Special Issue "Genomic Instability and Cancers"

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

Deadline for manuscript submissions: closed (15 April 2013)

Special Issue Editor

Guest Editor
Prof. Dr. Sabine Mai (Website)

Manitoba Institute of Cell Biology, University of Manitoba, 6046-675 McDermot Avenue, Winnipeg, Mb R3E 0V9, Canada
Interests: genomic instability; cancer; nuclear architecture; oncogenes; c-myc; mouse models of cancer; translational research; telomeres; molecular cytogenetics; molecular imaging; 3D imaging; super resolution imaging

Special Issue Information

Dear Colleagues,

This special issue on Genomic Instability and Cancer is dedicated to our understanding of the processes of genomic instability in cancer, to the initiation of genomic instability and the dynamics of its propagation. Focus will be mechanisms of genomic instability in cancer taking into account diverse approaches and models in the field.

Prof. Dr. Sabine Mai
Guest Editor

Submission

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. Papers will be published continuously (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 refereed through a 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 monthly 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 800 CHF (Swiss Francs).

Keywords

  • genomic instability
  • translocations
  • duplications
  • fragile sites
  • miRNAs
  • evolutionary breakpoints
  • complex rearrangements
  • microenvironment
  • tumor cell heterogeneity
  • cancer
  • experimental models of cancer
  • computer modeling
  • molecular imaging
  • arrays
  • next generation sequencing
  • nuclear architecture

Published Papers (5 papers)

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Research

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Open AccessArticle Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma
Cancers 2013, 5(2), 714-725; doi:10.3390/cancers5020714
Received: 18 April 2013 / Revised: 23 May 2013 / Accepted: 27 May 2013 / Published: 5 June 2013
Cited by 3 | PDF Full-text (883 KB) | HTML Full-text | XML Full-text
Abstract
In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques [...] Read more.
In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques at the single cell level has substantially improved our understanding of the molecular pathogenesis of HL. Gene expression profiling, comparative genomic hybridization analysis, micro-RNA expression profiling and viral oncogene sequencing have deepened our knowledge of numerous facets of H- and RS-cell gene expression deregulation. The question remains whether disturbed signaling pathways and deregulated transcription factors are at the origin of refractory/relapsing Hodgkin’s lymphoma or whether these hallmarks are at least partially related to another major factor. We recently showed that the 3D nuclear organization of telomeres and chromosomes marked the transition from H- to RS-cells in HL cell lines. This transition is associated with progression of telomere dysfunction, shelterin disruption and progression of complex chromosomal rearrangements. We reported analogous findings in refractory/relapsing HL and identified the shelterin proteins TRF1, TRF2 and POT1 as targets of the LMP1 oncogene in post-germinal center B-cells. Here we summarize our findings, including data not previously published, and propose a model in which progressive disruption of nuclear integrity, a form of genomic instability, is the key-player in refractory/relapsing HL. Therapeutic approaches should take these findings into account. Full article
(This article belongs to the Special Issue Genomic Instability and Cancers)

