Genetic Instability: Tipping the Balance

Oncogene (2013) 32, 4459–4470 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc REVIEW Genetic instability: tipping the balance A Janssen1,2 and RH Medema1 Tumor cells typically contain a genome that is highly divergent from the genome of normal, non-transformed cells. This genetic divergence is caused by a number of distinct changes that the tumor cell acquires during its transformation from a normal cell into a tumorigenic counterpart. Changes to the genome include mutations, deletions, insertions, and also gross chromosomal aberrations, such as chromosome translocations and whole chromosome gains or losses. This genetic disorder of the tumor cell has complicated the identification of crucial driver mutations that cause cancer. Moreover, the large genetic divergence between different tumors causes them to behave very differently, and makes it difficult to predict response to therapy. In addition, tumor cells are genetically unstable and frequently acquire new mutations and/or gross chromosomal aberrations as they divide. This is beneficial for the overall capacity of a tumor to adapt to changes in its environment, but newly acquired genetic alterations can also compromise the genetic dominance of the tumor cell and thus affect tumor cell viability. Here, we review the mechanisms that can cause gross chromosomal aberrations, and discuss how these affect tumor cell viability. Oncogene (2013) 32, 4459–4470; doi:10.1038/onc.2012.576; published online 17 December 2012 Keywords: chromosome instability; cancer; mitosis; DNA damage; translocations; aneuploidy STRUCTURAL CHROMOSOMAL INSTABILITY Breakage Syndrome, Bloom’s syndrome, ataxia telangiectasia or Translocations, one of the most prominent types of structural mutations in BRCA1 and 2, display an increased susceptibility to 18 chromosomal changes, have been found in many cancer types1 form structural chromosomal changes. Cells from these patients (Figure 1). In hematological malignancies, several translocations accumulate translocations due to mutations in DNA repair have been identified that contribute to specific gene fusions, which proteins, such as NBS1, BLM helicase, ATM kinase or the BRCA1 are thought to be drivers in the process of tumorigenesis.2 The first and BRCA2 proteins. Moreover, it was shown long ago that several identified translocation in human cancer was the Philadelphia DSB-inducing agents, such as ionizing irradiation, UV-light and 3 chemical mutagens, can also result in the formation of chromosome, which results in the formation of a fusion between 19 the BCR and Abl genes, and is causative in the development of chromosomal aberrations. chronic myeloid leukemia.4 Translocations found in cancer can be The structural instability of cancer cells is not merely caused by balanced, creating two reciprocal chromosomal fusions that are inherited genetic defects or damage induced by exogenous homogeneously present in all tumor cells.5 However, more often, agents. Cancer cells can also acquire new translocations through the breakage-fusion-bridge (BFB) cycle, a process first described in cancer cells within a tumor display mosaic structural changes, 20,21 indicating that chromosomes continue to rearrange at a high rate in maize meiosis. In the BFB cycle, chromosomes that are broken 6–11 by DSBs first fuse with other broken chromosomal parts, for the established tumor. Generally, these chromosome structure 22 instabilities are thought to promote tumorigenesis by providing example, through fusion at dysfunctional telomeres. These telomere fusion events result in dicentric (two centromeres) continuous genetic diversification within the tumor that facilitates chromosomes, often found in tumors.22,23 The presence of two adaptation to environmental changes, for example through loss of centromeres on these aberrantly shaped chromosomes can result certain tumor suppressors or gain of specific oncogenes.7,12 in improper microtubule (MT) attachments in mitosis, such that Moreover, this continued genetic diversification could help the the two centromeres on a single chromatid become attached to tumor in acquiring drug resistance, cope with increased hypoxia, or opposite spindle poles. These attachments can induce chromatin escape challenges by the immune system. In line with this, an bridging in telophase, resulting in breakage of the fused increased occurrence of structural chromosomal aberrations 20,24 1,13,14 chromosome during cytokinesis, starting another BFB cycle. correlates with increased tumor grade. Such repetitive BFB events increase the number of aberrant Structural chromosomal instabilities arise through mis- or chromosomes in the offspring.20,21 BFB has indeed been unrepaired DNA double-stranded breaks (DSBs). Homologous correlated with an