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Essentials of GENETICS Eighth Edition 16 The Genetics of Cancer William S. Klug Michael R. Cummings Charlotte A. Spencer Michael A. Palladino Lecture Presentations by Kiran Misra Edinboro University © 2013 Pearson Education, Inc. SEM of two prostrate cancer cells in the final stages of cell division. © 2013 Pearson Education, Inc. Chapter Contents 16.1 Cancer Is a Genetic Disease at the Level of Somatic Cells 16.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair, and Chromatin Modifications 16.3 Cancer Cells Contain Genetic Defects Affecting CellCycle Regulation and Apoptosis 16.4 Proto-oncogenes and Tumor-Suppressor Genes Are Altered in Cancer Cells Continued © 2013 Pearson Education, Inc. Chapter Contents 16.5 Cancer Cells Metastasize and Invade Other Tissues 16.6 Predisposition to Some Cancers Can Be Inherited 16.7 Viruses Contribute to Cancer in Both Humans and Animals 16.8 Environmental Agents Contribute to Human Cancers © 2013 Pearson Education, Inc. Introduction Cancer is the leading cause of death in Western countries. – More than 1 million cases are diagnosed in the United States each year, and more than 500,000 die from it. Cancer is a genetic disease at the somatic level, characterized by gene products derived from mutated or abnormally expressed genes. – Some cancers are inherited, but most are created within somatic cells that divide and form tumors. © 2013 Pearson Education, Inc. 16.1 Cancer Is a Genetic Disease at the Level of Somatic Cells © 2013 Pearson Education, Inc. Section 16.1 Cancer is a genetic disease Genomic alterations associated with cancer include, – Single-nucleotide substitutions – Large-scale chromosome rearrangements, – Amplifications, and – Deletions (Figure 16-1). © 2013 Pearson Education, Inc. Figure 16-1 Karyotype of a Normal cell Karyotype of a cancer cell © 2013 Pearson Education, Inc. Section 16.1 – Cancer is caused predominantly by mutations in somatic cells, only1 percent are germ-line mutations. – Rarely arises from a single mutation but from accumulation of mutations in many genes – The mutated genes can affect multiple cellular functions such as – repair of damaged DNA, – cell cycle or cell division, – apoptosis, etc.. © 2013 Pearson Education, Inc. Section 16.1 What Is Cancer? Cancer is a large complex of diseases, up to a hundred, that behave differently depending on their cellular type of origin. All cancers share two fundamental properties. – Abnormal cell growth and division (proliferation) – Defects in normal restraints that prevent cells from spreading (metastasis) It is this combination of cell proliferation and metastasic spread that makes cancer cells dangerous. © 2013 Pearson Education, Inc. Figure 8.9 Proliferation and metastasis of a malignant tumor of the breast Lymph vessels Blood vessel Tumor Tumor in another part of the body Glandular tissue Growth © 2013 Pearson Education, Inc. Invasion Metastasis Growing out of control, cancer cells produce malignant tumors Cancers are named according to the organ or tissue in which they originate. – Carcinomas arise in external or internal body coverings. – Sarcomas arise in supportive and connective tissue. – Leukemias and lymphomas arise from blood-forming tissues. © 2013 Pearson Education, Inc. © 2012 Pearson Education, Inc. Section 16.1 What Is Cancer? In normal cells cell division and spread is tightly controlled by gene products that are expressed appropriately in time and space. In cancer cells genes controlling above processes are either mutated or not expressed. © 2013 Pearson Education, Inc. Section 16.1 What Is Cancer? Benign tumors result from unregulated cell growth forming a multicellular mass that can be removed by surgery, causing no serious harm. Tumor cells that gain the ability to break loose, enter the blood stream and metastasize become Malignant tumors. – Malignant tumors are difficult to treat and may become life threatening. – May contain billions of cells – May invade and grow in numerous body parts © 2013 Pearson Education, Inc. Section 16.1 The Clonal Origin of Cancer Cells All cancer cells in primary and secondary tumors are clonal, meaning that they originated from a common ancestral cell that accumulated numerous specific mutations. Eg: Specific reciprocal chromosomal translocations are characteristic of many cancers. – Leukemias and lymphomas (involve white blood cells) © 2013 Pearson Education, Inc. Section 16.1 The Clonal Origin of Cancer Cells Burkitt’s lymphoma shows reciprocal