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Chapter 20 - Genetics of cancer: Cell cycle and cancer Two-hit mutation model Oncogenes and RNA/DNA tumor viruses Tumor suppressor genes Mutator genes.

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Presentation on theme: "Chapter 20 - Genetics of cancer: Cell cycle and cancer Two-hit mutation model Oncogenes and RNA/DNA tumor viruses Tumor suppressor genes Mutator genes."— Presentation transcript:

1 Chapter 20 - Genetics of cancer: Cell cycle and cancer Two-hit mutation model Oncogenes and RNA/DNA tumor viruses Tumor suppressor genes Mutator genes Carcinogens: chemicals and radiation

2 Some basic terminology: Oncogenesis = process of initiation of tumors (cancer) in an organism (onkos = mass; genesis = birth) Tumor = tissue composed of cells that deviate from normal program of cell division and differentiation. Benign tumor = tumor cells remain together in a single mass and do not invade or disrupt surrounding tissues Malignant tumor = tumor cells invade and disrupt surrounding tissues (diagnosed as cancer, and such cells can transform other cells to the cancerous state). Metastasis = spread of malignant tumor cells throughout the body (typically through the blood and lymphatic system)

3 Oncogenesis arises from: 1.Spontaneous gene or chromosome mutations. 2.Exposure to mutagens or radiation. 3.Activity of genes introduced by tumor viruses. 4.Some cancers are inherited (individuals may be predisposed).

4 Cell cycle and cancer: Cell differentiation occurs as cells proliferate to form tissues. Cell differentiation correlates with loss of ability to proliferate; highly specialized cells are terminally differentiated. Terminally differentiated cells have a finite life span, and are replaced with new cells produced from stem cells. Stem cells are capable of self-renewal; cells divide without undergoing terminal differentiation. Cell death (apoptosis) is equally important. Apoptosis is the normal outcome for most cells, and the sequence of events must be programmed correctly. Otherwise cells don’t die when they should, and uncontrolled cell division can result in cancer.

5 More about apoptosis: Insufficient iodine in the the diet, or chemicals that interfere with iodine pathways can inhibit the necessary process of apoptosis. Example, Potassium bromate is used in brominated flour in nearly all commercially produced bread products in the U.S. Potassium bromate is classified as a category 2B carcinogen (possibly carcinogenic to humans). It has been banned from use in the EU, Canada, Nigeria, Brazil, South Korea, Peru and some other countries. In the United States of America, it has not been banned. In California, a warning label is required.

6 Normal cell cycle is controlled by signal transduction: Growth factors bind to surface receptors on the cell; transmembrane proteins relay information to the cell by signal transduction. Two types of growth factors: 1.Growth factors stimulate cell division. 2.Growth-inhibiting factors inhibit cell division. Healthy cells divide only when growth factor and growth-inhibiting factor balance favors cell division. Cancer cells divide without constraint Cancer is primarily caused by mutations in growth and growth- inhibiting factor genes, and pathways that inhibit the normal sequence of events associated with apoptosis.

7 Fig. 20.3, Regulation of cell division by signal transduction.

8 Two-hit mutation model for cancer: Most cancers result from mutations in cellular genes. (other cancers are caused by viruses) Two types of cancer: Sporadicmore frequent, no hereditary cause Familialless frequent, hereditary Retinoblastoma (OMIM-180200) shows sporadic and hereditary forms and fits the pattern of a two-hit model. Most common eye tumor of children. Occurs from birth to 4 years of age. Early treatment with gamma radiation is 90% effective.

9 Two-hit mutation model for retinoblastoma (OMIM-180200): Sporadic retinoblastoma 60% of retinoblastoma cases. Develops in children with no family history. Occurs in one eye. Hereditary retinoblastoma 40% of retinoblastoma cases. Onset typically is earlier than sporadic cases. Multiple tumors involving both eyes. Consistent pedigrees; siblings and offspring develop the same type of tumors.


11 Alfred Knudson’s (1971) model for retinoblastoma (OMIM-180200): Two mutations are required for the development of retinoblastoma. Sporadic retinoblastoma Child starts with two wild type alleles (RB+/RB+). Both alleles must mutate to produce the disease (RB/RB). Probability of both mutations occurring in the same cell is low; only one tumor forms (e.g., one eye). Hereditary retinoblastoma Child starts with heterozygous alleles (RB/RB+). Only one mutation is required to produce disease (RB/RB). Mutations resulting in loss of heterozygosity (LOH) are more probable in rapidly dividing cells, and multiple tumors occur (e.g., both eyes).

12 Fig. 20.8, Knudson’s 2-hit mutation model for retinoblastoma.

13 Alfred Knudson’s (1971) model for retinoblastoma (OMIM-180200): Retinoblastoma alleles are recessive; only homozygotes (RB/RB) develop tumors. Retinoblastoma appears as dominant in pedigree analysis: RB/RB+ individuals are predisposed and have a significant incidence of the disease. Homozygous dominant individuals (RB+/RB+) require two mutations in the same cell to develop the cancer. Retinoblastoma was mapped to the long arm of chromosome 13 (13q14.1-q14.2). Mutations occur in a gene that encodes a growth inhibitory factors (a tumor suppressor gene). Retinoblastoma is rare among cancers; most cancers result from a series of mutations in many different genes. So retinoblastoma is easier to treat.

