Aneuploidy In Cancer Research Articles

Contribution of Aurora-A and -B expression to DNA aneuploidy in gastric cancers

DNA aneuploidy, which is characterized by cells containing an abnormal number of chromosomes, is closely associated with carcinogenesis and malignant progression. Aneuploidy occurs during cell division when the chromosomes do not separate properly. Aurora kinases (Aurora-A, -B, and -C) contribute to accurate cell division, and are candidate molecular targets for mitosis-specific anticancer drugs. We determined the expression of Aurora-A and -B in 110 gastric cancer specimens by performing an immunohistochemical analysis. We also determined the DNA content, TP53 gene mutations, and microsatellite instability in the same samples. We found the nuclear expression of Aurora-A and -B to increase in tumor tissue in comparison to that in normal epithelial tissue. A high Aurora-B expression significantly correlated with aneuploidy and TP53 mutations, but not with microsatellite instability. In contrast, the Aurora-A expression did not correlate with either aneuploidy or microsatellite instability. In addition, the expression of Aurora-A or -B was not significantly associated with the clinical outcomes or prognosis. Our results suggest that an overexpression of Aurora-B, but not of Aurora-A, might contribute to DNA aneuploidy in gastric cancers by promoting chromosomal instability.

Historical Perspective of Cell-Cell Fusion in Cancer Initiation and Progression

This review discusses the topic of cell-cell fusion as it related to cancer causation, progression and metastasis. The relevant time period is over a century of research and analysis from the observation and hypothesis of Theodor Boveri in circa 1902 to the most recent publications in 2012. There are three main intertwined thrusts in this history: (i) progress in our overall understanding of cancer and the relative importance of mutations and aneuploidy; (ii) evidence that cell-cell fusion occurs and leads to aneuploidy in somatic cells, especially that cell-cell fusion allows rapid evolution of cancer cells that, most importantly, acquire a repertoire of traits from bone marrow-derived cells that facilitate metastasis; and (iii) evidence that viruses catalyze cell-cell fusion and that aneuploidy evolving from the hybrid cells is an important if not the principal basis for the association of viruses with certain cancers. There have been many competing hypotheses concerning all aspects of cancer development during this time period. Overall, the cell-cell fusion hypothesis has never gained preeminence. As a result, it has gone through long periods of obscurity only to be re-discovered because new supportive data appeared. Technical advances (especially in our ability to sequence genomes and establish the evolution of cell clones through cytogenetics) have recently made tools available that could help elucidate the role of cell-cell fusion, aneuploidy and viruses in cancer. Evidence seems to be increasing in support of the ideas stated by Boveri a century ago.

Chromosomal instability and aneuploidy in cancer: from yeast to man

Aneuploidy is frequently associated with disease and developmental abnormalities. It is also a key characteristic of cancer. Several model systems have been developed to study the role of chromosomal instability and aneuploidy in tumorigenesis. The results are surprisingly complex, with the conditions sometimes promoting and sometimes inhibiting tumour formation. Here, we review the effects of aneuploidy and chromosomal instability in cells and model systems of cancer, propose a model that could explain these complex findings and discuss how the aneuploid condition could be exploited in cancer therapy.

Losing balance: the origin and impact of aneuploidy in cancer

Most solid human tumours are aneuploid, that is, they contain an abnormal number of chromosomes. Paradoxically, however, aneuploidy has been reported to induce a stress response that suppresses cellular proliferation in vitro. Here, we review the progress in our understanding of the causes and effects of aneuploidy in cancer and discuss how, in specific contexts, aneuploidy can provide a growth advantage and facilitate cellular transformation. We also explore the emerging possibilities for targeting the cause or consequences of aneuploidy therapeutically.

Abstract 3114: Mutational inactivation of STAG2 causes aneuploidy in human cancer

Abstract One of the hallmarks of cancer is chromosomal instability, which leads to aneuploidy, translocations, loss of heterozygosity, and other chromosomal aberrations. Chromosomal instability is an early event in cancer pathogenesis and is thought to help generate the large number of genetic lesions required for a cell to undergo malignant transformation. It has been hypothesized that this instability is due to inactivating mutations in genes that control the mitotic checkpoint and chromosome segregation. However, in the vast majority of human tumors the molecular basis of chromosomal instability and the aneuploidy it produces remains unknown. We have recently identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors (Science 333:1039, 2011). A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer. These findings and additional unpublished observations regarding the role of STAG2 inactivation in aneuploidy will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3114. doi:1538-7445.AM2012-3114

Cohesin-SA1 deficiency drives aneuploidy and tumourigenesis in mice due to impaired replication of telomeres

