Functional Genomics talk Westwood)

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BIO477

Cancer
Part I- Oct. 20, 2007 Part II- Oct. 27, 2007 Tim Westwood

Reading
Weinberg, R. A. (2007). The Biology of Cancer. Garland Science, New York.
Chapter 2- The Nature of Cancer Chapter 3- Tumor Viruses Chapter 4- Cellular Oncogenes

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Outline
A. Introduction - types, properties of cancer cells, history, epidemiology B. The 3 causes of cancer 1. Microbes 2. Mutagens (irritants) 3. Genetics

C. Epidemiology of Cancer D. Mutagens and Carcinogens - Ames test E. Tumour Viruses and Oncogenes 1. Rous sarcoma virus 2. DNA and RNA Tumor viruses 3. Retroviruses and the discovery of oncogenes

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Table 3.2 The Biology of Cancer ( Garland Science 2007)

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Table 23-1. Variation Between Countries in the Incidence of Some Common Cancers

SITE OF ORIGIN OF CANCER

HIGH-INCIDENCE POPULATION

LOW-INCIDENCE POPULATION

LOCATION

INCIDENCE*

LOCATION

INCIDENCE*

* Incidence = number of new cases per year per 100,000 population

Lung Breast Prostate Uterine cervix Stomach

USA (New Orleans, blacks) Hawaii (Hawaiians) USA (Atlanta, blacks) Brazil (Recife) Japan (Nagasaki) China (Shanghai) USA (Connecticut, whites) Australia (Queensland) Canada (Newfoundland) Canada (NWT and Yukon) Canada (Ontario)

110 94 91 83 82 34 34

India (Madras) Israel (non-Jews) China (Tianjin) Israel (non-Jews) Kuwait (Kuwaitis) Canada (Nova Scotia) India (Madras)

5.8 14.0 1.3 3.0 3.7 0.7 1.8

From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.

Liver Colon

Melanoma Lip Kidney

31 15 15

Japan (Osaka) Japan (Osaka) India (Poona)

0.2 0.1 0.7

Leukemia

12

India (Nagpur)

2.2

Table 2.5 part 1 of 2 The Biology of Cancer ( Garland Science 2007)

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Figure 2.20 The Biology of Cancer ( Garland Science 2007)

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Figure 23-17. The Ames test for mutagenicity. The test uses a strain of Salmonella bacteria that require histidine in the medium because of a defect in a gene necessary for histidine synthesis. Mutagens can cause a further change in this gene that reverses the defect, creating revertant bacteria that do not require histidine. To increase the sensitivity of the test, the bacteria also have a defect in their DNA repair machinery that makes them especially susceptible to agents that damage DNA. A majority of compounds that are mutagenic in tests such as this are also carcinogenic and vice versa.
From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.

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Figure from: Genes and the Biology of Cancer. H. Varmus and R. Weinberg. 1993. Sci. Am. Library, W.H. Freeman. N.Y, N.Y.

Table 2.8 The Biology of Cancer ( Garland Science 2007)

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Figure 3.2 The Biology of Cancer ( Garland Science 2007)

Table 23-2. Viruses Associated with Human Cancers

VIRUS ASSOCIATED TUMORS AREAS OF HIGH INCIDENCE

DNA Viruses
Papovavirus family Papillomavirus (many distinct strains) Hepadnavirus family Hepatitis-B virus Herpesvirus family Epstein-Barr virus Burkitt's lymphoma (cancer of B lymphocytes) nasopharyngeal carcinoma West Africa, Papua New Guinea southern China, Greenland liver cancer (hepatocellular carcinoma) Southeast Asia, tropical Africa warts (benign) carcinoma of the uterine cervix worldwide worldwide

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RNA viruses
Retrovirus family Human T-cell leukemia virus type I (HTLV-1) Human immuno-deficiency virus (HIV, the AIDS virus) adult T-cell leukemia/lymphoma Kaposi's sarcoma (HIV-indirect; HPV, herpesvisrus-direct) Japan, West Indies Central and Southern Africa

From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.

Table 15.2. Tumor Viruses

Virus family

Human tumors

Genome size (kb)

DNA tumor viruses Hepatitis B viruses SV40 and polyomavirus Papillomaviruses Adenoviruses Herpesviruses (e.g. Epstein-Barr virus) RNA tumor viruses Retroviruses Adult T-cell leukemia 9 Liver cancer None Cervical carcinoma, Kaposis sarcoma None Burkitt's lymphoma, nasopharyngeal carcinoma, Kaposi's sarcoma 3 5 8 35 100200

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Figure 5-73. The life cycle of a retrovirus. The retrovirus genome consists of an RNA molecule of about 8500 nucleotides; two such molecules are packaged into each viral particle. The enzyme reverse transcriptase first makes a DNA copy of the viral RNA molecule and then a second DNA strand, generating a double-stranded DNA copy of the RNA genome. The integration of this DNA double helix into the host chromosome is then catalyzed by a virus-encoded integrase enzyme. This integration is required for the synthesis of new viral RNA molecules by the host cell RNA polymerase, the enzyme that transcribes DNA into RNA

Figure 15.17. A typical retrovirus genome The DNA provirus, integrated into cellular DNA, is transcribed to yield genome-length RNA. This primary transcript serves as the genomic RNA for progeny virus particles, and as mRNA for the gag and pol genes. In addition, the full-length RNA is spliced to yield mRNA for env. The gag gene encodes the viral protease and structural proteins of the virus particle, pol encodes reverse transcriptase and integrase, and env encodes envelope glycoproteins.
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA

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Figure 15.18. Cell transformation by RSV and ALV Both RSV and ALV infect and replicate in chicken embryo fibroblasts, but only RSV induces cell transformation.

