly AML pathogenesis remains unexplored. KDM6 proteins are H3K27 demethylases that critically regulate chromatin architecture in multi-cellularity and tumorigenesis (Tran, Mol Cell Biol 2020). KDM6A escapes X-chr inactivation, and Utx-/- female mice spontaneously develop aging associated myeloid leukemia (Gozdecka, Nat Genet 2018; Sera, Blood 2021). In addition, KDM6A loss of function mutation is implicated in AML relapse (Stief, Leukemia 2020). In contrast, KDM6B primarily exerts an oncogenic function in heme-malignancies. Together, KDM6A and KDM6B play cell type-specific function in leukemia, and KDM6 proteins and associated signaling emerge as important focal point for developing molecular targeted therapy. We identify that KDM6 demethylase activity critically regulates DNA damage repair (DDR) gene expression program in AML. Transcriptome analysis indicated a significant downregulation of expression of DDR genesets in both KDM6A deficient human AML and Utx -/- pre-leukemic cells. Lentiviral shRNA screening performed in response to low-dose γ-irradiation in AML stem cells, revealed a radioprotective function of KDM6A. Expression of KDM6s is regulated by genotoxic stress in a time-dependent manner, and deficiency of JmjC catalytic function impaired DDR transcriptional activation and compromised repair potential. Mechanistically, quantitative ChIP experiments also revealed co-operation between KDM6A and SWI/SNF facilitating dynamic chromatin remodeling at TSS/promoter to induce DDR gene expression. To interrogate changes in chromatin accessibility we performed ATAC-seq analysis in KDM6 deficient AML. Motif enrichment highlighted that while KDM6A depletion led to reduced chromatin access to 140 transcription factors (TFs), only 56 TF binding sites showed increased accessibility. Overall, changes in chromatin accessibility, associated with a reduced binding of DDR regulatory TFs in KDM6 deficient AML, account for a compromised DDR function. In agreement with these findings an array of KDM6 deficient AML cells were more sensitive to PARP inhibition, and pre-clinical mice models xenotransplanted with KDM6A loss of function AML line showed an increased susceptibility to PARP blockade in vivo. FLT3-ITD positive AML with a lower KDM6A expression was more sensitive to olaparib. In addition, olaparib administration significantly reduced bone marrow engraftment of patient-derived xenografts of KDM6A-mutant primary AML. Interestingly, KDM6A expression is upregulated in venetoclax-resistant monocytic-AML compared to venet-sensitive primitive-AML. Using venet responsive isogenic lines we demonstrated that attenuation of KDM6 function increased mitochondrial activity, intracellular ROS levels, de-repressed BCL2 expression, and sensitized AML cells to venetoclax. Additionally, KDM6 loss resulted in transcriptional repression of BCL2A1, commonly associated with venet resistance (Zhang, Nat Cancer 2020). Corroborating these results, dual targeting of PARP with BCL2 was superior to PARP or BCL2 inhibitor monotherapy in inducing primary AML apoptosis, and KDM6A loss further enhanced this synergism. In sum, our study illustrates a molecular mechanistic rationale in support for a novel combination targeted therapy for AML, and posit KDM6A as a molecular determinant for therapeutic efficacy. Intriguingly, KDM6A functions as a gatekeeper of BCL2 and BCL2A1 expression. Similar to TET2 although bi-allelic Utx loss causes evolution to myeloid neoplasms, minimal KDM6 activity is important for survival of human AML cells. KDM6s have been implicated in solid tumors, and both PARP and BCL2 inhibitors are being tested in cancer patients, underscoring a wider scope of application. To conclude, KDM6A unfolds to be a central regulator for susceptibility of AML to both PARP and BCL2 inhibition, expanding the possibility to characterize effective combination targeted therapy for AML in clinical settings. Disclosures Minden: Astellas: Consultancy. Dick: Celgene, Trillium Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3346-3346
Author(s):  
Minako Mori ◽  
Vera Adema ◽  
Carmelo Gurnari ◽  
Simona Pagliuca ◽  
Laila Terkawi ◽  
...  

