scholarly journals MCM4 Is a Novel Biomarker Associated With Genomic Instability, BRCAness Phenotype, and Therapeutic Potentials in Soft-Tissue Sarcoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Qi Liu ◽  
Qiyuan Bao ◽  
Yiqi Xu ◽  
Yucheng Fu ◽  
Zhijian Jin ◽  
...  
Keyword(s):  
Dna Repair ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Genomic Instability ◽  
Expression Profiles ◽  
Parp Inhibitor ◽  
High Expression ◽  
Clinical Staging ◽  
Repair Pathways ◽  
Public Datasets

Soft-tissue sarcoma (STS) is represented by a heterogeneous group of rare malignancies with various molecular oncogenesis. Therapies targeting DNA repair pathways in STS have achieved minimal progress, potentially due to the lack of molecular biomarker(s) beyond the histology subtype. In this report, we comprehensively analyzed the expression profiles of 100 liposarcomas (LPSs), the most common STS subtype, in comparison with 21 adipose tissues from multiple GEO datasets to identify the potential prognostic and therapeutic biomarker for LPS. Furthermore, we investigated TCGA database, our archived tumor samples, and patient-derived tumor cell cultures (PTCCs) as a validation. We identified a total of 69 common differentially expressed genes (DEGs) among public datasets, with mini-chromosome maintenance protein 4 (MCM4) identified as a novel biomarker correlated with patients’ clinical staging and survival outcome. MCM4-high expression LPS was characterized by MCM4 copy number increase, genomic instability, and BRCAness phenotype compared with the MCM4-low expression counterpart. In contrast, the mutational and the immune landscape were minimally different between the two groups. Interestingly, the association of MCM4-high expression with genomic instability and BRCAness were not only validated in LPS samples from our institution (n = 66) but also could be expanded to the pan-sarcoma cohort from TCGA database (n = 263). Surprisingly, based on four sarcoma cell lines and eight PTCCs (three LPS and five other sarcoma), we demonstrated that MCM4 overexpression tumors were therapeutically sensitive to PARP inhibitor (PARPi) and platinum chemotherapy, independent of the histology subtypes. Our study, for the first time, suggested that MCM4 might be a novel prognostic biomarker, associated with dysregulated DNA repair pathways and potential therapeutic vulnerability in STS.

scholarly journals PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

2019 ◽  
Vol 8 (4) ◽  
pp. 435 ◽  
Author(s):  
Man Keung ◽  
Yanyuan Wu ◽  
Jaydutt Vadgama
Keyword(s):  
Dna Repair ◽  
Homologous Recombination ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Excision Repair ◽  
Parp Inhibitor ◽  
Predictive Biomarkers ◽  
Parp Inhibitors ◽  
Homologous Recombination Deficiency ◽  
Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

scholarly journals Distinct DNA repair pathways cause genomic instability at alternative DNA structures

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jennifer A. McKinney ◽  
Guliang Wang ◽  
Anirban Mukherjee ◽  
Laura Christensen ◽  
Sai H. Sankara Subramanian ◽  
...  
Keyword(s):  
Dna Repair ◽  
Genomic Instability ◽  
Dna Structures ◽  
Repair Pathways

scholarly journals Mechanisms of Genome Maintenance in Plants: Playing It Safe With Breaks and Bumps

2021 ◽  
Vol 12 ◽  
Author(s):  
Aamir Raina ◽  
Parmeshwar K. Sahu ◽  
Rafiul Amin Laskar ◽  
Nitika Rajora ◽  
Richa Sao ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Plant Growth ◽  
Genomic Instability ◽  
Model Organisms ◽  
Ultraviolet Rays ◽  
Genomic Integrity ◽  
Wide Range ◽  
Repair Pathways ◽  
Living Organisms

Maintenance of genomic integrity is critical for the perpetuation of all forms of life including humans. Living organisms are constantly exposed to stress from internal metabolic processes and external environmental sources causing damage to the DNA, thereby promoting genomic instability. To counter the deleterious effects of genomic instability, organisms have evolved general and specific DNA damage repair (DDR) pathways that act either independently or mutually to repair the DNA damage. The mechanisms by which various DNA repair pathways are activated have been fairly investigated in model organisms including bacteria, fungi, and mammals; however, very little is known regarding how plants sense and repair DNA damage. Plants being sessile are innately exposed to a wide range of DNA-damaging agents both from biotic and abiotic sources such as ultraviolet rays or metabolic by-products. To escape their harmful effects, plants also harbor highly conserved DDR pathways that share several components with the DDR machinery of other organisms. Maintenance of genomic integrity is key for plant survival due to lack of reserve germline as the derivation of the new plant occurs from the meristem. Untowardly, the accumulation of mutations in the meristem will result in a wide range of genetic abnormalities in new plants affecting plant growth development and crop yield. In this review, we will discuss various DNA repair pathways in plants and describe how the deficiency of each repair pathway affects plant growth and development.

scholarly journals MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma

2021 ◽  
Vol 10 ◽  
Author(s):  
Benjamin B. Morris ◽  
Nolan A. Wages ◽  
Patrick A. Grant ◽  
P. Todd Stukenberg ◽  
Ryan D. Gentzler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Dna Repair ◽  
Transcription Factor ◽  
Lung Adenocarcinoma ◽  
Genomic Instability ◽  
Replication Stress ◽  
Omics Data ◽  
Repair Pathways ◽  
Lung Adenocarcinomas

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

scholarly journals Analysis of Gene Expression Profiles of Soft Tissue Sarcoma Using a Combination of Knowledge-Based Filtering with Integration of Multiple Statistics

PLoS ONE ◽  
2014 ◽  
Vol 9 (9) ◽  
pp. e106801 ◽  
Author(s):  
Anna Takahashi ◽  
Robert Nakayama ◽  
Nanako Ishibashi ◽  
Ayano Doi ◽  
Risa Ichinohe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Knowledge Based
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