translocations between chromosome 8 and chromosomes 2, 14, or 22. – All cancer cells arise from a single cell that is passed to progeny. X-chromosome inactivation occurs early in development and occurs at 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. © 2013 Pearson Education, Inc. Section 16.1 The Cancer Stem Cell Hypothesis Many scientists now believe that tumors are composed of a mixture of cells, many of which do not proliferate. Cancer stem cell hypothesis: Tumor cells that proliferate give rise to cancer stem cells that have the capacity for self-renewal. – The stem cell divides unevenly, creating one daughter cell that becomes a mature cell type and one that remains a stem cell. Contrasts the theory that every tumor cell has the potential to form a new tumor. © 2013 Pearson Education, Inc. Section 16.1 The Cancer Stem Cell Hypothesis 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. © 2013 Pearson Education, Inc. Section 16.1 The Cancer Stem Cell Hypothesis Scientists are not sure about the origin of the cancer cells: 1.It is possible they may arise from normal adult stem cells within a tissue 2.Or they may be created from more differentiated cells that acquire properties similar to stem cells due to the mutations in genes. © 2013 Pearson Education, Inc. Section 16.1 Cancer is a multistep process requiring multiple mutations Age-related cancer is an indication that cancer develops from the accumulation of several mutagenic events in a single cell. – The incidence of most cancers rises exponentially with age. – Many independent mutations, occurring randomly and with a low probability, are necessary before a cell becomes malignant. © 2013 Pearson Education, Inc. Section 16.1 Cancer is a multistep process requiring multiple mutations Another indication that cancer is a multistep process is the delay that occurs between exposure to carcinogens and the appearance of the cancer. – An incubation period of five to eight years separated exposure to radiation from atomic explosions at Hiroshima and Nagasaki and the onset of leukemia. © 2013 Pearson Education, Inc. Section 16.1 Cancer is a multistep process requiring multiple mutations Cancers develop in progressive steps beginning with mildly aberrant cells and progressing to cells that are increasingly tumorigenic and malignant. Each step in tumorigenesis appears to be the result of two or more genetic alterations that progressively release the cell from the normal controls on cell proliferation and malignancy. – The progressive genetic alterations that create a cancer cell confer selective advantages to the cell and are propagated through cell divisions during the creation of tumors. © 2013 Pearson Education, Inc. Section 16.1 Cancer is a multistep process requiring multiple mutations Tens of thousands of somatic mutations are present in cancer cells. – Of these mutations only Driver mutations give growth advantage to tumor cells. The presence of fewer than a dozen mutated genes may be sufficient to create a cancer cell. © 2013 Pearson Education, Inc. 16.2 Cancer Cells Contain Genetic Defects Affecting Genomic Stability, DNA Repair, and Chromatin Modifications © 2013 Pearson Education, Inc. Section 16.2 Cancer Cells Contain Genetic Defects Cancer cells show higher than normal rates of – mutation. – chromosomal abnormalities. – 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 in cancer cells is known as the mutator phenotype. © 2013 Pearson Education, Inc. Section 16.2 Genomic Instability and Defective DNA Repair The genomic instability in cancer cells manifests itself in gross defects such as – translocations. – aneuploidy. – chromosome loss. – DNA amplification. – chromosomal deletions (Figures 16-1 and 16-2). © 2013 Pearson Education, Inc. Figure 16-2 DNA Amplification in neuroblastoma cells: Two cancer genes are amplified as small DNA fragments separate from chromosomes. © 2013 Pearson Education, Inc. Section 16.2 Genomic Instability and Defective DNA Repair Often cancers show specific chromosomal defects that are used to diagnose the type and stage of the cancer. – Chronic myelogenous leukemia (CML) – The C-ABL gene on chromosome 9 is translocated into the BCR gene on chromosome 22. – This structure is known as the Philadelphia chromosome (Figure 16-3). © 2013 Pearson Education, Inc. Figure 16-3 © 2013 Pearson Education, Inc. Section 16.2 Chronic myelogenous leukemia (CML) The normal C-ABL gene codes for a protein kinase that acts within signal transduction pathways, transferring growth factor signals