As introduced in Chapter 5, cytogenetic changes are hallmarks of cancer, whether sporadic or familial, particularly in later and more malignant or invasive stages of tumor development. Cytogenetic alterations suggest that a critical element of cancer progression includes defects in genes involved in maintaining chromosome stability and integrity and ensuring accurate mitotic segregation. Initially, most of the cytogenetic studies of tumor progression were carried out in leukemias because the tumor cells were amenable to being cultured and karyotyped by standard methods. For example, when CML, with the 9;22 Philadelphia chromosome, evolves from the typically indolent chronic phase to a severe, life-threatening blast crisis, there may be several additional cytogenetic abnormalities, including numerical or structural changes, such as a second copy of the 9;22 translocation chromosome or an isochromosome for 17q. In advanced stages of other forms of leukemia, other translocations are common. In contrast, a vast array of chromosomal abnormalities are seen in most solid tumors. Cytogenetic abnormalities found repeatedly in a specific type of cancer are likely to be driver chromosome mutations involved in the initiation or progression of the malignant neoplasm. A current focus of cancer research is to develop a comprehensive cytogenetic and genomic definition of these abnormalities, many of which result in enhanced proto-oncogene expression or the loss of TSG alleles. Whole-genome sequencing is replacing cytogenetic analysis in many instances, because it provides a level of sensitivity and precision well beyond detection of cytologically visible genome changes. In addition to translocations and other rearrangements, another cytogenetic aberration seen in many cancers is gene amplification, a phenomenon in which many additional copies of a segment of the genome are present in the cell (see Fig. 15-3). Gene amplification is common in many cancers, including neuroblastoma, squamous cell carcinoma of the head and neck, colorectal cancer, and malignant glioblastomas of the brain. Amplified segments of DNA are readily detected by comparative genome hybridization or whole-genome sequencing and appear as two types of cytogenetic change in routine chromosome analysis: double minutes (very small accessory chromosomes) and homogeneously staining regions that do not band normally and contain multiple, amplified copies of a particular DNA segment. How and why double minutes and homogeneously staining regions develop are poorly understood, but amplified regions are known to include extra copies of proto-oncogenes such as the genes encoding Myc, Ras, and epithelial growth factor receptor, which stimulate cell growth, block apoptosis, or both. For example, amplification of the MYCN proto-oncogene encoding N-Myc is an important clinical indicator of prognosis in the childhood cancer neuroblastoma. MYCN is amplified more than 200-fold in 40% of advanced stages of neuroblastoma; despite aggressive treatment, only 30% of patients with advanced disease survive 3 years. In contrast, MYCN amplification is found in only 4% of early-stage neuroblastoma, and the 3-year survival is 90%. Amplification of genes encoding the targets of chemotherapeutic agents has also been implicated as a mechanism for the development of drug resistance in patients previously treated with chemotherapy.
Cytogenetic Changes in Cancer
Aneuploidy and Aneusomy
Gene Amplification
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