Genetics of the Cancer Cell and of the

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Genetics of the Cancer Cell and of the Tumor-Bearing Host: Oncogenes and Tumor Suppressor Genes Folder Title: Cx. Genes(No. TP) Updated: April 12, 2016

Turning Point Opening Slide Rank 1 2 3 4 5 6 Responses

Biology of Cancer: What is Cancer Like? Like Part I of Biology of Cancer: What is Cancer Like as a Collection of Diseases? Why do we need to know about Cancer ? (Intro 501) What are cancers like as clinical diseases ? (Clinical) What are incidence patterns of cancers like? (Epidemio) How are cancers defined and classified ? (Def. Class) What do we study in cancer biology and cancer medicine? (Models) Part II of Biology of Cancer: What are Cancer Cells Like? When we study cancer cells, what features do we see? (Cell. Prop) Cancers as a collection of heterogenous cell populations. (Hetero) Aberrant differentiation and progression in Cancer (Progress) Cancer growth in culture, in non-human animals, and in patients (Growth) Invasion and metastasis in Cancer (Inv&Mets) Metastasis Models (Met. Models)

Part III: Biology of Cancer: Why is Cancer Like That? That What accounts for the phenomenology of cancers that we see? How do cancers get that way? What maintains them in their pathology? Why do they progress in their pathology and become malignant? What can we do about it? How can we prevent the appearance of cancers? How can we manage the cancers when they appear? How can we treat cancer patients in the clinic based on our understanding of what makes cancers “tick”?

Some Crucial Ideas on Applying What We Know about Biology To Making Something Happen in the Real World Some Ideas about Controlling the Outcome of Group Interactions in a Large Crowd

Why Does All of This Matter? Age Group and Lifetime Risk of Developing Invasive Cancers Knowing About Causes of Cancer May Allow Us to Mitigate This

Genetics in the Biology of Cancer Genetics of What? Genetics of the Host Before the Cancer Starts Genetics of the Cell that Gets Transformed Predisposing Factors in the Host In Response to the Cancer After It Appears Promoting or protecting the cancer Interfering with therapy approaches After Transformation - During Progression Genetics of the Cancer Cell: After It Appears

Why Genetics Must Be Intimately Involved in the Biology of Cancer: Cancer is not a transmissible infectious disease Multiple Apparently Unrelated Causative Agents: • All Can Affect Genetics of Cells and of Host Definition of Neoplasia: "Heritable Cellular Phenotype“ Long Latent Periods Progressive Acquisition of the Full Neoplastic Phenotype Diversity and Heterogeneity in Neoplasias Chromosomal Anaplasia • Chromosomal Anomalies and Cancer Progression • Specific Chromosomal Anomalies & Specific Cancers Specific Hereditary Diseases Linked to Specific Cancers Incidence of Some Heritable Cancers

How Might Genetics Be Involved in the Basic Biology of Cancer? In the Genes of the Cancer Cell Genome of the Host Cell that Becomes Transformed • Genetic Predisposition Facilitating Transformation Familial Cancer Genes: e. g. DCC in Colon Cancer (DCC = gene deleted in colon carcinoma) Weak or Labile Spots in Chromosomal Structures Vertical Transmission of Pro-virus or Germ-line Altered Gene • Chance Mutagenic Event Amplification of Copy Number of Genes whose Protein Product affects cell replication Genomes of Neoplastic Cell Sub-populations During Progression (Genetics of the Cancer Cell After Transformation)

How Might Genetics Be Involved in the Basic Biology of Cancer? In the Genes of the Host Genome of the Host Prior to Transformation Host Genetics Facilitating Transformation • Activation of Carcinogens • Viral Receptors • Inability to Repair DNA Damage • Inability to Respond to Altered Cell Genome of the Host After Transformation of Host Cell • Inability to Recognize and Respond to Growing Tumor • Response Facilitating Tumor Growth • Genetically-based Non-immunological Respones e. g. Stress, Hormones

How Do We Actually Know and Demonstrate that Cell Genetics is Intimately Involved in Human Cancers?

Groups of Individuals with High Leukemia Risk: Genetic Associations • Identical Twin of Child with Leukemia (within weeks or months) • Bloom's Syndrome* *Short stature, sun-sensitive skin (Fragile Chromosomes) • Hiroshima Survivors at 1000 meters • Down's Syndrome (Trisomy 21) • Radiation-treated Patients with Ankylosing Spondylitis** 1 in 5 1 in 8 1 in 60 1 in 95 1 in 270 ** Arthritis of spine; spinal disk fusion • Sibs of Children with Leukemia 1 in 720 • Unrelated U. S. Caucasian Children to 15 Years in 2, 880 From Pitot, Fundamentals of Oncology, 3 rd Edition, p. 117 1

Relationship Between Specific Genetic Diseases and Associated Neoplasms Fanconi's Anemia (AR) Acute Myelogenous Leukemia & Hepatocellular Carcinoma Bloom's Syndrome (AR) Xeroderma Pigmentosum* (Autosomal Recessive) Leukemia & Intestinal Cancers Skin Cancers (Squamous cell carcinoma and Malignant Melanoma Retinoblastoma (Bilateral) (AD) Ocular Neoplasms & Sarcoma Familial Polyposis Coli (AD) Gardner's Syndrome (AD) Severe Combined Immune Deficiency (Sex-linked) Li Fraumeni Syndrome * See Slide 15 Colon Carcinoma, Pancreatic, Thyroid, Adrenal, Bone, & Connective Tissue Neoplasms Lymphoma, Leukemia, Sarcoma Multiple cancers AR = Autosomal Recessive Red - Autosomal Dominant