from outside the cell to the nucleus. The BCR-ABL hybrid protein is an abnormal signal transduction molecule in CML cells that stimulate cell proliferation even in the absence of external growth signals. Drug that blocks the action of the abnormal protein is developed. This drug (Gleevac) controls the protein’s activity that WBCs are no longer produced in an © 2013 Pearson Education, Inc. © 2012 Pearson Education, Inc. Section 16.2 Chromatin Modifications and Cancer Epigenetics Epigenetics is the study of factors that affect gene expression but do not alter the nucleotide sequence of the DNA. – DNA methylation – Histone acetylation and deacetylation © 2013 Pearson Education, Inc. Section 16.2 Cancer Epigenetics Cancer cells are generally less methylated than normal cells (hypomethylation). However, the promoters of some genes can be hypermethylated. Histone modifications are disrupted in cancer cells. – Genes that encode histone-modifying enzymes are often mutated or aberrantly expressed in cancer cells. © 2013 Pearson Education, Inc. Section 16.2 Cancer Epigenetics Methylation generally suppresses expression by transcriptional repression, turning off genes. Hypomethylation can release the transcriptional repression turning on many genes that were previously turned off. Hypermethylation of the tumor suppressor genes such as those that repair DNA damage and control cell cycle leads to their repression (turning off genes that were previously turned on). © 2013 Pearson Education, Inc. 16.3 Cancer Cells Contain Genetic Defects Affecting Cell-Cycle Regulation and Apoptosis © 2013 Pearson Education, Inc. Section 16.3 One of the fundamental aberrations in all cancer cells is a loss of control over cell proliferation. In multicellular organisms, normal cell division replaces dead and damaged tissue, and this process is strictly regulated. In normal cells large number of gene products control – Steps in the cell cycle – Programmed cell death, and – Response to external growth factors © 2013 Pearson Education, Inc. Section 16.3 The Cell Cycle and Signal Transduction The cell cycle includes a sequence of events from one cell division to the next (Figure 16-4). Most differentiated cells in multicellular organisms can remain in the G0 phases (quiescent) indefinitely but cancer cells are unable to enter G0 and continuously cycle. © 2013 Pearson Education, Inc. Figure 16-4 © 2013 Pearson Education, Inc. Section 16.3 Cell-Cycle Control and Checkpoints The cell cycle is tightly regulated, and each step must be completed before entering the next. Three distinct check points in the cell cycle monitor external signals and internal equilibrium before proceeding to the next stage. – G1/S, – G2/M, and – M checkpoints © 2013 Pearson Education, Inc. Section 16.3 Cell-Cycle Control and Checkpoints G1/S checkpoints monitor cell size and determine whether DNA has been damaged. G2/M is where physiological conditions are checked (once G1/S are passed) prior to mitosis. M: The formation of the spindle-fiber system and the attachment of spindle fibers to the kinetochores associated with the centromeres are monitored. © 2013 Pearson Education, Inc. Figure 8.8B Growth factor EXTRACELLULAR FLUID Plasma membrane Relay proteins Receptor protein Signal transduction pathway G1 checkpoint G1 S Control system M G2 CYTOPLASM © 2013 Pearson Education, Inc. Section 16.3 Cell-Cycle Control by Growth Factors External growth signals can stimulate G0 cells to reenter the cell cycle. – Signals are delivered by molecules such as growth factors and hormones that bind to cell surface receptors. Eg: Endotheilial growth factor The process of transmitting growth signals from external environments to the nucleus is called signal transduction. – The process initiates a program of gene expression, stimulating G0 cells back into the cell cycle. – Cancer cells have defective signal transduction pathways, and malignant cells may not respond to external growth signals. © 2013 Pearson Education, Inc. Section 16.3 Mutation or mis-expression of any of the genes controlling the cell cycle can contribute to the development of cancer. Mutated genes controlling G1/S or G2/M checkpoints or those controlling cyclins may allow cells to continue to grow and divide without repairing DNA damage. © 2013 Pearson Education, Inc. Section 16.3 Control of Apoptosis Cells halt progress through the cell cycle if DNA replication, repair, or chromosome assembly is aberrant. If DNA damage is so severe that repair is impossible, the cell may initiate