Cohesin is a protein complex originally identified for its role in sister chromatid cohesion, although increasing evidence portrays it also as a major organizer of interphase chromatin. Vertebrate cohesin consists of Smc1, Smc3, Rad21/Scc1 and either stromal antigen 1 (SA1) or SA2. To explore the functional specificity of these two versions of cohesin and their relevance for embryonic development and cancer, we generated a mouse model deficient for SA1. Complete ablation of SA1 results in embryonic lethality, while heterozygous animals have shorter lifespan and earlier onset of tumourigenesis. SA1-null mouse embryonic fibroblasts show decreased proliferation and increased aneuploidy as a result of chromosome segregation defects. These defects are not caused by impaired centromeric cohesion, which depends on cohesin-SA2. Instead, they arise from defective telomere replication, which requires cohesion mediated specifically by cohesin-SA1. We propose a novel mechanism for aneuploidy generation that involves impaired telomere replication upon loss of cohesin-SA1, with clear implications in tumourigenesis.

Clinical aspect and molecular mechanism of DNA aneuploidy in gastric cancers

The biological characteristics of cancers depend mostly on genetic alterations in the cancer cells of individuals. Gastric cancers show a high frequency of DNA aneuploidy, a phenotype of chromosomal instability. Compared to diploid tumors, gastric carcinomas with aneuploidy have been shown to have high proliferative activity and high metastatic or invasive potential; these characteristics lead to a poor prognosis. It has been suggested that an abnormal spindle assembly checkpoint is involved in DNA aneuploidy, but the underlying mechanism is still unclear. This review, in order to determine whether gastric carcinomas that display aneuploidy are associated with a poorer prognosis than diploid tumors, and to discuss the biological mechanisms that induce aneuploidy, summarizes the results of studies on DNA ploidy in gastric cancer published in the English literature. Analysis of DNA ploidy in gastric cancer may provide clinically useful information from diagnostic, therapeutic, and prognostic standpoints. Further investigations may be needed to clarify the relationship between chromosome instability and DNA ploidy.

Role of RhoA-Specific Guanine Exchange Factors in Regulation of Endomitosis in Megakaryocytes

Polyploidization can precede the development of aneuploidy in cancer. Polyploidization in megakaryocytes (Mks), in contrast, is a highly controlled developmental process critical for efficient platelet production via unknown mechanisms. Using primary cells, we demonstrate that the guanine exchange factors GEF-H1 and ECT2, which are often overexpressed in cancer and are essential for RhoA activation during cytokinesis, must be downregulated for Mk polyploidization. The first (2N-4N) endomitotic cycle requires GEF-H1 downregulation, whereas subsequent cycles (>4N) require ECT2 downregulation. Exogenous expression of both GEF-H1 and ECT2 prevents endomitosis, resulting in proliferation of 2N Mks. Furthermore, we have shown that the mechanism by which polyploidization is prevented in Mks lacking Mkl1, which is mutated in megakaryocytic leukemia, is via elevated GEF-H1 expression; shRNA-mediated GEF-H1 knockdown alone rescues this ploidy defect. These mechanistic insights enhance our understanding of normal versus malignant megakaryocytopoiesis, as well as aberrant mitosis in aneuploid cancers.

Causes and consequences of aneuploidy in cancer

Genetic instability, which includes both numerical and structural chromosomal abnormalities, is a hallmark of cancer. Whereas the structural chromosome rearrangements have received substantial attention, the role of whole-chromosome aneuploidy in cancer is much less well-understood. Here we review recent progress in understanding the roles of whole-chromosome aneuploidy in cancer, including the mechanistic causes of aneuploidy, the cellular responses to chromosome gains or losses and how cells might adapt to tolerate these usually detrimental alterations. We also explore the role of aneuploidy in cellular transformation and discuss the possibility of developing aneuploidy-specific therapies.

Securin predicts aneuploidy and survival in breast cancer

Securin is known to participate in maintaining chromosomal integrity during the cell cycle through regulation of metaphase-anaphase transition, DNA damage repair, and apoptosis. The aim of this study was to investigate the role of securin in aneuploidy and prognosis in human breast cancer. The study was based on 603 breast cancer patients with up to 20 years of follow-up. DNA content was determined by image cytometry on cell imprints, and securin immunohistochemistry was performed on tissue microarrays of breast cancer tissue. We show, for the first time in human breast cancer, that high-level securin expression predicts abnormal DNA content, with up to 9.8-fold odds for aneuploid DNA content (P = 0.0007). Securin also shows strong independent prognostic value for disease-specific survival, with a significant difference in survival time between patients with low-level and high-level securin expression. The main result of the present study is the association of aneuploidy and securin expression. According to our results, securin immunohistochemistry is also a potential new prognosticator for treatment decisions concerning breast cancer patients.