14 Cancer and genes: Three classes of genes frequently are mutated in cancer: Proto-oncogenes ( oncogenes) Tumor suppressor genes Mutator genes

15 Proto-oncogenes  oncogenes: Proto-oncogenes Proto-oncgenes are genes that possess normal gene products and stimulate normal cell development. Oncogenes Oncogenes arise from mutant proto-oncogenes. Oncogenes are more active than normal or active at inappropriate times and stimulate unregulated cell proliferation. Some tumor viruses that infect cells possess oncogenes: RNA tumor viruses = possess viral oncogenes (derived from cellular proto-oncogenes) capable of transforming cells to a cancerous state. DNA tumor viruses = do not carry oncogenes, but induce cancer by activity of viral gene products on the cell (no transformation per se).

16 Retroviruses and oncogenes: Retrovirus = Single-stranded RNA virus that replicates via double-stranded DNA intermediate. RNA is converted to cDNA by reverse transcriptase. DNA integrates into host chromosome and is transcribed. Retroviruses typically possess: 2 copies of a 7-10 kb ssRNA genome protein viral core glycolipid envelope (glycoproteins recognize host cells) Transducing retroviruses possesses oncogenes, which can cause cancer when integrated into the host chromosome.

17 Fig. 20.4, Structure of a retrovirus

18 Retroviruses and oncogenes: All RNA tumor viruses are retroviruses. RNA viral oncogenes are altered forms of normal host “growth factor” or “growth-inhibiting factor” genes that occur in the virus genome. Examples of retroviruses include: Rous sarcoma virus (RSV), Feline leukemia virus, Mouse mammary tumor virus Human immunodeficiency virus (HIV) Not all retroviruses are transducing or cause cancer.

19 Life cycle of a retrovirus: First characterized in 1910 by F. Peyton Rous from a chicken tumor, later named the Rous sarcoma virus. 1.ssRNA genome is released from the virus particle and is reverse transcribed to dsDNA (proviral DNA). 2.Reverse transcriptase occurs in the virus particle and lacks 3’ to 5’ exonuclease activity (no proofreading  lots of mutations). 3.Long terminal repeat sequences (LTRs) on each end of the genome contain transcription regulatory signals for the viral genes, and are ligated to produce circular dsDNA. 4.Proviral DNA and host chromosome DNA cross-over and are joined by recombination. 5.Host RNA polymerase transcribes proviral DNA and produces viral mRNAs required for the virus life cycle.

20 Fig. 22.5, 2nd edition Life cycle of the Rous sarcoma virus

21 Retroviruses and oncogenes: Three types of genes occur in most retroviruses: 1.gag (group antigen): codes the protein core 2.pol (polymerase): codes reverse transcriptase and an enzyme for proviral integration. 3.env (envelope): codes envelope glycoproteins. Nononcogenic retroviruses possess no oncogenes and direct their own life cycle (e.g., HIV infects and destroys T helper cells).

22 Retroviruses and oncogenes: Oncogenic retroviruses (v-onc) transform the cell and cause cancer (also called transducing viruses) Different retroviruses carry different oncogenes responsible for different types of cancer (e.g. v-src in RSV). Most oncogenic retroviruses (but not RSV) are defective and do not possess a full set of virus life-cycle genes. (transform cells but do not produce progeny viruses) Defective retroviruses produce progeny with the help of a normal virus that co-infects cell and supplies missing gene products. When coinfected - a helper virus supplies missing gene products -> assists with viral expression and replication.

23 Structures of defective oncogenic retroviruses.

24 Cellular proto-oncogenes: mid-1970s: J. Michael Bishop & Harold Varmus (Nobel Prize 1989) Demonstrated normal animal cells contain non-cancer causing genes closely related to viral oncogenes. early-1980s: R. A. Weinberg & M. Wigler Demonstrated a variety of human tumor cells contain oncogenes, which transform normal cells growing in culture to cancer cells. Most human and animal oncogenes are mutated forms of normal cellular genes (proto-oncogene = normal state). v-oncviral oncogene, carried by a virus c-onccellular oncogene, resides in host chromosome

25 Fig. 22.7 2nd edition Chicken c-src proto-oncogene and and v-src oncogene.

26 How are retroviruses oncogenes created? 1.Retrovirus integrates into host chromosome near a cellular proto- oncogene by recombination. 2.Deletion fuses retrovirus transcription signal sequences with proto-oncogene sequences. 3.In the process, parts of the viral DNA sequences typically are deleted (this is how the defective oncogene is created). 4.Viral “progeny” carry the cellular gene, but now under the influence of viral promoters. 5.Most transducing viral oncogenes are defective and cannot replicate independently. 6.If mRNA is packaged into a virus particle along with a normal virus genome (co-infection), reverse transcriptase produces a new defective oncogene by switching templates during cDNA synthesis. 7.Template switching + lack of proofreading during DNA replication result in rapid evolution of oncogenic retroviruses.

