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Genomic Instability in Multiple Myeloma and Solid Malignancies: Role of...
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Genomic Instability in Multiple Myeloma and Solid Malignancies: Role of DNA Repair from Prognostic Marker to Therapeutic Target

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 7286

Special Issue Editors

Dr. Daniele Caracciolo

E-Mail Website
Guest Editor
Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
Interests: multiple myeloma; genomic instability; DNA damage response; DNA repair inhibitors
Dr. Masood A. Shammas

E-Mail Website
Guest Editor
Department of Medical Oncology, Harvard (Dana Farber) Cancer Institute, Boston, MA, USA
Interests: multiple myeloma; esophageal cancer; genomic instability; DNA damage respons
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Genomic instability is a common feature of human cancer. Although the molecular bases of genomic instability are largely unknown, growing evidence suggests that impairment of DNA repair machinery plays a crucial role.

Multiple Myeloma (MM) is characterized by deep genomic instability that leads to abnormal proliferation of malignant plasma cells, which harbor several karyotype aberrations similar to solid tumors. Indeed, cytogenetic abnormalities are critical prognostic factors, and, at the same time, they represent a potential the epiphenomenon of still unknown therapeutic targets, to be exploited for synthetic lethality.

We are pleased to invite manuscripts aimed to elucidate the role of genomic instability as oncogenic driver and therapeutic target in MM and other cancer cells. This Special Issue aims to elucidate strategies to exploit DNA repair deregulation as specific cancer Achilles’ heel.

In this Special Issue, original research articles and reviews are welcome. We are specifically interested in manuscripts investigating the mechanisms underpinning the link among DNA damage induced by inactivation of DNA repair and the immune recognition/destruction of cancer cells. We also welcome manuscripts focusing on the strengthening effects among DNA repair inhibitors and standard therapeutics. By devoting a special issue to DNA repair deregulation in MM and solid malignancies, we hope to join efforts from different investigators and empower the knowledge in the specific field. We think that it is now time for a new era of therapeutic discoveries on genomic instability to increase the cure of cancer patients.

We look forward to receiving your contributions.

Dr. Daniele Caracciolo
Dr. Masood A. Shammas
Guest Editors

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 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.

Keywords

  • DNA repair
  • multiple myeloma
  • genomic instability
  • synthetic lethality
  • DNA damage

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Published Papers (2 papers)

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16 pages, 3001 KiB  
Article
RAD51 Is Implicated in DNA Damage, Chemoresistance and Immune Dysregulation in Solid Tumors
by Chengcheng Liao, Srikanth Talluri, Jiangning Zhao, Shidai Mu, Subodh Kumar, Jialan Shi, Leutz Buon, Nikhil C. Munshi and Masood A. Shammas
Cancers 2022, 14(22), 5697; https://doi.org/10.3390/cancers14225697 - 20 Nov 2022
Cited by 8 | Viewed by 3612
Abstract
Background: In normal cells, homologous recombination (HR) is tightly regulated and plays an important role in the maintenance of genomic integrity and stability through precise repair of DNA damage. RAD51 is a recombinase that mediates homologous base pairing and strand exchange during DNA [...] Read more.
Background: In normal cells, homologous recombination (HR) is tightly regulated and plays an important role in the maintenance of genomic integrity and stability through precise repair of DNA damage. RAD51 is a recombinase that mediates homologous base pairing and strand exchange during DNA repair by HR. Our previous data in multiple myeloma and esophageal adenocarcinoma (EAC) show that dysregulated HR mediates genomic instability. Purpose of this study was to investigate role of HR in genomic instability, chemoresistance and immune dysregulation in solid tumors including colon and breast cancers. Methods: The GEO dataset were used to investigate correlation of RAD51 expression with patient survival and expression of various immune markers in EAC, breast and colorectal cancers. RAD51 was inhibited in cancer cell lines using shRNAs and a small molecule inhibitor. HR activity was evaluated using a plasmid-based assay, DNA breaks assessed by evaluating expression of γ-H2AX (a marker of DNA breaks) and p-RPA32 (a marker of DNA end resection) using Western blotting. Genomic instability was monitored by investigating micronuclei (a marker of genomic instability). Impact of RAD51 inhibitor and/or a DNA-damaging agent was assessed on viability and apoptosis in EAC, breast and colon cancer cell lines in vitro and in a subcutaneous tumor model of EAC. Impact of RAD51 inhibitor on expression profile was monitored by RNA sequencing. Results: Elevated RAD51 expression correlated with poor survival of EAC, breast and colon cancer patients. RAD51 knockdown in cancer cell lines inhibited DNA end resection and strand exchange activity (key steps in the initiation of HR) as well as spontaneous DNA breaks, whereas its overexpression increased DNA breaks and genomic instability. Treatment of EAC, colon and breast cancer cell lines with a small molecule inhibitor of RAD51 inhibited DNA breaking agent-induced DNA breaks and genomic instability. RAD51 inhibitor potentiated cytotoxicity of DNA breaking agent in all cancer cell types tested in vitro as well as in a subcutaneous model of EAC. Evaluation by RNA sequencing demonstrated that DNA repair and cell cycle related pathways were induced by DNA breaking agent whereas their induction either prevented or reversed by RAD51 inhibitor. In addition, immune-related pathways such as PD-1 and Interferon Signaling were also induced by DNA breaking agent whereas their induction prevented by RAD51 inhibitor. Consistent with these observations, elevated RAD51 expression also correlated with that of genes involved in inflammation and other immune surveillance. Conclusions: Elevated expression of RAD51 and associated HR activity is involved in spontaneous and DNA damaging agent-induced DNA breaks and genomic instability thus contributing to chemoresistance, immune dysregulation and poor prognosis in cancer. Therefore, inhibitors of RAD51 have great potential as therapeutic agents for EAC, colon, breast and probably other solid tumors. Full article
(This article belongs to the Special Issue Genomic Instability in Multiple Myeloma and Solid Malignancies: Role of DNA Repair from Prognostic Marker to Therapeutic Target)
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Review

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14 pages, 2472 KiB  
Review
Understanding DNA Damage Response and DNA Repair in Multiple Myeloma
by Cole Petrilla, Joshua Galloway, Ruchi Kudalkar, Aya Ismael and Francesca Cottini
Cancers 2023, 15(16), 4155; https://doi.org/10.3390/cancers15164155 - 17 Aug 2023
Cited by 9 | Viewed by 3024
Abstract
Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance [...] Read more.
Multiple myeloma (MM) is a plasma cell malignancy characterized by several genetic abnormalities, including chromosomal translocations, genomic deletions and gains, and point mutations. DNA damage response (DDR) and DNA repair mechanisms are altered in MM to allow for tumor development, progression, and resistance to therapies. Damaged DNA rarely induces an apoptotic response, given the presence of ataxia-telangiectasia mutated (ATM) loss-of-function or mutations, as well as deletions, mutations, or downregulation of tumor protein p53 (TP53) and tumor protein p73 (TP73). Moreover, DNA repair mechanisms are either hyperactive or defective to allow for rapid correction of the damage or permissive survival. Medications used to treat patients with MM can induce DNA damage, by either direct effects (mono-adducts induced by melphalan), or as a result of reactive oxygen species (ROS) production by proteasome inhibitors such as bortezomib. In this review, we will describe the mechanisms of DDR and DNA repair in normal tissues, the contribution of these pathways to MM disease progression and other phenotypes, and the potential therapeutic opportunities for patients with MM. Full article
(This article belongs to the Special Issue Genomic Instability in Multiple Myeloma and Solid Malignancies: Role of DNA Repair from Prognostic Marker to Therapeutic Target)
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