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Cancers
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Genome Maintenance in Cancer Biology and Therapy
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Genome Maintenance in Cancer Biology and Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: 18 April 2024 | Viewed by 9193

Special Issue Editor

Dr. Spencer Collis

E-Mail Website
Collection Editor
Weston Park Cancer Centre, Department of Oncology & Metabolism, University of Sheffield, Sheffield, S10 2RX, UK.
Interests: genome stability; DNA damage and repair; DNA replication; cell cycle checkpoints; cancer biology and therapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genome instability is a defined hallmark of cancer, and is an important mechanism in tumour development, progression, heterogeneity and drug resistance; the latter two being two common barriers to effective treatment. Genome instability in tumour cells often arises through heightened DNA damage and/or replication stress; a respective consequence of increased metabolic processes that produce DNA damaging by-products, and an increased proliferative state due to the action of activated oncogenes.

To preserve genomic integrity, human cells have developed interconnected genome maintenance mechanisms that facilitate an orchestration of DNA damage response pathways, DNA repair mechanisms, cell cycle checkpoints and cell division processes. The many cancer predisposing human diseases that are associated with underlying mutations in/dysregulation of key proteins within these pathways highlights the importance of genome stability mechanisms in the suppression of tumour development and progression.

In addition to a deeper understanding of cancer biology, the study of genome maintenance mechanisms and their co-ordinated regulation has revealed new therapeutic targets to improve the effectiveness of existing radio-/chemotherapy regimes, as well as identifying exploitable tumour-selective vulnerabilities around which both novel or repurposed therapeutic strategies can be developed. Furthering our understanding of genome maintenance mechanisms is therefore vital to help understand how such processes become dysfunctional in cancer development/progression, and to identify new targets and/or biomarkers to develop new therapeutic strategies to improve the clinical management of these disease and improve patient survival.

This new Topic section of Cancers therefore aims to publish new research articles and timely reviews on aspects of genome maintenance mechanisms that either play a role in cancer development and progression or reveal new therapeutic opportunities to better treat this disease.

