Chromosomal instability

Encyclopedia of Cancer. 2015




Chromosomal instability is the gain and/or loss of whole chromosomes or chromosomal segments at a higher rate in a population of cells, such as cancer cells, compared to their normal counterparts (normal cells). In some cancers, each cell within the tumor has a different chromosomal constitution (karyotype) due to chromosomal instability, which may be defined in practical terms as numerical and/or structural chromosomal alterations that vary from cell to cell. Although the terms chromosomal instability and genomic instability have been used interchangeably, this is technically incorrect, as they refer to different forms of genetic instability.


Chromosomal instability is a characteristic of cancer cells, especially solid tumors (rather than most hematologic (blood cell) malignancies). Several cellular mechanisms lead to numerical and structural chromosomal instability in cancer cells, including defects in (i) chromosomal distribution to the daughter cells (chromosome segregation), (ii) cell cycle checkpoints that protect against proliferation of abnormal cells, (iii) telomere (specialized structures that cap the ends of chromosomes) stability, and (iv) the DNA damage response. Although in the past, these mechanisms were thought to be unrelated, it has become clear that they are intimately intertwined, connecting the complex network of cellular pathways. Human papillomavirus and other oncogenic viruses interfere with these processes, causing chromosomal instability and tumor formation in the cells that they infect. Chromosomal instability plays an important role in cancer by creating large-scale genetic changes in as little as one cell generation, leading to rapid cancer cell evolution. The rate of discoveries about the mechanisms leading to chromosomal instability in cancer cells is accelerating, improving our understanding of how cells become cancer cells and how cancer cells become more dangerous to the patient by progressing and/or metastasizing.

Both clonal numerical and structural chromosomal alterations and chromosomal instability are common features of human cancers. Aneuploidy is the condition in which the chromosome number in a cell, population of cells, or person is not an exact multiple of the usual haploid chromosome number (N = 23 for humans). Aneuploidy results from numerical chromosomal alterations. Cancers with chromosomal instability are characterized by aneusomy, a condition in which a population of cells contain different numbers of chromosomes. In tumor cells, gains and losses of chromosomal segments arise as a result of structural chromosomal alterations, including reciprocal and nonreciprocal chromosomal translocations, homogeneously staining regions (in which a cassette of contiguous genes, including at least one oncogene or growth-related gene, is tandemly repeated (amplified) at least five times on a diploid background), other forms of gene amplification (e.g., double minute chromosomes), insertions, and deletions. Structural alterations may result in a further imbalance in gene expression, resulting in chromosomal instability. In some tumors, each cell within the tumor has a different karyotype due to chromosomal instability.

Historical background

Chromosomal instability is thought to be the means by which cells develop the features that enable them to become cancer cells. In spite of the presence of cell-to-cell chromosomal instability, the tumor karyotype is thought to be quite stable over time, probably because advanced tumors have evolved a genetic makeup (genotype) optimized for growth, making it less likely that additional genetic alterations will confer an additional growth advantage. Chromosomal alterations and karyotypic instability in human tumor cells have been investigated for nearly a century. David von Hansemann first identified abnormal dividing cells in tissue sections of tumors, including cell divisions that appeared to have asymmetric spindles or multiple spindle poles (multipolar spindles) that would lead to unequal distribution of the chromosomes to the daughter cells, and chromosomes stretched between the two spindle poles late in cell division (anaphase bridges). Theodor Boveri (Hanahan and Weinberg 2011), while studying chromosomal segregation in Ascaris worms and Paracentrotus sea urchins in the early 1900s suggested that malignant tumors arise from a single cell with an abnormal genetic constitution acquired as a result of defects in the mitotic spindle apparatus. Today we know that numerical chromosomal instability arises as a result of chromosome segregational defects, most frequently resulting from multipolar spindles. Structural chromosomal instability results from chromosome breakage and rearrangement due to defects in cell cycle checkpoints, the DNA damage response, and/or loss of telomere integrity. Structural chromosomal instability frequently results from breakage-fusion-bridge (BFB) cycles, first described in maize by geneticist Barbara McClintock in 1938. In this process, a chromatid break occurs, exposing an unprotected chromosomal end which, after replication, is thought to fuse with either another broken chromatid or its sister chromatid to produce a dicentric chromosome. During the anaphase stage of mitosis, the two centromeres are pulled to opposite poles, forming a bridge which breaks, resulting in more unprotected chromosomal ends, and thus the cycle continues. Our studies of cancer cells suggest that structural chromosomal instability, including gene amplification, can occur by BFB cycles. The basis for these BFB cycles is not entirely clear, although recent studies of chromosomal fragile site breakage, some of which occurs as a result of cigarette smoking and leads to induction of BFB cycles, telomere dynamics, and the DNA damage response, suggest that these critical cellular processes play major roles in the development of structural chromosomal instability. In this contribution, defects in chromosomal segregation, cell cycle checkpoints, telomere function, and the DNA damage response and their role in mechanisms leading to chromosomal instability are introduced and literature citations (References) are provided for the interested reader.

