Unveiling the Mysteries of Cancer Mutations

Genomic Instability, DNA Repair, and Epigenetic Modifications in Cancer Cells

• Cancer cells have a derangement of their normal ability to repair DNA damage, leading to a mutator phenotype characterized by high levels of genomic instability.
• The mutator phenotype results in an increased mutation rate for every gene in the genome, including those controlling cell proliferation, programmed cell death, and metastasis.
• Chromosomal defects in cancer cells, such as translocations, aneuploidy, chromosome loss, DNA amplification, and deletions, are used to diagnose the type and stage of the cancer.
• Inherited cancers, like xeroderma pigmentosum and hereditary nonpolyposis colorectal cancer, are caused by defects in genes controlling DNA repair, which lead to higher than normal mutation rates and genomic instability.
• The BCR-ABL fusion gene codes for a chimeric BCR-ABL protein in chronic myelogenous leukemia cells, which stimulates these cells to proliferate even in the absence of external growth signals.
• Epigenetic modifications, such as DNA methylation and histone modifications, affect gene expression without altering the nucleotide sequence of DNA.
• DNA methylation patterns in cancer cells are altered, resulting in the release of transcription repression over the bulk of genes that would be silent in normal cells, including cancer-causing genes.
• Histone modifications are also disrupted in cancer cells, with genes that encode histone acetylases, deacetylases, methyltransferases, and demethylases often mutated or aberrantly expressed.
• The large numbers of epigenetic abnormalities in tumors suggest that there may be more epigenetic defects in cancer cells than there are gene mutations.
• The effects of chromatin modifications and epigenetic factors on gene expression and hereditary disease are discussed in more detail in the text's Special Topic Chapter 1.
• Cancer epigenetics is a new field of study providing new perspectives on the genetics of cancer.
• Understanding genomic instability, DNA repair defects, and epigenetic modifications in cancer cells can lead to new approaches in cancer diagnosis, treatment, and prevention.

Cell Cycle and Cancer

• Loss of control over cell proliferation is a fundamental aberration in all cancer cells.
• The cell cycle is regulated by three major checkpoints: G1/S, G2/M, and M checkpoints.
• Cyclins and cyclin-dependent kinases (CDKs) regulate progress through the cell cycle.
• Differentiated cells are specialized for specific functions and do not divide frequently.
• External growth signals can stimulate cells in the G0 phase to reenter the cell cycle.
• Signal transduction is the process of transmitting growth signals from the external environment to the cell nucleus.
• Cancer cells often have defects in signal transduction pathways.
• Progress through the cell cycle is tightly regulated in normal cells.
• The G1/S checkpoint monitors cell size and DNA damage before proceeding to the S phase.
• The G2/M checkpoint monitors physiological conditions in the cell before mitosis.
• The M checkpoint monitors the formation of the spindle-fiber system and attachment of spindle fibers to kinetochores.
• Mutation or misexpression of genes controlling the cell cycle can contribute to the development of cancer.