genetically controlled apoptosis, or programmed cell death. – Prevents cancer – Also eliminates cells not contributing the final adult organism © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc. Section 16.3 The steps in apoptosis are – fragmentation of nuclear envelope & DNA. – disruption of internal cellular structures. – dissolution of cells into small, spherical apoptotic bodies. – engulfing of the apoptotic bodies by phagocytic cells. Apoptosis reduces the number of mutations passed to the next generation. – The same genes controlling the cell cycle also initiate apoptosis. Disruption of these genes prevent DNA repair and apoptosis. © 2013 Pearson Education, Inc. 16.4 Proto-oncogenes and Tumor-Suppressor Genes Are Altered in Cancer Cells © 2013 Pearson Education, Inc. Section 16.4 Proto-oncogenes and TumorSuppressor Genes Two general categories of cancer-causing genes are mutated or misexpressed in cancer cells. – Proto-oncogenes and – Tumor-suppressor genes © 2013 Pearson Education, Inc. Section 16.4 Proto-oncogenes Proto-oncogenes are normal genes whose products promote cell growth and division. These genes encode – transcription factors that stimulate expression of other genes. – signal transduction molecules that stimulate cell division. – cell-cycle regulators that move the cell through the cell cycle. © 2013 Pearson Education, Inc. Table 16.1 © 2013 Pearson Education, Inc. Section 16.4 Mutations in Proto-oncogenes result in Oncogenes In cancer cells, one or more proto-oncogenes are altered in such a way that their activities cannot be controlled in a normal fashion. – This is due to a mutation in the proto-oncogenes, resulting in a protein that acts abnormally. – In other cases, proto-oncogenes are overexpressed or expressed at an incorrect time. When a proto-oncogene is mutated or aberrantly expressed and contributes to cancer, it is known as an oncogene. © 2013 Pearson Education, Inc. Figure 11.16A Proto-oncogene (for a protein that stimulates cell division) DNA A mutation within the gene Multiple copies of the gene Oncogene Hyperactive growthstimulating protein in a normal amount © 2013 Pearson Education, Inc. The gene is moved to a new DNA locus, under new controls New promoter Normal growthstimulating protein in excess Normal growthstimulating protein in excess Section 16.4 Mutations in Proto-oncogenes result in Oncogenes An oncogene (a cancer-causing gene) is a mutated or aberrantly expressed proto-oncogene, a gain-offunction alteration. – Only one allele of the proto-oncogene needs to mutate or be misexpressed in order to trigger uncontrolled growth. – Oncogenes confer a dominant cancer phenotype. © 2013 Pearson Education, Inc. Section 16.4 The ras Proto-oncogenes The ras genes are mutated in more than 30 percent of human tumors and encode signal transduction molecules that are associated with the cell membrane and regulate cell growth and division. Ras proteins transmit signals from the cell membrane to the nucleus, stimulating cell division. Alternate between active and inactive state © 2013 Pearson Education, Inc. Section 16.4 The ras Proto-oncogenes Mutations that convert the ras proto-oncogene to an oncogene freeze the ras protein into its active (“on”) conformation, constantly stimulating the cell to divide, even in the absence of growth factors. © 2013 Pearson Education, Inc. Section 16.4 Tumor-suppressor genes In cells with severe DNA damage, products of tumorsuppressor genes regulate – cell-cycle checkpoints or – initiate the process of apoptosis. © 2013 Pearson Education, Inc. Section 16.4 Tumor-suppressor genes In response to DNA damage or growth-suppression signals from the extracellular, tumor-suppressor genes produce proteins that halt progress through the cell cycle. Mutated or inactivated tumor-suppressor genes are unable to respond normally to cell-cycle checkpoints or are unable to undergo programmed cell death if DNA is extensive. Inactivation of both tumor-suppressive alleles keeps the cell growing and dividing and may become tumorigenic. © 2013 Pearson Education, Inc. Section 16.4 The p53 Tumor-Suppressor Gene The p53 tumor-suppressor gene, mutated in more than 50 percent of all cancers, p53 gene encodes a nuclear protein that acts as a transcription factor repressing or stimulating transcription of more than 50 different genes. © 2013 Pearson Education, Inc. Figure 11.16B Tumor-suppressor gene Normal growthinhibiting protein Cell division under control © 2013 Pearson Education, Inc. Mutated tumor-suppressor gene Defective, nonfunctioning