17-1 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Genetics of Cancer - Lecture IV Dr. Steven J. Pittler VH375B Office Cell Suggested Reading: Lewis 2 nd Edition Chapter on Genetics of Cancer

17-2 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer Cancer is a group of diseases caused by loss of cell cycle control. Cancer is associated with abnormal uncontrolled cell growth. Carcinogens are substances which cause cancer by mutating DNA (mutagens). Many genes that can mutate to cause cancer control the cell cycle or DNA maintenance (repair).

17-3 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer Is a complication of being a multicellular organism All specialized cells must follow the cell cycle If a cell escapes it forms a growth called a tumor In the blood such a cell will take over the population of blood cells A benign tumor grows in place It is malignant or cancerous when it infiltrates the nearby tissues A malignant tumor invades locally and it also sends parts of itself into the bloodstream and gets transported to other areas. This process of spread is called metastasis

17-4 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer 10% of cancer cases are single-gene disorders More often mutations in cancer-causing genes occur in somatic cells over a lifetime Cancer is a genetic disease at the cellular level and not the whole-body level It is likely that combinations of particular gene variants sum to increase the risk of cancer- run in families Takes years to develop as a sequence of genes mutate in the affected tissue

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17-7 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Origin of cancer Cancer begins from the growth of a single abnormal cell. A mutation occurs allowing a cell to undergo cell division when it would not normally divide. Division produces more abnormal cells. Mutations can occur: In somatic cells -> sporadic cancer only affecting the individual In germline cells -> mutations that are inherited Germline mutations usually require second somatic mutation also.

17-8 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Origin of cancer There are more than 100 oncogenes –Cause cancer when they are inappropriately activated More than 30 tumor suppressor genes whose deletion or inactivation causes cancer Cancer is a consequence of disruption of the cell cycle –The cell divides more frequently or more times –Timing, rate, and number of mitoses depends on protein growth factors from outside the cell, and on transcription factors from within –The immune system destroys most cancer-cells A mutation in a gene that normally halts or slows the cell cycle can lift the constraint, leading to inappropriate mitosis Failure to pause long enough to repair DNA is another cell-cycle-related cause of cancer Loss of control over telomere length may also contribute to cancer –Human telomeres consists of the DNA sequence TTAGGG repeated thousands of times –Normally lost as the cell matures –Specialized cells have shorter telomeres

17-9 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Control of the cell cycle

17-10 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Telomeres affect the cell cycle Telomerase is the protein and enzyme complex that adds telomere sequences to the ends of chromosomes. Presence of telomerase and telomeres allows cells to pass a cell cycle checkpoint and divide.

17-11 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Telomeres affect the cell cycle When telomerase is absent, telomeres are not added. Lack of telomeres signals cessation of cell division.

17-12 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Inherited Versus Sporadic cancer Most cancers are isolated or sporadic-the causative mutation occurs only in cells of the affected tissue: Somatic mutation –May result from a single dominant mutation, or from two recessive mutations in the same gene –Inherited or germline cancer susceptibility is directly passed to future generations because it is present in every cell, including gametes Inherited or germline cancer susceptibility is directly passed to future generations because it is present in every cell, including the gametes –Cancer develops when a second mutation occurs in the somatic cell –The cancer site in the body is the site of the second mutation

17-13 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Germline versus sporadic cancer

17-14 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Characteristics of Cancer Cells A cell divides or if it stops dividing or whether it expresses the sets of genes that make it special depends upon biochemical signals from surrounding cells A cancer cell stops listening to these signals Mutations that affect any stage of signal transduction or gene expression can send a cell toward unrestrained division

17-15 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cell division rates of normal and cancer cells Normal cells Hours between cell division Bone marrow precursors 18 Lining cells of large intestine 39 Lining cells of rectum 48 Fertilized ovum36-60 Cancer cells Hour between cell divisions Stomach72 Acute myeloblastic leukemia Chronic myeloid leukemia 120 Lung (bronchus carcinoma) Some cancer cell types grow more slowly than some normal cell types.

17-16 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Characteristics of Cancer Cells A cancerous tumor eventually grows faster than the surrounding tissue because of its greater proportion of cells that are dividing A cancer cell looks different than a normal cell –Rounder: does not adhere to normal cells –Plasma membrane is more fluid, different substances can cross it

17-17 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Types of cancer genes Types of proteinsMutated functionNormal functionType of gene Enzymes for mismatch or excision repair Fail to repair DNA mutations Repair DNA mutations DNA repair gene mutation Checkpoint molecules Fails to suppress division Suppresses cell division Tumor suppressor gene Growth factorsPromotes division - abnormal time or cell type Promotes division Oncogene

17-18 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Characteristics of cancer cells Divide continually (given space and nutrients) Heritable mutations: cells with mutations have daughter cells which inherit the same mutations. Transplantable: if a cancer cell is injected into a healthy animal of the same species, the cell will proliferate Dedifferentiated: cells lose their specialized identity Different appearance: reflects dedifferentiation Lack contact inhibition: will divide in a crowd of cells and pile on top of each other Induce angiogenesis (local blood vessel formation) Increased mutation rate Invasive: squeeze into any space available Metastasize: cells move to new location in the body

17-19 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer can progress slowly over years

17-20 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cells starved for oxygen within a tumor secrete vascular endothelial growth factor which stimulates capillaries to extend branches toward the tumor

17-21 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Genes that Cause Cancer

17-22 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes Proto-oncogenes are normal versions of genes which promote cell division. Expression at the wrong time or in the wrong cell type leads to cell division and cancer. Proto-oncogenes are called oncogenes in their mutated form, onco means cancer One copy of an oncogenic mutation is sufficient to promote cell division.

