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 lifetime o More than 1 million cases diagnosed in the United States each year and more than 500 000 die from it o Cancer cid 224 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 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 cid 224 germ line mutations o Rarely arises from a single mutation but from a single mutation but from accumulation of mutations in many genes cid 224 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 cid 224 large complex of diseases cid 224 up to a hundred cid 224 depending on their cellular behave differently type origin cid 224 metastasis o All cancers share two fundamental properties 1 Abnormal cell growth and division cid 224 proliferation 2 Defects in normal restraints that prevent cells from spreading in normal cells cid 224 functions tightly controlled by genes cid 224 expressed appropriately in time and place cancer cells cid 224 Genes controlling this are mutated or not expressed o combination of uncontrolled cell proliferation and metastatic spread cid 224 cancer cells dangerous o 1 Benign tumors cid 224 result from unregulated cell growth forming a multicellular mass that can be removed by surgery causing no serious harm o 2 Malignant tumors cid 224 result from cells that break loose and form secondary tumors cid 224 metastases cid 224 become malignant Malignant tumors cid 224 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 cid 224 may invade and grow in numerous parts of body o All cancer cells in primary and secondary tumors cid 224 clonal cid 224 originated from a common ancestral cell cid 224 accumulated numerous specific mutations cid 224 important in understanding molecular basis of cancer and implications of its diagnosis o Reciprocal chromosomal translocations cid 224 characteristic of many cancers Leukemias and lymphomas cid 224 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 cid 224 all cancer cells arise from a single cell cid 224 passed to progeny o X chromosome inactivation cid 224 occurs early in development cid 224 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 cid 224 cancer stem cell o Tumors cid 224 mixture of cells cid 224 many of which don t proliferate Those that do proliferate and give rise to all cells within tumor cid 224 cancer stem cells o Cancer stem cell hypothesis cid 224 Tumor cells that proliferate give rise to cancer stem cells that have the capacity for self renewal cid 224 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 Cancer Cells Contain Genetic Defects Affecting Genomic Stability DNA Repair mutations and Chromatin Modifications o A single mutation is not sufficient to transform normal cell to tumor forming malignant cell 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 replication o age related because cancer develops from accumulation of several mutagenic events in a single cell cid 224 chance rises exponentially with age o Cancer cid 224 multistep process cid 224 delay that occurs between exposure to carcinogens and appearance of cancer Cancer develops in progressive steps cid 224 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 cid 224 progressive genetic alterations that create cancer cell confer selective advantages to cell cid 224 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 cid 224 mutator phenotype o fundamental defect in cancer cells cid 224 derangement of the cell s ability to repair DNA damage cid 224 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 cid 224 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 cid 224 chromosome 9 cid 224 translocated into the BCR gene on chromosome 22 philadelphia chromosome BCR ABL protein cid 224 abnormal signal transduction
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