From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA

Figure 15.19. The RSV genome RSV contains an additional gene, src, that is not present in ALV and encodes the Src protein-tyrosine kinase.
From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA

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Figure 3.20 The Biology of Cancer ( Garland Science 2007)

Fig. 3.22 Capture of src by avian leukosis virus

The Biology of Cancer ( Garland Science 2007)

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Table 15.3. Retroviral Oncogenes

Oncogene Virus Species

abl erbA erbB ets fes fms fos fps jun kit

Abelson leukemia Avian erythroblastosis-ES4 Avian erythroblastosis-ES4 Avian erythroblastosis-E26 Gardner-Arnstein feline sarcoma McDonough feline sarcoma FBJ murine osteogenic sarcoma Fujinami sarcoma Avian sarcoma-17 Hardy-Zuckerman feline sarcoma

Mouse Chicken Chicken Chicken Cat Cat Mouse Chicken Chicken Cat

mos mpl myb myc p3k qin raf rasH rasK rel ros sea sis ski src

Moloney sarcoma Myeloproliferative leukemia Avian myeloblastosis Avian myelocytomatosis Avian sarcoma-16 Avian sarcoma-31 3611 murine sarcoma Harvey sarcoma Kirsten sarcoma Reticuloendotheliosis UR2 sarcoma Avian erythroblastosis-S13 Simian sarcoma Avian SK Rous sarcoma

Mouse Mouse Chicken Chicken Chicken Chicken Mouse Rat Rat Turkey Chicken Chicken Monkey Chicken Chicken

From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA

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The Biology of Cancer ( Garland Science 2007)

Figure 24-4. The identification and molecular cloning of the rasD oncogene. Addition of DNA from a human bladder carcinoma to a culture of mouse 3T3 cells causes about one cell in a million to divide abnormally and form a focus, or clone of transformed cells. To clone the oncogene responsible for transformation, advantage is taken of the fact that most human genes have nearby repetitive DNA sequences called Alu sequences. DNA from the initial focus of transformed mouse cells is isolated, and the oncogene is separated from adventitious human DNA by secondary transfer to mouse cells. The total DNA from a secondary transfected mouse cell is then cloned into bacteriophage ; only the phage that receives human DNA hybridizes with an Alu probe. The hybridizing phage should contain part or all of the transforming oncogene. This expected result can be proved by showing either that the phage DNA can transform cells (if the oncogene has been completely cloned) or that the cloned piece of DNA is always present in cells transformed by DNA transfer from the original donor cell.
From: Molecular Cell Biology. 4th ed. 2000. Lodish et al. W.H. Freeman, NY, NY.

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From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.

Figure 23-24. Cancer-critical genes fall into two readily distinguishable categories, dominant and recessive. Oncogenes act in a dominant manner: a gain-of-function mutation in a single copy of the cancer-critical gene can drive a cell toward cancer. Tumor suppressor genes, on the other hand, generally act in a recessive manner: the function of both alleles of the cancer-critical gene must be lost to drive a cell toward cancer. In this diagram, activating mutations are represented by solid red boxes, inactivating mutations by hollow red boxes.

Figure 23-27. Three ways in which a proto-oncogene can be made overactive to convert it into an oncogene.

From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y.

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Fig. 3.23. Insertional mutagenesis.

The Biology of Cancer ( Garland Science 2007)

Table 15.4. Representative Oncogenes of Human Tumors

Oncogene Type of cancer Activation mechanism

abl

Chronic myelogenous leukemia, acute lymphocytic leukemia Ovarian and pancreatic carcinomas Follicular B-cell lymphoma Parathyroid adenoma, B-cell lymphoma Breast and ovarian carcinomas Adrenal cortical and ovarian carcinomas Glioblastoma

Translocation

akt bcl-2 D1 erbB-2

Amplification Translocation Translocation Amplification

gip

Point mutation

gli

Amplification

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hox-11 lyl c-myc c-myc L-myc N-myc PDGFR PML/RA R rasH rasK rasN ret ret SMO

Acute T-cell leukemia Acute T-cell leukemia Burkitt's lymphoma Breast and lung carcinomas Lung carcinoma Neuroblastoma, lung carcinoma Chronic myelomonocytic leukemia Acute promyelocytic leukemia Thyroid carcinoma Colon, lung, pancreatic, and thyroid carcinomas Acute myelogenous and lymphocytic leukemias, thyroid carcinoma Multiple endocrine neoplasia types 2A and 2B Thyroid carcinoma Basal cell carcinoma

Translocation Translocation Translocation Amplification Amplification Amplification Translocation Translocation Point mutation Point mutation Point mutation Point mutation
DNA rearrangement

Point mutation

From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA

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