Test 5 Genetics Study Guide Ch 16 The Genetics of Cancer Cancer is the leading cause of death in Western countries o 1 3 people will experience a cancer diagnosis sometime in their o More than 1 million cases diagnosed in the United States each year and more than 500 000 die from it o Cancer genetic disease at the somatic level characterized by gene products derived from mutated or abnormally expressed genes o Some inherited most are created within somatic cells that divide lifetime tumors WIDE RANGE OF CAUSES including o Single nucleotide substitutions to large scale chromosome rearrangements amplifications and deletions o Mostly affects somatic cells 1 percent germ line mutations o Rarely arises from a single mutation but from a single mutation but from accumulation of mutations in many genes 6 12 o Affects multiple cellular functions repair of damaged DNA cell division apoptosis cellular a Spectral karyotype of a normal cell male b Karyotype of a cancer cell female showing translocations deletions aneuploidy characteristic features of cancer cells Note Loss of Euploidy What Is Cancer o Cancer large complex of diseases up to a hundred behave differently depending on their cellular type origin o All cancers share two fundamental properties 1 Abnormal cell growth and division proliferation 2 Defects in normal restraints that prevent cells from spreading metastasis in normal cells functions tightly controlled by genes expressed appropriately in time and place cancer cells Genes controlling this are mutated or not expressed o combination of uncontrolled cell proliferation and metastatic spread cancer cells dangerous o 1 Benign tumors result from unregulated cell growth forming a multicellular mass that can be removed by surgery causing no serious harm o 2 Malignant tumors result from cells that break loose and form secondary tumors metastases become malignant Malignant tumors difficult to treat and may become life threatening May contain billions of cells May invade and grow in numerous body parts The Clonal Origin of Cancer Cells o Although malignant tumors may contain billions of cells may invade and grow in numerous parts of body o All cancer cells in primary and secondary tumors clonal originated from a common ancestral cell accumulated numerous specific mutations important in understanding molecular basis of cancer and implications of its diagnosis o Reciprocal chromosomal translocations characteristic of many cancers Leukemias and lymphomas involve white blood cells evidence for clonal nature of cancers o Burkitt s lymphoma shows reciprocal translocations between chromosome 8 and chromosomes 2 14 or 22 Translocation breakpoints at near c myc gene and immunoglobulin gene DNA sequences All patients contain identical translocation break points all cancer cells arise from a single cell passed to progeny o X chromosome inactivation occurs early in development random All cancer cells within a tumor both primary and metastatic within one female individual contain the same inactivated X chromosome All cancer cells arose from a common ancestral cell The Cancer Stem Cell Hypothesis o Clonal origin of cancer cells cancer stem cell o Tumors mixture of cells many of which don t proliferate Those that do proliferate and give rise to all cells within tumor cancer stem cells o Cancer stem cell hypothesis Tumor cells that proliferate give rise to cancer stem cells that have the capacity for self renewal stem cell divides unevenly one daughter cell that goes on to differentiate into a mature cell type and one that remains a stem cell o Evidence is accumulating that cancer stem cells do exist and have been identified in leukemia brain cancer breast cancer colon cancer ovarian cancer pancreatic cancer prostate cancer o scientists not sure about origin of cancer but it is possible they arise from normal adult stem cells may be created from more differentiated cells that acquire properties similar to stem cells after accumulating numerous mutations Cancer Cells Contain Genetic Defects Affecting Genomic Stability DNA Repair and Chromatin Modifications forming malignant cell o A single mutation is not sufficient to transform normal cell to tumor o if it were sufficient cancer would be far more prevalent o in humans mutations occur spontaneously at rate of 10 6 mutations per gene per cell division mainly due to intrinsic error rates of DNA o age related because cancer develops from accumulation of several mutagenic events in a single cell chance rises exponentially with replication age o Cancer multistep process delay that occurs between exposure to carcinogens and appearance of cancer Cancer develops in progressive steps begins with mildly abberant cells progressing to cells that are increasingly tumorgenic and malignant o Each step in tumorgenesis malignant tumor development appears to be a result of 2 or more genetic alterations that release the cells progressively from controls that normally operate on proliferation and malignancy progressive genetic alterations that create cancer cell confer selective advantages to cell propagated through cell divisions during creation of tumors Genomic Instability and Defective DNA Repair o Cancer cells show higher than normal rates of mutation chromosomal abnormalities genomic instability o The high level of genomic instability in cancer cells mutator phenotype o fundamental defect in cancer cells derangement of the cell s ability to repair DNA damage loss of genomic integrity leads to general increase in mutation rate for every gene in genome including specific genes controlling processes that lead to cancer o accumulation of mutations in genes cancer o genomic instability cancer cells manifests itself in gross defects such as translocations aneuploidy chromosome loss DNA amplification chromosomal deletions o Often cancers show specific chromosomal defects that are used to diagnose the type and stage of the cancer o Chronic myelogenous leukemia CML C ABL gene chromosome 9 translocated into the BCR gene on chromosome 22 philadelphia chromosome BCR ABL protein abnormal signal transduction molecule Normal ABL protein protein kinase acts with signal transduction pathways from external environment to CML cells stimulate cell proliferation even in the absence of nucleus external growth signals o Philadelphia chromosome often associated with chronic myelogenous leukemia CML BCR ABL fusion protein stimulates cell proliferation o Hereditary nonpolyposis colorectal
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