Chromosome segregational defects lead to chromosomal instability

One of the fundamental processes required in the life of a cell, whether from a unicellular or multicellular organism, is chromosome segregation. Fidelity of chromosome segregation, whether in meiosis or mitosis, is necessary for genomic stability and the continuation of life as we know it. Abnormal chromosome segregation results in aneuploidy, abnormal numbers of chromosomes being distributed to daughter cells, such that the daughter cells don’t match each other or their mother cell. This is the essence of chromosomal instability. Recent studies have shown that several factors can result in segregation defects, including abnormal chromosome-spindle interactions, premature chromatid separation, centrosome amplification, multipolar spindles, and abnormal cytokinesis (cell division). Chromosomal segregational defects (multipolar spindles, lagging chromosomes at metaphase and anaphase, and anaphase bridges) in cancer cell lines are an intrinsic, heritable trait in the general tumor cell population. Tumor cells expressing chromosomal instability cannot be “cloned,” as they continue to express numerical and structural chromosomal instability generation after generation. In some cancers, ongoing chromosomal instability is a feature of both primary tumors in the patient and cell lines cultured in the laboratory from biopsies removed from those tumors. Many studies of proteins involved in the process of chromosome segregation, spindle function, and cytokinesis are in progress in numerous laboratories. The role of these proteins in chromosomal instability and implications in the diagnosis, prognosis, and therapy of human tumors will be revealed in the next few years.

A defective response to DNA damage leads to chromosomal instability

For many years, cytogeneticists (scientists who examine chromosomes) have known that patients with “chromosome breakage” syndromes express chromosomal instability. Yet, until recently, features of these syndromes have not been utilized to define defects in the DNA damage response in cancer cells. Causes of DNA damage include attack by ultraviolet light, ionizing radiation (X-rays), or environmental chemicals, and cellular errors, such as “spelling errors” (base pair mismatch) during DNA replication, replication fork collapse, or defects caused by naturally occurring reactive oxygen species. One type of DNA damage is the double strand break, which leads to a cascade of cellular events (the DNA damage response) that usually results in repair of the damage or cell death. Failure in the DNA damage response and double strand break repair can lead to genetic alteration or chromosomal instability, which can result in transformation from a normal cell to a cancer cell. The DNA damage response involves the sensing of DNA damage followed by transduction of the damage signal to a network of cellular pathways, from those involved in the cellular survival response, including cell cycle checkpoints, DNA repair, and stress responses to telomere maintenance, and the apoptotic pathway. To make a simple analogy in an effort to describe the complex DNA damage response to double strand breaks, we can say that our cellular instruction book for all of the activities that go on in our cells and in our bodies is made up of 23 chapters, the chromosomes, and for safety’s sake, we have two copies of the book, one from our mother and one from our father, although they aren’t exact copies (e.g., the set of eye color genes from your mother may code for blue eyes and the one from your father, brown). The genes are like sentences in a chapter, made up of three letter words composed of the four letters of DNA, A, T, C, and G. The 23 different chromosomes in the cells, composed of many genes, are equivalent to the 23 chapters in the book, made up of many sentences. The total genome is equivalent to the whole instruction book for the cells, and the instructions code for proteins, the molecules that do the work in our bodies. So in total, we have 46 chromosomes, two copies of each one. Sometimes, this very long set of DNA instructions becomes damaged (like the pages in the book can become torn or fall out) from smoking, chemicals, X-rays, oxidants that occur naturally in our bodies (why some of us take “antioxidant” vitamins), or other insults. Although our DNA is a code of letters like words in a book, it really looks like a ladder or even like railroad tracks. To more easily think about DNA repair, we need to visualize it as railroad tracks. Like the railroad company, which has special vehicles that check the integrity of the tracks, we have proteins that check our DNA (sensor proteins and checkpoint proteins). If the sensor protein spots a double strand break or another defect that might derail the train or cause a defect in the cellular instructions (mutation), she then tells the communications officer (signal transducer) to call headquarters which in turn calls the repair team. This happens in our cells, in which case the repair team is a series of proteins that carry out sequential multistep assessment and repair of the damage (the DNA damage response). If they find that a cargo train has already been instructed by the defect to race out of control, analogous to a cell proliferating in an uncontrolled fashion, making more and more copies of itself, on the way to making a cancer, they kill that cell. But, what if the protein that has the job of pushing the kill switch is sick that day, the cell cannot be killed and a cancer ensues. In our cells, this DNA damage response pathway is carried out by about 50 proteins in a carefully choreographed process. With the advances in the human genome project, we are learning more about the proteins in this pathway and how defects (mutations) in them can cause predisposition to cancer.