protein Cell division not under control Section 16.4 p53: Guardian of the genome In normal cells p53 protein is continuously synthesized but rapidly degraded, and thus is present at low levels. The p53 protein becomes more stable and transcriptionally active in response to: – Chemical damage to DNA – Double-stranded breaks in DNA by ionizing radiation – DNA-repair intermediates generated by UV light exposure increases © 2013 Pearson Education, Inc. Section 16.4 p53: Guardian of the genome The p53 protein initiates two different responses to DNA damage. – Arrest cell cycle followed by DNA repair, or – Apoptosis and cell death if damage can’t be repaired p53 acts as a transcription factor to stimulate or repress the expression of genes involved in each of the above responses. © 2013 Pearson Education, Inc. Section 16.4 p53: Guardian of the genome Normal cells: p53 arrests the cell cycle at G1/S and G2/M checkpoints and retards the progression through the S phase. – Inhibits cyclin/CDK complexes and regulates the transcription of other genes involved Activated p53 instructs damaged cells to commit suicide by apoptosis. – p53 activates the transcription of genes whose products control this process. – In cancer cells that lack functional p53, gene products are not synthesized and apoptosis doesn’t occur. © 2013 Pearson Education, Inc. Section 16.4 p53: Guardian of the genome Cells lacking functional p53 have high mutation rates and accumulate the types of mutations that lead to cancer. p53 is important for genomic integrity and is referred to as the “guardian of the genome.” © 2013 Pearson Education, Inc. Section 16.4 The RB1 Tumor-Suppressor Gene Loss or mutation of both alleles of the RB1 (retinoblastoma 1) tumor-suppressor gene contributes to the development of many cancers due to unregulated progression through the cell cycle. – Breast, bone, lung, and bladder cancers © 2013 Pearson Education, Inc. 16.5 Cancer Cells Metastasize and Invade Other Tissues © 2013 Pearson Education, Inc. Section 16.5 To metastasize from the primary tumor, cancer cells must digest components of the extracellular matrix and basal lamina, which normally separate the body’s tissues and thus inhibit migration of cells. © 2013 Pearson Education, Inc. Section 16.5 Once cancer cells have disengaged, they enter the blood or lymphatic system to invade surrounding tissue, and to develop into secondary tumors. – Only about 0.01 percent of metastatic cells become metastatic tumors. Metastasis is controlled by a large number of genes, including those that encode cell-adhesion molecules, cytoskeleton regulators, and proteolytic enzymes. © 2013 Pearson Education, Inc. Section 16.5 Like tumor-suppressor genes that are mutated in primary cancers, metastasis-suppressor genes are mutated or disrupted in metastatic tumors. The expression of these genes is reduced by epigenetic mechanisms rather than by mutation. © 2013 Pearson Education, Inc. 16.6 Predisposition to Some Cancers Can Be Inherited © 2013 Pearson Education, Inc. Section 16.6 Inherited predisposition to cancer Most cancers result from somatic cell mutations, but 50 forms of hereditary cancer (1–2 percent) are known (Table 16.2). © 2013 Pearson Education, Inc. Table 16.2 © 2013 Pearson Education, Inc. Section 16.6 Inherited predisposition to cancer Most inherited cancer-susceptibility alleles are not sufficient in themselves to trigger cancer development. At least one other somatic mutation in the other copy of the gene must occur to drive a cell toward tumorigenesis. – Loss of heterozygosity © 2013 Pearson Education, Inc. Section 16.6 Inherited predisposition to cancer Mutations in other genes are also usually necessary to fully express the cancer phenotype. – Other proto-oncogenes and tumor-suppressor genes Thus inherited mutations in one allele of a gene contributes only one step in a multistep pathway leading to malignancy. © 2013 Pearson Education, Inc. Section 16.6 Inherited form of colon cancer In familial adenomatous polyposis (FAP) individuals inherit one mutant copy of the APC (adenomatous polyposis) gene whose product acts as a tumor suppressor controlling cell–cell contact and growth inhibition. FAP results from one mutant copy of the APC gene (chromosome 5, deletions frameshift, and point mutations). – Heterozygous APC mutation causes formation of hundreds to thousands of rectal polyps or adenomas in early life. – A second APC mutation leads to later stage of cancer (Figure 16-7). © 2013 Pearson Education, Inc. Section 16.6 The