27 Formation of a transducing retrovirus oncogene.

28 Proto-oncogene and oncogene protein products: ~100 different oncogenes have been identified. To understand the cancer, must understand the function of protein products coded by the proto-oncogenes. All known proto-oncogenes are involved in positive control of cell growth and division. Two classes: Growth & growth-inhibiting factors, regulatory genes involved in the control of cell multiplication. Protein kinases, add phosphate groups to target proteins, important in signal transduction pathways. Mutations relax cell control of growth, allowing unregulated proliferation.

29 DNA tumor viruses: Do not carry oncogenes. Transform cells to the cancerous state through actions of genes (and gene products) in the viral genome. Examples include viruses in the following groups: papovaviruses (warts and human cervical cancer) hepatitis B Herpes Adenoviruses pox viruses DNA tumor virus gene products induce production of cellular DNA replication enzymes for viral replication. Viral gene products stimulate cells to proliferate unrestrained.

30 Tumor suppressor genes: First discovered in 1960s by Henry Harris. Harris fused tumor cells with normal cells and discovered some of the hybrid cells were normal. Harris hypothesized that the normal cells produced gene products that suppressed uncontrolled cell proliferation. Some cancers show deletions of specific sites (tumor repressor genes) that normally inhibit cell growth and division. e.g., breast cancer, colon cancer, lung cancer Two mutations (one on each allele) are required to inactivate tumor suppressor genes.

31 Retinoblastoma tumor suppressor genes: Mapped to gene chromosome 13 and sequenced. 180 kb; codes a 4.7 kb mRNA that produces a 928 amino acid nuclear phosphoprotein, pRB. pRB is expressed in every tissue that has been examined and regulates the cell cycle. Retioblastoma tumor cells possess point mutations or deletions, which render pRB defective. In hereditary retinoblastoma, second RB mutation often is identical to the inherited one (a possible example of gene conversion).

32 Role of pRB in regulating cell division.

33 p53 tumor suppressor genes: Mutations in p53 are implicated in ~50% of human cancers, including cancers of the: breast, brain, liver, lung, colorectal, bladder, and blood Development of tumors requires mutations on two p53 alleles. Codes a 393 amino acid protein involved in transcription, cell cycle control, DNA repair, and apoptosis (programmed cell death). p53 binds to several genes, including WAF1, and interacts with at least 17 cellular and viral proteins. Transgenic mice with deletions of both p53 alleles are viable, but 100% develop cancer by ten months of age.

34 Fig. 20.10, Effects of DNA damage and normal (non-mutant) p53 lead to apoptosis, resulting in cell growth arrest.

35 Breast cancer tumor suppressor genes: Breast cancer affects 1 in 10 women and represents 31% of cancers in women (~185,000 women diagnosed each year). ~5% of breast cancers are hereditary; age of onset for hereditary breast cancer is earlier than other forms (mutations at 2 alleles). Many genes involved; BRCA1 and BRCA2 are thought to be tumor suppressor genes. BRCA1 is important for homologous recombination, cellular repair of DNA damage, and transcription of mRNA. Mutations in BRCA1 also are involved in ovarian cancer. BRCA2 plays a role in timing of mitosis in the cell cycle.

36 Mutator genes: Mutator gene increases spontaneous mutation rate of other genes. Mutator gene products are involved in DNA replication and repair; mutations make the cell error prone. HNPCC-OMIM 120435, Human non-polyposis colon cancer Mutation at any one of 4 genes (hMSH2, hMLH1, hPMS1, hPMS2) leads to predisposition. Tumor formation requires mutation at the second allele. All four genes have homologs in yeast. DNA blood tests are available for all four genes.

37 Multi-step nature of cancer: Cancer is a stepwise process, typically requiring accumulation of mutations in a number of genes. ~6-7 independent mutations typically occur over several decades: Conversion of proto-oncogenes to oncogenes Inactivation of tumor suppressor genes

38 Fig. 20.11, Bert Vogelstein’s model of colorectal cancer OMIM-175100

39 Carcinogens-chemicals: Carcinogen = natural or artificial agents that increases the frequency of mutations and cancerous cells. Chemicals are responsible for more cancers than viruses. Sir Percival Pott first correlated scrotal cancer with exposure to coal soot in chimney sweeps in 18th century Britain. Many present day cancers arise from occupational exposure risks to chemicals: asbestos, PVCs. Tobacco smoke and diet implicated in ~50-60% of U.S. cancers. Two types of chemical carcinogens cause point mutations: Direct acting carcinogens mutate DNA directly (e.g., alkylating agents) Procarcinogens are metabolically converted to carcinogens (e.g., cigarette smoke, aflatoxins [fungi], nitrosamines)

40 Carcinogens-radiation: Sources of radiation include the sun, cell phones, radon gas, electric power lines, and household appliances. ~2% of cancers deaths are caused by radiation. Ionizing radiation (x-rays, radon gas, radioactive material) can cause leukemia and thyroid cancer. Ultraviolet light: UV-B (290-320 nm) is the main cause of sunburn and is directly mutagenic. UV-A (320-400 nm) increases the effects of UV-B on skin.




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