Exam 5 Study Guide Chapter 16 The Genetics of Cancer Cancer is a genetic disease at the somatic level characterized by gene products derived from mutated genes While some are inherited most are created within somatic cells that divide and form tumors Birth to death statistics show that men have a 1 in 2 chance of getting cancer in their lifetime and women have a 1 in 3 chance 16 1 Cancer is a Genetic Disease at the Level of Somatic Cells Genomic alterations range from single nucleotide substitutions to large scale chromosome rearrangements amplifications and deletions Unlike other genetic diseases cancer is caused by mutations that occur predominately in somatic cells Only about 1 percent of cancers are associated with germ line mutations Rarely arises from a single mutation but from the accumulation of mutations in genes These mutations can affect cellular functions including repair of DNA damage cell division apoptosis cellular differentiation migratory behavior and cell cell contact What is Cancer A large number of complex diseases up to a hundred that behaves differently depending on the cell types from which they originate They all share two fundamental properties o 1 Abnormal cell growth and division proliferation o 2 Defects in the normal restraints that keep cells from spreading and invading other parts of the body metastasis In normal cells these functions are tightly controlled by genes that are expressed appropriately in time and place In cancer cells these genes are either mutated or expressed inappropriately When a cell simply loses control over cell growth it may grow into a multicellular mass a benign tumor Such a tumor can often be removed by surgery and may cause no serious harm Malignant tumors result from cells that break loose and form secondary tumors metastasis These are more difficult to treat and may become life threatening The Clonal Origin of Cancer Cells All cancer cells in primary and secondary tumors are clonal meaning that they originated form a common ancestral cell that accumulated numerous specific mutations Numerous data support the concept of cancer clonality For example reciprocal chromosomal translations are characteristic of many cancers including leukemias and lymphomas involve white blood cells o Burkitt s lymphoma shows reciprocal translocations between chromosome 8 with translocations at or near the c myc proto oncogene and chromosomes 2 14 OR 22 Each Burkitt s lymphoma patient exhibits unique breakpoints in his or her c myc and immunoglobin gene DNA sequences however all lymphoma cells within that patient contain identical translocation breakpoints This demonstrates that all cancer cells in each case of Burkitt s lymphoma arise from a single cell and this cell passes on its genetic aberrations to its progeny C myc is a proto oncogene that is a hallmark of certain cancers when misregulated It functions a transcription factor regulates cell cycle differentiation and apoptosis o X chromosome inactivation occurs early in development and occurs at random All cancer cells within a tumor contain both primary and metastatic within one female individual contain the same inactivated X chromosome This supports the concept that all cancer cells in that patient arose from a common ancestral cell The Cancer Stem Hypothesis Tumor cells that proliferate give rise to cancer stem cells that have the capacity for self renewal a process in which the stem cell divides unevenly creating one daughter cell that goes on to differentiate into a mature cell type and one that remains a stem cell Evidence is accumulating that cancer stem cells do exist The origins are still unknown they may arise form normal adult stem cells or they may be created from more differentiated cells that acquire properties similar to stem cells after accumulating numerous mutations Cancer is a multistep process requiring multiple mutations There is a delay that occurs between the exposure to carcinogens and the onset of cancer Also cancers develop in progressive steps beginning with mildly aberrant cells and progressing to cells that are increasingly tumorigenic and malignant Researchers believe that only a handful of mutations in somatic cells driver mutations give a growth advantage to a tumor cell 16 2 Cancer cells contain Genetic Defects Affecting Genomic Stability DNA Repair and Chromatin Modifications Cancer cells show higher rates of mutation chromosomal abnormalities and genomic instability The fundamental defect in cancer cells is a derangement of the cell s ability to repair DNA damage The high level of genomic instability is known as the mutator phenotype Genomic Instability and Defective DNA Repair Genomic instability in cancer cells is characterized by the presence of gross defects such as translocations aneuploidy chromosome loss DNA amplification and chromosome deletions Often cancer cells show specific chromosomal defects that are used to diagnose the type and stage of cancer For example leukemic white blood cells in patients with chronic myelogenous leukemia CML bear a specific translocation in which the c ABL gene on chromosome 9 is translocated into the BCR gene on chromosome 22 This translocation creates a structure known as the Philadelphia chromosome The BCR ABL fusion gene codes for chimeric BCR ABL protein The normal ABL protein is a protein kinase that acts within signal transduction pathways transferring growth factors from the external environment to the nucleus The BCR ABL protein is an abnormal signal transduction molecule in CML cells that stimulate cell proliferation even in the absence of external growth signals Hereditary nonpolyposis colorectal cancer HNPCC is also caused by mutations controlling DNA repair The observation that hereditary defects in genes controlling nucleotide excision repair and DNA mismatch repair lead to high rates of cancer lends support to the idea that the mutator phenotype is a significant contributor to the development of cancer Chromatin Modifications and Cancer Epigenetics Epigenetics is the study of factors that affect gene expression but do not alter the nucleotide sequence of DNA There is much less DNA methylation in cancer cells than normal cells At the same time the promotors of some genes are hypermethylated in cancer cells Histone modifications are also disrupted in cancer cells Genes that encode histone modifying enzymes are often mutated of aberrantly expressed in cancer cells Epigenic modifications are reversible
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