17-23 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes A single base change in a proto-oncogene causes bladder cancer A proto-oncogene may be moved near a gene that is highly expressed, then, it to becomes highly expressed Some proto-oncogenes encode transcription factors –That as oncogenes are too highly expressed

17-24 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes: overexpression of a normal function Viruses integrated next to a proto-oncogene can cause transcription when the virus is transcribed. Moving a proto-oncogene to a new location can separate the coding region from regulatory regions of the gene leading to incorrect expression. Moving a proto-oncogene next to a highly transcribed gene can lead to erroneous transcription of the proto-oncogene.

17-25 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Fusion Proteins with New Functions Oncogenes are activated when a proto-oncogene moves next to another gene, and the gene pair is transcribed and translated together, as if one gene –Double gene product: fusion protein activates or lifts controls of cell division The first cancer-causing fusion protein was found in chronic myeloid leukemia –Most CML have a Philadelphia chromosome- tip of 9 translocated to chromosome 21 –One gene from chromosome 9, the Abelson oncogene (abl) and the other from chromosome 22, the breakpoint cluster region (bcr) –Reciprocal translocation produces two different fusion genes bcr-abl fusion gene causes CML Encodes for BCR-ABL oncoprotein- a form of the tyrosine kinase This cancer causing form of tyrosine kinase is active for too long, stimulating the cell to divide for too long

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17-27 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Gleevec replaces the ATP in the oncoprotein’s pocket Without phosphorylation of the tyrosine substrate division of the abnormal cells stops. As cancer progresses, some cells undergo mutations that make the shape of their pockets unable to bind the drug

17-28 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Receiving an Overly Aggressive Division Signal 25% of woman affected with breast cancer have 1-2 million copies of a cell surface protein called Her-2/neu a product of an oncogene Her-2/neu proteins are receptors for epidermal growth factors

17-29 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Oncogenes: new functions from old Rearrangement of the genome can create a novel gene from portions of the two original genes. promoter coding region Proto-oncogene protein signals cell division promotercoding region Gene expressed in brain promoter coding region Fusion gene: Protein signals cell division in brain inappropriately

17-30 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Tumor suppressor genes Cancer can be caused by loss of genes that inhibit cell division. Tumor suppressor gene mutation that causes cancer is typically a deletion, removal of function A point mutation can cause loss of function as well but this is rare DNA viruses (SV40, adenovirus, and human papilloma virus) interact with the normal products of tumor suppressor genes Tumor suppressor genes normally stop a cell from dividing. Mutations of both copies of a tumor suppressor gene is usually required to allow cell division.

17-31 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Retinoblastoma: A rare childhood eye cancer Alfred Knudson, 1971 examined cases of retinoblastoma in Houston and determined: –One eye or two with tumor –Age of diagnosis –Relatives with retinoblastoma –Number of tumors per eye Observed that 50% of children of an affected parent were affected. Boys and girls were equally frequently affected. Children with bilateral (both eyes) tumors were diagnosed earlier.

17-32 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Knudson’s two hit hypothesis Knudson proposed: Two mutations are required, one in each copy of the RB gene. For sporadic cases, retinoblastoma is a result of two somatic mutations. For familial cases, retinoblastoma is inherited as an autosomal recessive mutation followed by a somatic mutation in the normal allele. The chance of a second somatic mutation is high and creates a dominant “susceptibility” to cancer in the family.

17-33 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. p53 coordinates cell cycle regulation p53 acts as a cell cycle protein which determines if a cell has repaired DNA damage. If damage cannot be repaired, p53 can induce apoptosis. More that 50% of human cancers involve an abnormal p53 gene. Rare inherited mutations in the p53 gene cause a disease called Li-Fraumeni syndrome in which family members have many different types of cancer at early ages. Reading on page 368

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17-35 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. BRCA1, a breast cancer susceptibility gene Within families a mutation in BRCA1 leads to breast cancer susceptibility, inherited as a dominant trait. One mutation in the BRCA1 gene is inherited. Tumors in people acquire a second mutation in the normal allele of BRCA1. Lack of any functional BRCA1 leads to cancer cells. At the level of the cell, BRCA1 acts in a recessive manner.

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17-39 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Multiple genes contribute to cancer progression Multiple genetic changes in astrocytes, nerve support cells, cause in cancer growth.

17-40 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Colon cancer results from genetic alterations in multiple genes Inherited mutations in the APC gene dramatically increase risk of colon cancer

17-41 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Environment impacts cancer Exposure to carcinogens Carcinogens in tobacco smoke are correlated with lung cancer incidence. Exposure to radiation Burns from overexposure to sunlight can cause skin cancer. Variation in diet Fatty diets are correlated with increased estrogen and increased breast cancer.

17-42 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cruciferous vegetables can lower cancer risk

17-43 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Methods for evaluating environmental impacts of cancer Population studies compare incidence of a cancer trait among different populations. Case-control studies compare individuals with cancer to healthy individuals matched for characteristics such as age, sex, and ethnic background. Prospective studies follow the outcome of individuals placed in two or more groups who have different treatments, conditions, or procedures.

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17-45 Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cancer treatments for breast cancer Radiation or chemotherapy to kill dividing cells Destroy cancerous tissue Gene expression profile on DNA microarray to guide drug choice Genomic level Her-2/neu positive cancers targeted with herceptin MAb Use genotype to select drug Estrogen receptor positive women take tamoxifen Use phenotype to select drug SurgeryRemove cancerous tissue ExamplesStrategy