Abstract C57: Role of aneuploidy in cellular adaptation, drug resistance, and cancer

Abstract Cancer is a multistep Darwinian process whereby mutant cells able to escape internal, environmental, or drug-mediated proliferative roadblocks expand and outcompete less-fit cells. Mutations characterizing this somatic evolution range from single-point mutations to whole-chromosome aneuploidy. Although sequence mutations clearly play a role in cancer evolution, the role of aneuploidy in cancer is far less clear. Previously, we investigated how yeast cells can adapt in response to a proliferative roadblock and the role of aneuploidy during this process. We showed that aneuploidy could provide a source of heritable variation driving the emergence of large phenotypic changes that can be adaptive under strong selective conditions. Recently, we provided evidence that aneuploidy is sufficient to generate global changes at the proteome level and to provide phenotypic variation. Taken together, our data suggest that aneuploidy might thus be beneficial to cancer cells that are trying to escape growth inhibitory signals and chemotherapy treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr C57.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Mutational inactivation of STAG2 causes aneuploidy in human cancer.

Most cancer cells are characterized by aneuploidy, an abnormal number of chromosomes. We have identified a clue to the mechanistic origins of aneuploidy through integrative genomic analyses of human tumors. A diverse range of tumor types were found to harbor deletions or inactivating mutations of STAG2, a gene encoding a subunit of the cohesin complex, which regulates the separation of sister chromatids during cell division. Because STAG2 is on the X chromosome, its inactivation requires only a single mutational event. Studying a near-diploid human cell line with a stable karyotype, we found that targeted inactivation of STAG2 led to chromatid cohesion defects and aneuploidy, whereas in two aneuploid human glioblastoma cell lines, targeted correction of the endogenous mutant alleles of STAG2 led to enhanced chromosomal stability. Thus, genetic disruption of cohesin is a cause of aneuploidy in human cancer.

The Causes and Consequences of Polyploidy in Normal Development and Cancer

Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid state of the mammalian genome. Unscheduled whole-genome duplications, which lead primarily to tetraploid cells, also take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of these polyploidization events and their consequences for tumor progression are explored in this review.

Increased sperm aneuploidy in two male carriers of germline TP53 mutations

Li-Fraumeni syndrome is a rare autosomal dominant cancer predisposition syndrome characterized by a broad spectrum of tumors. The disorder is caused by germline mutations in the TP53 gene. We studied chromosomes in the sperm of two male carriers of TP53 mutations. We observed increased sperm aneuploidy, mainly concerning the gonosomes when compared to four normal male controls. This observation may correlate with the involvement of the p53 protein in spermatogenesis, with its role in aneuploidy in cancer, and with the occurrence of two cases of Turner syndrome in families with germline TP53 mutations reported in the literature.

Nuclear envelope structural defects cause chromosomal numerical instability and aneuploidy in ovarian cancer

BackgroundDespite our substantial understanding of molecular mechanisms and gene mutations involved in cancer, the technical approaches for diagnosis and prognosis of cancer are limited. In routine clinical diagnosis of cancer, the procedure is very basic: nuclear morphology is used as a common assessment of the degree of malignancy, and hence acts as a prognostic and predictive indicator of the disease. Furthermore, though the atypical nuclear morphology of cancer cells is believed to be a consequence of oncogenic signaling, the molecular basis remains unclear. Another common characteristic of human cancer is aneuploidy, but the causes and its role in carcinogenesis are not well established.MethodsWe investigated the expression of the nuclear envelope proteins lamin A/C in ovarian cancer by immunohistochemistry and studied the consequence of lamin A/C suppression using siRNA in primary human ovarian surface epithelial cells in culture. We used immunofluorescence microscopy to analyze nuclear morphology, flow cytometry to analyze cellular DNA content, and fluorescence in situ hybridization to examine cell ploidy of the lamin A/C-suppressed cells.ResultsWe found that nuclear lamina proteins lamin A/C are often absent (47%) in ovarian cancer cells and tissues. Even in lamin A/C-positive ovarian cancer, the expression is heterogeneous within the population of tumor cells. In most cancer cell lines, a significant fraction of the lamin A/C-negative population was observed to intermix with the lamin A/C-positive cells. Down regulation of lamin A/C in non-cancerous primary ovarian surface epithelial cells led to morphological deformation and development of aneuploidy. The aneuploid cells became growth retarded due to a p53-dependent induction of the cell cycle inhibitor p21.ConclusionsWe conclude that the loss of nuclear envelope structural proteins, such as lamin A/C, may underlie two of the hallmarks of cancer - aberrations in nuclear morphology and aneuploidy.