Review

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Open AccessReview Dynamic Length Changes of Telomeres and Their Nuclear Organization in Chronic Myeloid Leukemia
Cancers 2013, 5(3), 1086-1102; doi:10.3390/cancers5031086
Received: 8 May 2013 / Revised: 8 August 2013 / Accepted: 16 August 2013 / Published: 22 August 2013
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Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic [...] Read more.
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the t(9;22) translocation. As in most cancers, short telomeres are one of the features of CML cells, and telomere shortening accentuates as the disease progresses from the chronic phase to the blastic phase. Although most individual telomeres are short, some of them are lengthened, and long individual telomeres occur non-randomly and might be associated with clonal selection. Telomerase is the main mechanism used to maintain telomere lengths, and its activity increases when CML evolves toward advanced stages. ALT might be another mechanism employed by CML cells to sustain the homeostasis of their telomere lengths and this mechanism seems predominant at the early stage of leukemogenesis. Also, telomerase and ALT might jointly act to maintain telomere lengths at the chronic phase, and as CML progresses, telomerase becomes the major mechanism. Finally, CML cells display an altered nuclear organization of their telomeres which is characterized by the presence of high number of telomeric aggregates, a feature of genomic instability, and differential positioning of telomeres. CML represents a good model to study mechanisms responsible for dynamic changes of individual telomere lengths and the remodeling of telomeric nuclear organization throughout cancer progression. Full article
(This article belongs to the Special Issue Genomic Instability and Cancers)
Open AccessReview Induction of Chromosomal Instability via Telomere Dysfunction and Epigenetic Alterations in Myeloid Neoplasia
Cancers 2013, 5(3), 857-874; doi:10.3390/cancers5030857
Received: 17 April 2013 / Revised: 17 June 2013 / Accepted: 25 June 2013 / Published: 4 July 2013
Cited by 5 | PDF Full-text (461 KB) | HTML Full-text | XML Full-text
Abstract
Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic [...] Read more.
Chromosomal instability (CIN) is a characteristic feature of cancer. In this review, we concentrate on mechanisms leading to CIN in myeloid neoplasia, i.e., myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). The pathogenesis of myeloid neoplasia is complex and involves genetic and epigenetic alterations. Chromosome aberrations define specific subgroups and guide clinical decisions. Genomic instability may play an essential role in leukemogenesis by promoting the accumulation of genetic lesions responsible for clonal evolution. Indeed, disease progression is often driven by clonal evolution into complex karyotypes. Earlier studies have shown an association between telomere shortening and advanced MDS and underlined the important role of dysfunctional telomeres in the development of genetic instability and cancer. Several studies link chromosome rearrangements and aberrant DNA and histone methylation. Genes implicated in epigenetic control, like DNMT3A, ASXL1, EZH2 and TET2, have been discovered to be mutated in MDS. Moreover, gene-specific hypermethylation correlates highly significantly with the risk score according to the International Prognostic Scoring System. In AML, methylation profiling also revealed clustering dependent on the genetic status. Clearly, genetic instability and clonal evolution are driving forces for leukemic transformation. Understanding the mechanisms inducing CIN will be important for prevention and for novel approaches towards therapeutic interventions. Full article
(This article belongs to the Special Issue Genomic Instability and Cancers)
Open AccessReview Synthetic Genetic Targeting of Genome Instability in Cancer
Cancers 2013, 5(3), 739-761; doi:10.3390/cancers5030739
Received: 23 April 2013 / Revised: 3 June 2013 / Accepted: 6 June 2013 / Published: 24 June 2013
Cited by 7 | PDF Full-text (693 KB) | HTML Full-text | XML Full-text
Abstract
Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently [...] Read more.
Cancer is a leading cause of death throughout the World. A limitation of many current chemotherapeutic approaches is that their cytotoxic effects are not restricted to cancer cells, and adverse side effects can occur within normal tissues. Consequently, novel strategies are urgently needed to better target cancer cells. As we approach the era of personalized medicine, targeting the specific molecular defect(s) within a given patient’s tumor will become a more effective treatment strategy than traditional approaches that often target a given cancer type or sub-type. Synthetic genetic interactions are now being examined for their therapeutic potential and are designed to target the specific genetic and epigenetic phenomena associated with tumor formation, and thus are predicted to be highly selective. In general, two complementary approaches have been employed, including synthetic lethality and synthetic dosage lethality, to target aberrant expression and/or function associated with tumor suppressor genes and oncogenes, respectively. Here we discuss the concepts of synthetic lethality and synthetic dosage lethality, and explain three general experimental approaches designed to identify novel genetic interactors. We present examples and discuss the merits and caveats of each approach. Finally, we provide insight into the subsequent pre-clinical work required to validate novel candidate drug targets. Full article
(This article belongs to the Special Issue Genomic Instability and Cancers)
Open AccessReview Histologic and Genetic Advances in Refining the Diagnosis of “Undifferentiated Pleomorphic Sarcoma”
Cancers 2013, 5(1), 218-233; doi:10.3390/cancers5010218
Received: 19 December 2012 / Revised: 26 January 2013 / Accepted: 17 February 2013 / Published: 22 February 2013
Cited by 3 | PDF Full-text (236 KB) | HTML Full-text | XML Full-text
Abstract
Undifferentiated pleomorphic sarcoma (UPS) is an inclusive term used for sarcomas that defy formal sub-classification. The frequency with which this diagnosis is assigned has decreased in the last twenty years. This is because when implemented, careful histologic assessment, immunohistochemistry, and ultra-structural evaluation [...] Read more.
Undifferentiated pleomorphic sarcoma (UPS) is an inclusive term used for sarcomas that defy formal sub-classification. The frequency with which this diagnosis is assigned has decreased in the last twenty years. This is because when implemented, careful histologic assessment, immunohistochemistry, and ultra-structural evaluation can often determine lineage of differentiation. Further attrition in the diagnostic frequency of UPS may arise by using array-comparative genomic hybridization. Gene expression arrays are also of potential use as they permit hierarchical gene clustering. Appraisal of the literature is difficult due to a historical perspective in which specific molecular diagnostic methods were previously unavailable. The American Joint Committee on Cancer (AJCC) classification has changed with different inclusion criteria. Taxonomy challenges also exist with the older term “malignant fibrous histiocytoma” being replaced by “UPS”. In 2010 an analysis of multiple sarcoma expression databases using a 170-gene predictor, re-classified most MFH and “not-otherwise-specified” (NOS) tumors as liposarcomas, leiomyosarcomas or fibrosarcomas. Interestingly, some of the classifier genes are potential molecular therapeutic targets including Insulin-like growth factor 1 (IGF-1), Peroxisome proliferator-activated receptor γ (PPARγ), Nerve growth factor β (NGF β) and Fibroblast growth factor receptor (FGFR). Full article
(This article belongs to the Special Issue Genomic Instability and Cancers)

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