Loss, mutation, or altered function of the genes that code for some of the DNA damage response proteins cause familial cancer syndromes and in some cases, chromosomal breakage syndromes, which may affect heterozygous gene carriers or affected (homozygous) individuals. Although not clear at this time, the role of these critical DNA damage response genes in chromosomal instability merits further investigation. The DNA damage response genes involved in known familial cancer syndromes include ATM, TP53, BRCA1, BRCA2, FANC, CHEK2, BLM, and MRE11A. The involvement of the DNA damage response genes, BRCA1 and BRCA2, in familial breast and ovarian cancer is well known. Both genes also appear to be associated with an increased risk of prostate cancer, and BRCA2 is involved in familial pancreatic cancer. Germline TP53 mutation carriers have Li-Fraumeni syndrome which is associated with a high risk of breast and brain tumors, sarcomas (muscle tumors), leukemia (blood cell tumors), laryngeal (voice box) and lung cancer, and other tumors. Germline CHEK2 mutation carriers may present with a Li-Fraumeni-like syndrome and may have an increased risk for a wide range of tumors including breast, prostate, and colorectal (intestinal) cancer. Patients with ataxia telangiectasia, the autosomal recessive genetic disorder characterized by a defective ATM gene, manifest progressive cerebellar ataxia (staggering gait), telangiectases (“blood shot” eyes and skin), immune dysfunction, chromosomal instability, increased sensitivity to ionizing radiation (X-rays), and predisposition to cancer, especially leukemia. Heterozygous ATM carriers (both human and mouse) of dominant-negative (interfering) missense mutations are at increased risk for solid tumors, including breast cancer. Fanconi anemia (FA) is a rare genetic cancer susceptibility syndrome characterized by skeletal abnormalities, skin pigmentation abnormalities, bone marrow failure, chromosomal instability in the form of rearrangements between nonhomologous chromosomes, and sensitivity to DNA crosslinking agents. FA patients are predisposed to developing cancer, primarily leukemia and epithelial tumors, especially squamous cell carcinoma of the mouth and throat (called head and neck cancer) or cervical cancer. The risk of solid tumors in FA patients is ~50-fold higher for all solid tumors compared to the general population, but about 700-fold higher for head and neck cancers. Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, sun-sensitive facial redness, hypo- and hyper-pigmented skin, sterility in males, reduced fertility in females, predisposition to a variety of malignancies, and chromosomal instability. Thus, patients with cancer predisposition and “chromosomal breakage” syndromes will continue to educate us about the cellular processes that lead to chromosomal instability and cancer.

Telomere dysfunction may lead to chromosomal instability

Telomere loss or dysfunction is a cause of chromosomal instability in the laboratory mouse. Telomere loss can result from DNA damage or occur spontaneously in cancer cells which often have a high rate of telomere loss due to telomere shortening with each cell division. Telomere alterations in certain genetically engineered mice mirror those in human epithelial tumors, lending support to the hypothesis that telomere defects drive chromosomal instability in cancer cells and age-related epithelial carcinogenesis. Thus, in mouse and man, telomere dysfunction leads to chromosomal instability, as shown by studies of telomere dysfunction in the mouse, chromosomal breakage patterns in human tumors, and the observation that cancer predisposition syndromes can lead to both telomere dysfunction and chromosomal instability. Consistent with this hypothesis, both telomere shortening and cancer incidence increase with age. Telomeres play an important role in chromosomal instability, but the exact details remain under active investigation.

Cell cycle disturbances result in chromosomal instability

Oncogenic (cancer causing) viruses, such as human papillomavirus (a sexually transmitted disease which causes cervical cancer in women, penile cancer in men, and oral and anal cancer in both men and women), recapitulate the abnormalities, including defects in chromosome segregation, centrosome dynamics, telomere mechanics, the DNA damage response, cell cycle regulation, and cell cycle checkpoints, that appear to play important roles in the development and maintenance of chromosomal instability. The primary impact of chromosomal instability is cancer. In addition, chromosomal instability is a major cause of tumor evasion of or resistance to therapy. Therefore, a complete understanding of the biological basis of chromosomal instability is essential for developing therapies targeted against the defects in cancer cells.