increase in intratumor heterogeneity and recombination and non-homologous end joining are thought to might therefore be an important factor in structural instability.25 be the two main repair pathways contributing to the formation of structural aberrations.15–17 Especially the error-prone non- homologous end joining pathway, which can ligate any two broken DNA ends together, is held responsible for the formation NUMERICAL CHROMOSOMAL INSTABILITY of structural aberrations.15 Indeed, individuals with genetic defects Another striking hallmark of cancer cells is the presence of an that affect repair of DSBs, such as patients with Nijmegen abnormal chromosome number8,26,27 (Figure 1), termed 1Division of Cell Biology, Netherlands Cancer Institute, Amsterdam, The Netherlands and 2Department of Medical Oncology and Cancer Genomics Center, University Medical Center Utrecht, Utrecht, The Netherlands. Correspondence: Dr R Medema, Netherlands Cancer Institute Division of Cell Biology, Plesmanlaan 121, Amsterdam, Holland 1066 CX, The Netherlands. E-mail: [email protected] Received 24 September 2012; revised 23 October 2012; accepted 24 October 2012; published online 17 December 2012 Genetic instability in tumors A Janssen and RH Medema 4460 Figure 1. Typical karyotype of a cancer cell. Karyotype of a human osteosarcoma cell line (U2OS) revealing a variety of numerical and structural chromosomal abnormalities. aneuploidy, a state in which cells do not contain an exact multiple of the haploid DNA content. On average, 25 percent of the genome of a cancer cell is affected by numerical changes of either whole chromosomes or complete chromosomal arms.6 The aneuploid karyotype can be stably propagated in a population of (tumor) cells,6,28,29 but more often chromosome numbers continuously change between cancer cells and their offspring.30 This continuous change in chromosome number is termed whole chromosomal instability (CIN)30.31 and is correlated 32–38 Figure 2. Various mitotic defects can lead to CIN. Absence of mitotic with tumor grade, metastasis and poor prognosis. Moreover, checkpoint signaling allows anaphase initiation in the presence of CIN has been associated with resistance to chemotherapeutics, unattached kinetochores, whereas cohesion loss or merotelic such as the widely used MT-stabilizing agent Paclitaxel.39–41 attachments induce chromosomal segregation errors by incorrect Various hypotheses have been postulated on how CIN and kinetochore orientation or the induction of lagging chromatids aneuploidy could contribute to tumorigenesis.42–46 The general respectively. idea is that whole chromosome gains and losses during cell division can, as suggested above for structural changes, provide a mode for cancer cells to adapt to their environment and and causes embryonic lethality in mouse,51–58 likely because it continuously divide.47,48 results in continuous chromosome missegregation. Thus, subsequent cell divisions of a viable aneuploid karyotype results in improper propagation of the genetic material, resulting in high CAUSES OF NUMERICAL CIN rates of cell death in the respective daughter cells. In contrast, Since the initial discovery of CIN in a variety of colon cancer cell partial checkpoint dysfunction results in a low frequency of lines in 1997,30 many researchers have investigated the underlying chromosome segregation errors, a low rate of cell death and the cause of this striking phenotype, found to be present in many potential to generate a new viable karyotype that is relatively other tumor types as well. Several mechanisms have been stable. Partial mitotic checkpoint activity could be responsible for CIN in tumor cells by allowing mitotic exit in the presence of one proposed and tested using a variety of cancer cell lines and 51,58–60 mouse models. It seems highly unlikely that one single or more unattached kinetochores (Figure 2). However, CIN mechanism can be held responsible for the CIN observed in the cancer cell lines that were initially thought to have a severely different types of tumors. Below we outline the different cellular impaired mitotic checkpoint due to mutations in the mitotic checkpoint kinase Bub1,61 were subsequently shown to have a causes that have been postulated and the genetic defects that 62 could underlie these phenotypes. very sturdy mitotic checkpoint. Nonetheless, altered expression levels and mutations in mitotic checkpoint genes have been identified in human cancer that compromise checkpoint Causes of numerical CIN: Mitotic checkpoint defects function.43,63–76 In one specific syndrome, mosaic-variegated The mitotic checkpoint has evolved to safeguard genetic stability, aneuploidy, which is linked to cancer predisposition at a very a function it performs by monitoring

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