Genomic instability—An evolving hallmark of cancer

Department of Molecular Biology, CH-1205 Geneva, Switzerland.
Nature Reviews Molecular Cell Biology (Impact Factor: 36.46). 03/2010; 11(3):220-8. DOI: 10.1038/nrm2858
Source: PubMed

ABSTRACT Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

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    • "Inability to repair DSBs leads to DNA fragmentation and cell death. Unfaithful repair results in genetic instability (GIN) where cells may survive but chromosomes become rearranged, and genetic material mutated, duplicated, or deleted (Negrini et al., 2010). GIN is a defining characteristic of cancer (Schmitt et al., 2012) promoting initiation and somatic evolution, in turn, linking to disease progression and therapy resistance. "
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    ABSTRACT: Deficiencies in DNA double-strand break (DSB) repair lead to genetic instability, a recognized cause of cancer initiation and evolution. We report that the retinoblastoma tumor suppressor protein (RB1) is required for DNA DSB repair by canonical non-homologous end-joining (cNHEJ). Support of cNHEJ involves a mechanism independent of RB1's cell-cycle function and depends on its amino terminal domain with which it binds to NHEJ components XRCC5 and XRCC6. Cells with engineered loss of RB family function as well as cancer-derived cells with mutational RB1 loss show substantially reduced levels of cNHEJ. RB1 variants disabled for the interaction with XRCC5 and XRCC6, including a cancer-associated variant, are unable to support cNHEJ despite being able to confer cell-cycle control. Our data identify RB1 loss as a candidate driver of structural genomic instability and a causative factor for cancer somatic heterogeneity and evolution. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 03/2015; 10(12). DOI:10.1016/j.celrep.2015.02.059 · 7.21 Impact Factor
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    • "In line with the notion that induced pluripotency and tumorigenic transformation are related processes [5], hPSCs share many hallmark characteristics with human cancer cells, including similar genomic [6] [7] and epigenomic [8] [9] landscapes, unique activation of some signal transduction pathways (e.g., [10]), high levels of telomerase activity [11] and lack of contact inhibition [1]. Undoubtedly, one of the most striking similarities between hPSCs and human cancer cells is their genomic instability [12]; both hPSCs and cancer cells are genomically unstable, and are prone to acquire genetic aberrations at the levels of whole chromosomes , sub-chromosomal loci or single genes (reviewed in [13] [14] [15]). "
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    ABSTRACT: Cancer cells and stem cells share many traits, including a tendency towards genomic instability. Human cancers exhibit tumor-specific genomic aberrations, which often affect their malignancy and drug response. During their culture propagation, human pluripotent stem cells (hPSCs) also acquire characteristic genomic aberrations, which may have significant impact on their molecular and cellular phenotypes. These aberrations vary in size from single nucleotide alterations to copy number alterations to whole chromosome gains. A prominent challenge in both cancer and stem cell research is to identify "driver aberrations" that confer a selection advantage, and "driver genes" that underlie the recurrence of these aberrations. Following principles that are already well-established in cancer research, candidate driver genes have also been suggested in hPSCs. Experimental validation of the functional role of such candidates can uncover whether these are bona fide driver genes. The identification of driver genes may bring us closer to a mechanistic understanding of the genomic instability of stem cells. Guided by terminologies and methodologies commonly applied in cancer research, such understanding may have important ramifications for both stem cell and cancer biology. This article is part of a Special Issue entitled: Stress as a fundamental theme in cell plasticity
    Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms 08/2014; 1849(4). DOI:10.1016/j.bbagrm.2014.08.005 · 5.44 Impact Factor
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    • "Evidence indicates that insufficient apoptosis can manifest as cancer or autoimmunity, while accelerated cell death is evident in acute and chronic degenerative diseases, immunodeficiency, and infertility. Under many stressful conditions like precancerous lesions, activation of the DNA damage checkpoint pathway can serve to remove potentially harmful DNA-damaged cells via apoptosis induction to block carcinogenesis [4] [5]. Thus, the apoptotic signals help to safeguard the genomic integrity [3] [6] [7] while dysregulation of the apoptotic pathways may not only promote tumorigenesis but also render the cancer cell resistant to treatment. "
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    ABSTRACT: Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction.
    BioMed Research International 06/2014; 2014:150845. DOI:10.1155/2014/150845 · 2.71 Impact Factor
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