Dr. Spencer Collis
Collection Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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14 pages, 2775 KiB  
Article
Development and Optimisation of Tumour Treating Fields (TTFields) Delivery within 3D Primary Glioma Stem Cell-like Models of Spatial Heterogeneity
by Callum G. Jones, Aurelie Vanderlinden, Ola Rominiyi and Spencer J. Collis
Cancers 2024, 16(5), 863; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16050863 - 21 Feb 2024
Viewed by 785
Abstract
Glioblastoma is an aggressive, incurable brain cancer with poor five-year survival rates of around 13% despite multimodal treatment with surgery, DNA-damaging chemoradiotherapy and the recent addition of Tumour Treating Fields (TTFields). As such, there is an urgent need to improve our current understanding [...] Read more.
Glioblastoma is an aggressive, incurable brain cancer with poor five-year survival rates of around 13% despite multimodal treatment with surgery, DNA-damaging chemoradiotherapy and the recent addition of Tumour Treating Fields (TTFields). As such, there is an urgent need to improve our current understanding of cellular responses to TTFields using more clinically and surgically relevant models, which reflect the profound spatial heterogeneity within glioblastoma, and leverage these biological insights to inform the rational design of more effective therapeutic strategies incorporating TTFields. We have recently reported the use of preclinical TTFields using the inovitroTM system within 2D glioma stem-like cell (GSC) models and demonstrated significant cytotoxicity enhancement when co-applied with a range of therapeutically approved and preclinical DNA damage response inhibitors (DDRi) and chemoradiotherapy. Here we report the development and optimisation of preclinical TTFields delivery within more clinically relevant 3D scaffold-based primary GSC models of spatial heterogeneity, and highlight some initial enhancement of TTFields potency with temozolomide and clinically approved PARP inhibitors (PARPi). These studies, therefore, represent an important platform for further preclinical assessment of TTFields-based therapeutic strategies within clinically relevant 3D GSC models, aimed towards accelerating clinical trial implementation and the ultimate goal of improving the persistently dire survival rates for these patients. Full article
(This article belongs to the Special Issue Genome Maintenance in Cancer Biology and Therapy)
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21 pages, 5611 KiB  
Article
Molecular Basis of XRN2-Deficient Cancer Cell Sensitivity to Poly(ADP-ribose) Polymerase Inhibition
by Talysa Viera, Quinn Abfalterer, Alyssa Neal, Richard Trujillo and Praveen L. Patidar
Cancers 2024, 16(3), 595; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16030595 - 30 Jan 2024
Viewed by 785
Abstract
R-loops (RNA–DNA hybrids with displaced single-stranded DNA) have emerged as a potent source of DNA damage and genomic instability. The termination of defective RNA polymerase II (RNAPII) is one of the major sources of R-loop formation. 5′-3′-exoribonuclease 2 (XRN2) promotes genome-wide efficient RNAPII [...] Read more.
R-loops (RNA–DNA hybrids with displaced single-stranded DNA) have emerged as a potent source of DNA damage and genomic instability. The termination of defective RNA polymerase II (RNAPII) is one of the major sources of R-loop formation. 5′-3′-exoribonuclease 2 (XRN2) promotes genome-wide efficient RNAPII termination, and XRN2-deficient cells exhibit increased DNA damage emanating from elevated R-loops. Recently, we showed that DNA damage instigated by XRN2 depletion in human fibroblast cells resulted in enhanced poly(ADP-ribose) polymerase 1 (PARP1) activity. Additionally, we established a synthetic lethal relationship between XRN2 and PARP1. However, the underlying cellular stress response promoting this synthetic lethality remains elusive. Here, we delineate the molecular consequences leading to the synthetic lethality of XRN2-deficient cancer cells induced by PARP inhibition. We found that XRN2-deficient lung and breast cancer cells display sensitivity to two clinically relevant PARP inhibitors, Rucaparib and Olaparib. At a mechanistic level, PARP inhibition combined with XRN2 deficiency exacerbates R-loop and DNA double-strand break formation in cancer cells. Consistent with our previous findings using several different siRNAs, we also show that XRN2 deficiency in cancer cells hyperactivates PARP1. Furthermore, we observed enhanced replication stress in XRN2-deficient cancer cells treated with PARP inhibitors. Finally, the enhanced stress response instigated by compromised PARP1 catalytic function in XRN2-deficient cells activates caspase-3 to initiate cell death. Collectively, these findings provide mechanistic insights into the sensitivity of XRN2-deficient cancer cells to PARP inhibition and strengthen the underlying translational implications for targeted therapy. Full article
(This article belongs to the Special Issue Genome Maintenance in Cancer Biology and Therapy)
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13 pages, 298 KiB  
Article
CHEK2 Alterations in Pediatric Malignancy: A Single-Institution Experience
by Eman Abdelghani, Kathleen M. Schieffer, Catherine E. Cottrell, Anthony Audino, Kristin Zajo and Nilay Shah
Cancers 2023, 15(6), 1649; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15061649 - 08 Mar 2023
Cited by 2 | Viewed by 2002
Abstract
Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience [...] Read more.
Background: Approximately 10% of pediatric malignancies are secondary to germline alterations in cancer-predisposing genes. Checkpoint kinase 2 (CHEK2) germline loss-of-function variants have been reported in pediatric cancer patients, but clinical phenotypes and outcomes are poorly described. We present our single-institution experience of pediatric oncology patients with CHEK2 germline alterations, including clinical presentations and outcomes. Methods: Pediatric oncology patients with CHEK2 germline alterations were identified among those assessed by clinical or translational research at the Institute for Genomic Medicine at Nationwide Children’s Hospital. A chart review of disease course was conducted on identified patients. Results: We identified 6 patients with germline CHEK2 variants from a cohort of 300 individuals, including 1 patient with concurrent presentation of Burkitt lymphoma and neuroblastoma, 3 patients with brain tumors, 1 patient with Ewing sarcoma, and 1 patient with myelodysplastic syndrome. Three patients had a family history of malignancies. Four patients were in remission; one was undergoing treatment; one patient had developed treatment-related meningiomas. We review prior data regarding CHEK2 variants in this population, challenges associated with variant interpretation, and genetic counseling for individuals with CHEK2 variants. Conclusions: CHEK2 germline loss-of-function alterations occur in patients with a variety of pediatric tumors. Larger multicenter studies will improve our understanding of the incidence, phenotype, and molecular biology of CHEK2 germline variants in pediatric cancers. Full article
(This article belongs to the Special Issue Genome Maintenance in Cancer Biology and Therapy)
19 pages, 3865 KiB  
Article
High Temperature Drives Topoisomerase Mediated Chromosomal Break Repair Pathway Choice
by Mohamed E. Ashour, Walaa Allam, Waheba Elsayed, Reham Atteya, Menattallah Elserafy, Sameh Magdeldin, Mohamed K. Hassan and Sherif F. El-Khamisy
Cancers 2021, 13(10), 2315; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13102315 - 12 May 2021
Cited by 4 | Viewed by 3635
Abstract
Cancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in [...] Read more.
Cancer-causing mutations often arise from inappropriate DNA repair, yet acute exposure to DNA damage is widely used to treat cancer. The challenge remains in how to specifically induce excessive DNA damage in cancer cells while minimizing the undesirable effects of genomic instability in noncancerous cells. One approach is the acute exposure to hyperthermia, which suppresses DNA repair and synergizes with radiotherapy and chemotherapy. An exception, however, is the protective effect of hyperthermia on topoisomerase targeting therapeutics. The molecular explanation for this conundrum remains unclear. Here, we show that hyperthermia suppresses the level of topoisomerase mediated single- and double-strand breaks induced by exposure to topoisomerase poisons. We further uncover that, hyperthermia suppresses hallmarks of genomic instability induced by topoisomerase targeting therapeutics by inhibiting nuclease activities, thereby channeling repair to error-free pathways driven by tyrosyl-DNA phosphodiesterases. These findings provide an explanation for the protective effect of hyperthermia from topoisomerase-induced DNA damage and may help to explain the inverse relationship between cancer incidence and temperature. They also pave the way for the use of controlled heat as a therapeutic adjunct to topoisomerase targeting therapeutics. Full article
(This article belongs to the Special Issue Genome Maintenance in Cancer Biology and Therapy)
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Review

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25 pages, 3477 KiB  
Review
The Versatile Attributes of MGMT: Its Repair Mechanism, Crosstalk with Other DNA Repair Pathways, and Its Role in Cancer
by Qingming Fang
Cancers 2024, 16(2), 331; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers16020331 - 11 Jan 2024
Cited by 2 | Viewed by 1230
Abstract
O6-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O6-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents [...] Read more.
O6-methylguanine-DNA methyltransferase (MGMT or AGT) is a DNA repair protein with the capability to remove alkyl groups from O6-AlkylG adducts. Moreover, MGMT plays a crucial role in repairing DNA damage induced by methylating agents like temozolomide and chloroethylating agents such as carmustine, and thereby contributes to chemotherapeutic resistance when these agents are used. This review delves into the structural roles and repair mechanisms of MGMT, with emphasis on the potential structural and functional roles of the N-terminal domain of MGMT. It also explores the development of cancer therapeutic strategies that target MGMT. Finally, it discusses the intriguing crosstalk between MGMT and other DNA repair pathways. Full article
(This article belongs to the Special Issue Genome Maintenance in Cancer Biology and Therapy)
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