Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol

Department of Molecular Biology, CH-1205 Geneva, Switzerland.
Nature Reviews Molecular Cell Biology (Impact Factor: 37.81). 03/2010; 11(3):220-8. DOI: 10.1038/nrm2858
Source: PubMed
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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    • "Emerging evidence suggests that defects in DSB repair can lead to oncogenic genomic instability and, in support of this notion, mutations in DNA break repair factors are implicated in a number of human tumors, including breast, colon, and lung cancers[56]. In addition, somatic mutations in NHEJ factors have been identified in different types of human tumors including hypomorphic mutations of Artemis in EBV-associated lymphomas[57], mutations of Lig4 or XLF associated with non-Hodgkin's diffuse large B cell lymphoma585960, and mutations of DNA-PKcs in glioblastoma and lung cancer[56]. TP53 mutations were associated with human BL, its leukemic counterpart L3-type B cell acute lymphoblastic leukemia, B cell chronic lymphocytic leukemia (CLL), and, in particular, its stage of progression known as Richter's transformation[61]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Activated B lymphocytes harbor programmed DNA double-strand breaks (DSBs) initiated by activation-induced deaminase (AID) and repaired by non-homologous end-joining (NHEJ). While it has been proposed that these DSBs during secondary antibody gene diversification are the primary source of chromosomal translocations in germinal center (GC)-derived B cell lymphomas, this point has not been directly addressed due to the lack of proper mouse models. Methods In the current study, we establish a unique mouse model by specifically deleting a NHEJ gene, Xrcc4, and a cell cycle checkpoint gene, Trp53, in GC B cells, which results in the spontaneous development of B cell lymphomas that possess features of GC B cells. Results We show that these NHEJ deficient lymphomas harbor translocations frequently targeting immunoglobulin (Ig) loci. Furthermore, we found that Ig translocations were associated with distinct mechanisms, probably caused by AID- or RAG-induced DSBs. Intriguingly, the AID-associated Ig loci translocations target either c-myc or Pvt-1 locus whereas the partners of RAG-associated Ig translocations scattered randomly in the genome. Lastly, these NHEJ deficient lymphomas harbor complicated genomes including segmental translocations and exhibit a high level of ongoing DNA damage and clonal heterogeneity. Conclusions We propose that combined NHEJ and p53 defects may serve as an underlying mechanism for a high level of genomic complexity and clonal heterogeneity in cancers.
    Full-text · Article · Dec 2016 · Journal of Hematology & Oncology
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    • "Because RasGAPs contribute to tumorigenesis, we suggested an MEK inhibitor (as a single agent or in combination) for the treatment of AYA01 [30, 31]. AYA02, olfactory neuroblastoma: chromosome instability and loss-of-function of CDKN2C AYA02 harbored a chromosome-level alteration with a TP53 missense mutation that contributed to chromosome instability [32]. Interestingly, AYA02 showed a double peak of a relative copy number change and armlevel alterations, which differed from other tumors (Fig. 3a and b ). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Although adolescent and young adult (AYA) cancers are characterized by biological features and clinical outcomes distinct from those of other age groups, the molecular profile of AYA cancers has not been well defined. In this study, we analyzed cancer genomes from rare types of metastatic AYA cancers to identify driving and/or druggable genetic alterations. Methods: Prospectively collected AYA tumor samples from seven different patients were analyzed using three different genomics platforms (whole-exome sequencing, whole-transcriptome sequencing or OncoScan™). Using well-known bioinformatics tools (bwa, Picard, GATK, MuTect, and Somatic Indel Detector) and our annotation approach with open access databases (DAVID and DGIdb), we processed sequencing data and identified driving genetic alterations and their druggability. Results: The mutation frequencies of AYA cancers were lower than those of other adult cancers (median = 0.56), except for a germ cell tumor with hypermutation. We identified patient-specific genetic alterations in candidate driving genes: RASA2 and NF1 (prostate cancer), TP53 and CDKN2C (olfactory neuroblastoma), FAT1, NOTCH1, and SMAD4 (head and neck cancer), KRAS (urachal carcinoma), EML4-ALK (lung cancer), and MDM2 and PTEN (liposarcoma). We then suggested potential drugs for each patient according to his or her altered genes and related pathways. By comparing candidate driving genes between AYA cancers and those from all age groups for the same type of cancer, we identified different driving genes in prostate cancer and a germ cell tumor in AYAs compared with all age groups, whereas three common alterations (TP53, FAT1, and NOTCH1) in head and neck cancer were identified in both groups. Conclusion: We identified the patient-specific genetic alterations and druggability of seven rare types of AYA cancers using three genomics platforms. Additionally, genetic alterations in cancers from AYA and those from all age groups varied by cancer type.
    Full-text · Article · Dec 2016 · BMC Cancer
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    • "Multiple genomic mutations are considered responsible for the malignant transformation of normal cells, which includes: capacity of tissue invasion and metastasis, insensitivity to antigrowth signals, sustained angiogenesis, ability to evade apoptosis, self-sufficient growth signals, limitless replication potential [1] evasion of immune surveillance [2], DNA damage and several causative conditions of cellular stress such as DNA replication, mitosis and oxidative proteotoxic and metabolic processes [3]. However, an interesting emphasis has been given to the genomic instability as one of the most important hallmarks because of its presence in all cancer stages [4]. The final stage of malignant cells is determined by multiple mutations that confer distinct fitness advantages, and occur stochastically. "
    [Show abstract] [Hide abstract] ABSTRACT: Tumor initiation presents a complex and unstable genomic landscape; one of the earliest hallmark events of cancer, and its progression is probably based on selection mechanisms under specific environments that lead to functional tumor cell speciation. We hypothesized that viable tumor phenotypes possess common and highly stable karyotypes and their proliferation is facilitated by an attuned high telomerase activity. Very few investigations have focused on the evolution of common chromosomal rearrangements associated to molecular events that result in functional phenotypes during tumor development. We have used cytogenetic, flow cytometry and cell culture tools to investigate chromosomal rearrangements and clonality during cancer development using the murine sarcoma TG180 model, and also molecular biology techniques to establish a correlation between chromosome instability and telomerase activity, since telomeres are highly affected during cancer evolution. Cytogenetic analysis showed a near-tetraploid karyotype originated by endoreduplication. Chromosomal rearrangements were random events in response to in vitro conditions, but a stable karyotypic equilibrium was achieved during tumor progression in different in vivo conditions, suggesting that a specific microenvironment may stabilize the chromosomal number and architecture. Specific chromosome aberrations (marker chromosomes) and activated regions (rDNAs) were ubiquitous in the karyotype, suggesting that the conservation of these patterns may be advantageous for tumor progression. High telomerase expression was also correlated with the chromosomal rearrangements stabilization. Our data reinforce the notion that the sarcoma cell evolution converges from a highly unstable karyotype to relatively stable and functional chromosome rearrangements, which are further enabled by telomerase overexpression.
    Full-text · Article · Dec 2016 · Journal of Biomedical Science
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