Abstract Loss of chr7 (-7) and partial deletions of its long arm (del7q) are observed in 10% of de novo myeloid neoplasms (MNs), 50% of therapy related MDS, up to 60% of post aplastic anemia MNs and occur frequently as evolution of congenital bone marrow failure syndromes (e.g., GATA2 and SAMD9L deficiency, FA). LOH of one or more chr7 genes has been considered the culprit in the pathogenesis of -7/del7q MNs. In addition to the loss of protective alleles, deletion resulting in haploinsufficiency (HI) of tumor suppressor genes (TSGs) in CDRs might be also a cause of leukemogenic drive behind -7/del7q. To date, albeit many candidate genes have been associated with -7/del7q, the search for genes responsible for clinical phenotype has failed to identify causative -7/del7q TSGs and their putative loss would be difficult to target. Irrespective of the important goal of clarification of leukemogenic effects of -7/del7q, loss of genes in CDRs may create a vulnerability phenotype, which could be exploited with synthetic lethal approaches. Such strategies would rely on the higher resistance of diploid vs -7/del7q cells, thus allowing for a therapeutic window. Here, we studied the molecular profile of 8160 MN patients (del7q: 1.7%; -7: 6%). EZH2 mutations were enriched in -7/del7q compared to chr7 diploid cases (3.8 vs 1.2%, P<.0001) also by absolute numbers heterozygous mutations were more numerous. We also detected somatic CUX1 mutations (1.7 vs 0.9%), SAMD9/SAMD9L (0.3 vs 0.1%), and LUC7L2 (0.3 vs 0.1%) in -7/del7q vs diploid. In -7/del7 cases somatic alterations were detected in BRAF (n=7), POT1 (n=3), PCLO (n=5) and PSMC2 (n=1) while no mutations in CUL1 and KMT2C were found. We then investigated the presence of driver mutations located on other chromosomes in -7/del7q. Del7q/-7 cases showed a lower frequency of TET2 and SF3B1 mutations vs diploid cases. In isolated/+1 del7q/-7 cases, TP53 mutations were significantly less frequent, but were increased in -7/del7q with complex karyotype (P<.0001). Higher frequencies of RAS genes, RUNX1 and ETV6 hits were also found. Del7q and TP53 mutations were founder lesions (dominant) in 38% and 54% of -7/del7q, while -7 was dominant in 63% of -7 cases. TP53 was the only mutation significantly associated with further worsening the already poor prognosis of -7/del7q cases (HR=1.629 P< .01). Germline alterations were more common in -7/del7q as compared to diploid cases (13 vs 5% P< .0001) of which most were FA or DNA repair gene variants also in other genes including (e.g., SAMD9L, 7%, DDX41, 3.7%). Having defined the genotype of -7/del7q, we set to identify genes which could be possible targets for the therapy chiefly synthetic lethality. Criteria for selection included: consistent HI in most of the patients, genes not affected by hemizygous LOF mutations and embryonic lethality in knockout (KO) configuration. Expression data of -7/del7q (n=86), diploid cases (n=1066) and healthy controls (n=84; MLL and BEAT AML to increase precision) were analyzed. Our algorithm included selection of genes with mRNA expression inversely correlating with copy number (deletion copy number). Out of 694 genes on chr7, 147 genes were deleted in all patients and 101 genes had more inconsistent HI levels. In total 35 genes showed significant negative correlation with -7/del7q ploidyincluding ACTR3B,AGK,ATP06V0E2,CUL1,FASTK,GALNT11,GSTK1, IMPDH1, PLXNA4, SLC37A3, ZNF277, KMT2C, NUP205, TMEM209, ZC3HC1 and GIMAP1/2/4/6, a cluster ofnucleotide binding proteins. Following adjustment to ploidy, HI was found for EZH2 (76% cases), CUX1 (76%), KMT2C (70%), LUC7L2 (60%), and SAMD9/9L (32%/50%) but also even more consistently in SSBP1 (88%), PSMC2 (86%), CUL1, ZNF398, and RHEB (all 84%) and TNPO3 (82%). Among those genes homozygous KO of Ezh2 and Cul1 lead to embryonic lethality, Gimap family deletion reduces normal hematopoiesis, Samd9l +/-and Samd9l-/- mice develop MDS and die after 1.5yrs and Cux1 knockdown causes an MDS like phenotype. Existing inhibitors are available for CUL1 (MLN4924), CUX1 (BER modulating agents) and EZH2 (EPZ6438, GSK343), but the presence of homozygous mutations (UPD7q) argues that EZH2 inhibition is unlikely to be successful. In conclusion, we showed a comprehensive molecular topography of -7/del7q and identified novel HI genes which could be targeted by novel or repurposed drugs. Ongoing drug screens for identified targets performed in cells with -7/del7q will be presented at the meeting. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Maciejewski: Bristol Myers Squibb/Celgene: Consultancy; Novartis: Consultancy; Regeneron: Consultancy; Alexion: Consultancy.


Author(s):  
Binbin Yuan ◽  
Chengfei Jiang ◽  
Lingyan Chen ◽  
Jinlong Cui ◽  
Min Chen ◽  
...  