second mutation in polyp cells that contain an APC gene occurs in the ras proto-oncogene which, brings about the development of intermediate adenomas. – Cells grown in culture are not growth-inhibited by contact with other cells (transformation). The loss of function of both alleles of the DCC gene results in the formation of late-stage adenomas, which then progresses to cancerous adenomas (Ioss of p53 function). – The final step toward malignancy involves loss of genes associated with metastasis. © 2013 Pearson Education, Inc. Figure 16-7 A model for multistep development of colon cancer © 2013 Pearson Education, Inc. Figure 11.17A Stepwise development of a typical colon cancer An oncogene A tumor-suppressor DNA changes: is activated gene is inactivated A second tumorsuppressor gene is inactivated Cellular Increased changes: cell division 1 Growth of a malignant tumor 3 Colon wall © 2013 Pearson Education, Inc. Growth of a polyp 2 Figure 11.17B Accumulation of mutations in the development of a cancer cell 1 Chromosomes mutation Normal cell © 2013 Pearson Education, Inc. 2 mutations 3 4 mutations mutations Malignant cell 16.7 Viruses Contribute to Cancer in Both Humans and Animals © 2013 Pearson Education, Inc. Section 16.7 Viruses Contribute to Cancer Fifteen percent of human cancers are associated with viruses, the second greatest risk of cancer next to tobacco smoke (Table 16.3). Retroviruses (RNA virus) can contribute to the development of cancer in animals and humans. Retroviruses integrate into the host genome as a provirus that is replicated with the host’s DNA during the normal cell cycle. © 2013 Pearson Education, Inc. Table 16.3 © 2013 Pearson Education, Inc. Section 16.7 A retrovirus can cause cancer by integrating near a proto-oncogene or by integrating a copy of a host proto-oncogene into its genome. The RNA genome of the virus is copied into DNA by the reverse transcriptase enzyme, which is brought into the cell by the infecting virus. – The DNA copy enters the host-cell DNA and integrates at random. © 2013 Pearson Education, Inc. Section 16.7 The integrated DNA copy is called a provirus and gets replicated along with the host DNA. A retrovirus may not kill a cell but may continue to use it as a factory to replicate more viruses that will then infect surrounding cells. © 2013 Pearson Education, Inc. 16.8 Environmental Agents Contribute to Human Cancers © 2013 Pearson Education, Inc. Section 16.8 Environmental Agents Any substance or event that damages DNA has the potential to be carcinogenic if it causes mutations to occur in proto-oncogenes or tumor-suppressor genes, which lead to abnormal replication of the cell cycle or disruption of controls over apoptosis or metastasis. Carcinogens, both natural and human-made, include chemicals, radiation, some viruses, and chronic infections. © 2013 Pearson Education, Inc. Section 16.8 Environmental Agents The most significant environmental carcinogen is tobacco smoke, which contains at least 60 mutagenic chemicals. – 30 percent of human cancer deaths are associated with cigarette smoking. Consumption of red meat and animal fat is associated with colon, prostate, and breast cancer. Alcohol may cause inflammation and lead to liver cancer. © 2013 Pearson Education, Inc. Section 16.8 Environmental Agents Some natural substances and natural processes are potentially carcinogenic. Mold on bread and corn, aflatoxin, is one of the most carcinogenic chemicals known. Naturally occurring nitrosamines, used as meat preservative, are known to cause cancer. Naturally occurring pesticides and antibiotics in plants can be carcinogenic but do not diminish the serious cancer risk upon exposure to synthetic pesticides or asbestos. © 2013 Pearson Education, Inc. Section 16.8 Environmental Agents Natural radiation (UV light, X rays), natural dietary substances, and substances in the external environment can cause DNA lesions, producing mutations that lead to cancer. Natural metabolism creates oxidative end products that can damage DNA, proteins, and lipids. Daily, the human body suffers about 10,000 lesions due to the actions of oxygen free radicals. © 2013 Pearson Education, Inc. Section 16.8 When DNA repair enzymes miss these damages, they become permanent mutations. Substances such as growth factors or hormones that stimulate cell division are ultimately mutagenic and carcinogenic. Chronic inflammation due to infection can result in accumulation of DNA lesions during tissue repair and cellular replication. © 2013 Pearson Education, Inc.