Mechanisms of aneuploidy and its suppression by tumour suppressor proteins

Aneuploidy, as a result of numerical changes in chromosome number, was observed in tumours almost a century ago. The molecular mechanisms underlying this phenomenon and their impact on tumour development are still poorly understood. A series of recent observations provide direct linkages between the normal function of tumour suppressor proteins and the suppression of aneuploidy. The prospects that these findings offer for understanding the role of aneuploidy in cancer are discussed in this review.

A non-genetic route to aneuploidy in human cancers

Aneuploidy is common in human tumours and is often indicative of aggressive disease. Aneuploidy can result from cytokinesis failure, which produces binucleate cells that generate aneuploid offspring with subsequent divisions. In cancers, disruption of cytokinesis is known to result from genetic perturbations to mitotic pathways or checkpoints. Here we describe a non-genetic mechanism of cytokinesis failure that occurs as a direct result of cell-in-cell formation by entosis. Live cells internalized by entosis, which can persist through the cell cycle of host cells, disrupt formation of the contractile ring during host cell division. As a result, cytokinesis frequently fails, generating binucleate cells that produce aneuploid cell lineages. In human breast tumours, multinucleation is associated with cell-in-cell structures. These data define a previously unknown mechanism of cytokinesis failure and aneuploid cell formation that operates in human cancers.

Expression analysis of mitotic spindle checkpoint genes in breast carcinoma: role of NDC80/HEC1 in early breast tumorigenicity, and a two-gene signature for aneuploidy

BackgroundAneuploidy and chromosomal instability (CIN) are common abnormalities in human cancer. Alterations of the mitotic spindle checkpoint are likely to contribute to these phenotypes, but little is known about somatic alterations of mitotic spindle checkpoint genes in breast cancer.MethodsTo obtain further insight into the molecular mechanisms underlying aneuploidy in breast cancer, we used real-time quantitative RT-PCR to quantify the mRNA expression of 76 selected mitotic spindle checkpoint genes in a large panel of breast tumor samples.ResultsThe expression of 49 (64.5%) of the 76 genes was significantly dysregulated in breast tumors compared to normal breast tissues: 40 genes were upregulated and 9 were downregulated. Most of these changes in gene expression during malignant transformation were observed in epithelial cells.Alterations of nine of these genes, and particularly NDC80, were also detected in benign breast tumors, indicating that they may be involved in pre-neoplastic processes.We also identified a two-gene expression signature (PLK1 + AURKA) which discriminated between DNA aneuploid and DNA diploid breast tumor samples. Interestingly, some DNA tetraploid tumor samples failed to cluster with DNA aneuploid breast tumors.ConclusionThis study confirms the importance of previously characterized genes and identifies novel candidate genes that could be activated for aneuploidy to occur. Further functional analyses are required to clearly confirm the role of these new identified genes in the molecular mechanisms involved in breast cancer aneuploidy. The novel genes identified here, and/or the two-gene expression signature, might serve as diagnostic or prognostic markers and form the basis for novel therapeutic strategies.

Highly aneuploid zebrafish malignant peripheral nerve sheath tumors have genetic alterations similar to human cancers.

Aneuploidy is a hallmark of human cancers, but most mouse cancer models lack the extensive aneuploidy seen in many human tumors. The zebrafish is becoming an increasingly popular model for studying cancer. Here we report that malignant peripheral nerve sheath tumors (MPNSTs) that arise in zebrafish as a result of mutations in either ribosomal protein (rp) genes or in p53 are highly aneuploid. Karyotyping reveals that these tumors frequently harbor near-triploid numbers of chromosomes, and they vary in chromosome number from cell to cell within a single tumor. Using array comparative genomic hybridization, we found that, as in human cancers, certain fish chromosomes are preferentially overrepresented, whereas others are underrepresented in many MPNSTs. In addition, we obtained evidence for recurrent subchromosomal amplifications and deletions that may contain genes involved in cancer initiation or progression. These focal amplifications encompassed several genes whose amplification is observed in human tumors, including met, cyclinD2, slc45a3, and cdk6. One focal amplification included fgf6a. Increasing fgf signaling via a mutation that overexpresses fgf8 accelerated the onset of MPNSTs in fish bearing a mutation in p53, suggesting that fgf6a itself may be a driver of MPNSTs. Our results suggest that the zebrafish is a useful model in which to study aneuploidy in human cancer and in which to identify candidate genes that may act as drivers in fish and potentially also in human tumors.