Gastric cancer is a heterogeneous group of diseases with only a fraction of patients responds to immunotherapy. The relationships between tumor DNA damage response, the immune system and immunotherapy have recently attracted attention. Accumulating evidence indicate that DNA repair landscape is a significant factor in driving response to immune checkpoint blockade (ICB) therapy. In this study, to explore new prognostic and predictive biomarkers for gastric cancer patients who are sensitive and responsible to immunotherapy, we developed a novel 15-DNA repair gene signature (DRGS) and its related scoring system and evaluated the efficiency of DRGS in discriminating different molecular and immune characteristics and therapeutic outcomes of gastric adenocarcinoma. The results showed that DRGS high score patients showed significantly better therapeutic outcomes compared to DRGS low score patients (P < 0.001). Integrated analysis of multi-omics data demonstrated that the patients with high DRGS score were characteristic of high levels of anti-tumor lymphocytes infiltration, tumor mutation burden (TMB) and PD-L1 expression, and these patients exhibited a longer overall survival and may benefit more from ICB therapy, as compared to the low-score patients. Therefore, the DRGS and its scoring system may have implications in tailoring immunotherapy in gastric cancers.


Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5114
Author(s):  
Arvind Pandey ◽  
Satyendra C. Tripathi ◽  
Junhua Mai ◽  
Samir M. Hanash ◽  
Haifa Shen ◽  
...  

New strategies that improve median survivals of only ~15–20 months for glioblastoma (GBM) with the current standard of care (SOC) which is concurrent temozolomide (TMZ) and radiation (XRT) treatment are urgently needed. Inhibition of polo-like kinase 1 (PLK1), a multifunctional cell cycle regulator, overexpressed in GBM has shown therapeutic promise but has never been tested in the context of SOC. Therefore, we examined the mechanistic and therapeutic impact of PLK1 specific inhibitor (volasertib) alone and in combination with TMZ and/or XRT on GBM cells. We quantified the effects of volasertib alone and in combination with TMZ and/or XRT on GBM cell cytotoxicity/apoptosis, mitochondrial membrane potential (MtMP), reactive oxygen species (ROS), cell cycle, stemness, DNA damage, DNA repair genes, cellular signaling and in-vivo tumor growth. Volasertib alone and in combination with TMZ and/or XRT promoted apoptotic cell death, altered MtMP, increased ROS and G2/M cell cycle arrest. Combined volasertib and TMZ treatment reduced side population (SP) indicating activity against GBM stem-like cells. Volasertib combinatorial treatment also significantly increased DNA damage and reduced cell survival by inhibition of DNA repair gene expression and modulation of ERK/MAPK, AMPK and glucocorticoid receptor signaling. Finally, as observed in-vitro, combined volasertib and TMZ treatment resulted in synergistic inhibition of tumor growth in-vivo. Together these results identify new mechanisms of action for volasertib that provide a strong rationale for further investigation of PLK1 inhibition as an adjunct to current GBM SOC therapy.


2021 ◽  
Vol 22 (19) ◽  
pp. 10319
Author(s):  
Saman Sargazi ◽  
Mahwash Mukhtar ◽  
Abbas Rahdar ◽  
Mahmood Barani ◽  
Sadanad Pandey ◽  
...  

Nanotechnology has revolutionized novel drug delivery strategies through establishing nanoscale drug carriers, such as niosomes, liposomes, nanomicelles, dendrimers, polymeric micelles, and nanoparticles (NPs). Owing to their desirable cancer-targeting efficacy and controlled release, these nanotherapeutic modalities are broadly used in clinics to improve the efficacy of small-molecule inhibitors. Poly(ADP-ribose) polymerase (PARP) family members engage in various intracellular processes, including DNA repair, gene transcription, signal transduction, cell cycle regulation, cell division, and antioxidant response. PARP inhibitors are synthetic small-molecules that have emerged as one of the most successful innovative strategies for targeted therapy in cancer cells harboring mutations in DNA repair genes. Despite these advances, drug resistance and unwanted side effects are two significant drawbacks to using PARP inhibitors in the clinic. Recently, the development of practical nanotechnology-based drug delivery systems has tremendously improved the efficacy of PARP inhibitors. NPs can specifically accumulate in the leaky vasculature of the tumor and cancer cells and release the chemotherapeutic moiety in the tumor microenvironment. On the contrary, NPs are usually unable to permeate across the body’s normal organs and tissues; hence the toxicity is zero to none. NPs can modify the release of encapsulated drugs based on the composition of the coating substance. Delivering PARP inhibitors without modulation often leads to the toxic effect; therefore, a delivery vehicle is essential to encapsulate them. Various nanocarriers have been exploited to deliver PARP inhibitors in different cancers. Through this review, we hope to cast light on the most innovative advances in applying PARP inhibitors for therapeutic purposes.


Sign in / Sign up

Export Citation Format

Share Document