Congenital Abnormalities Associated with Increased Cancer Incidence (from Online Medical Dictionary) Bloom’s Syndrome: Congenital telangiectatic erythema (rash), primarily butterfly distribution, on face, hands, forearms, with sensitivity to skin lesions and dwarfism with normal body proportions except for narrow face and altered skull. Chromosomes are excessively fragile. (Autosomal recessive inheritance. ) Fanconi’s Anemia: Aplastic anemia with increased risk of leukemia (DNA repair defect) Gardner’s Syndrome: Multiple polyposis of the colon predisposing to colon carcinoma. Also multiple tumors including osteomas of the skull, epidermoid cysts, fibromas. (Autosomal dominant inheritance. ) APC Gene Defect (Adenomatous polyposis coli gene) Li-Fraumeni Syndrome: Incrased risk of early onset multiple cancers (p 53 Suppressor gene defect)

Xeroderma Pigmentosum: Skin Lesions and Progression to Squamous Cell Carcinoma and Malignant Melanoma Figure 12. 25 The Biology of Cancer (© Garland Science 2007) p. 499

Age of Onset of Skin Cancers in X. Pigmentosum Patients vs General Population Figure 12. 26 The Biology of Cancer (© Garland Science 2007) p. 499

Specific Genetic Anomalies Generating Cancers: Oncogenes and Suppressor Genes Demonstration that there are Cancer Genes that can transmit the cancer phenotype in cell culture

Figure 4. 1, Weinberg 2 nd Edition, p. 106 Transfection of DNA from transformed cells into normal mouse cells to generate transformed cells in culture that are tumorigenic in matched hosts. There must be cancer genes that can confer the cancer phenotype

Figure 4. 2, Weinberg 2 nd Edition, p. 107 Transfection of DNA from human bladder cancer cells into normal cells to generate transformed human cells in culture Spindle-shaped, densely packed and over-grown DNA from human T 24 Bladder carcinoma tumor Cell line transfected into normal human fibroblasts gives transformed cells that form tumor foci in a monolayer of fibroblasts in culture Normal nontransformed fibroblasts

Specific Chromosomal Abnormalities Associated with Specific Cancers Chronic Myelogenous Leukemia Reciprocal Translocation, 9&22 Human Breast Cancer Her 2 Neu Amplification Burkitt's Lymphoma Reciprocal Translocation, 8&14 Myelodysplasia and Acute Myelogenous Leukemia Trisomy 8 Meningioma Monosomy 22 Neuroblastoma N-Myc Amplification

Specific Genes Associated with Specific Cancers: The Existence of Oncogenes

Figure 4. 4(B) Weinberg, 2 nd Edition, p. 110 Amplification of oncogene coding for growth factor receptor leads to poor survival prognosis Her 2/Neu = growth factor receptor associated with cancer when mis-expressed. Therefore called a cellular onocogene.

Amplification of N-Myc Gene in Neuroblastoma: Relationship to Survival Figure 4. 11 b The Biology of Cancer (© Garland Science 2007) p. 107

Amplification of N-Myc Gene in Neuroblastoma: Relationship to Survival From Myc Cancer Gene Web-site: The MYC cancer gene contains instructions for the production of the c -Myc protein. The c-Myc protein is now known as a transcription factor or a regulator of other genes. It is a protein that binds DNA at specific sites and instructs genes whether or not they should be transcribed into messages for cells to make additional or other new proteins. Figure 4. 11 a The Biology of Cancer (© Garland Science 2007) p. 107

These are Three Turning Point Questions

Retro-Virus Gene Transduction, Point Mutations and Oncogenes

Oncogenes present in retroviruses that have been found in mutated form in human cancers. Named for virus induced cancer

Table 4. 2 Weinberg 2 nd Edition. P. 117 Point Mutations in Crucial RAS Oncogene in Human Cancers

Figure 4. 9, Weinberg, 2 nd Edition, p. 115: Point Mutation in #Endogenous RAS Gene leading to Oncogene Activation (Changes control of cell growth signaling pathways)

What Can Go Wrong with Normal Cellular Oncogene Product that is Mutated? Figure 4. 15, Weinberg 2 nd Edition p. 124 Normal Cell Signaling: Turns on or off depending on presence or absence of growth factor Cancer cell Signaling: Always on without or with growth factor

Figure 4. 6, Weinberg 2 nd Edition, p 112: Amplifications or Deletions in Specific Chromosomes Associated with Nine different human cancers Why so high? Why so low? Largest Chromosomes To Here. Thursday April 7, 2016

Genetics and Cancer : The Roles of Oncogenes and Suppressor Genes Cx. Genes. ppt in Biology of Cancer Course Chapters Involving Cancer Genetics in Weinberg’s Biology of Cancer, 2 nd Edition Chapter 4: Cellular Oncogenes Chapter 5: Growth Factors, Receptors, and Cancer Chapter 6: Cytoplasmic Signaling Circuitry Program Chapter 7: Tumor Suppressor Genes Chapter 8: p. Rb Control of the Cell Cycle Clock Chapter 9: p 53 and Apoptosis: Master Guardian and Executioner Chapter 10: Eternal Life: Cell Immortalizaton and Tumorigenesis 7 Chapters out of a Total of 16 Chapters!

Oncogenes present in retroviruses that have been found in mutated form in human cancers. Named for virus induced cancer

Roles of Oncogene Products TK = Tyrosine Kinase (kinase means it can attach a phosphoryl group to an acceptor such as a protein hydroxyl group or to a carbohydrate acceptor) e. g src abl erb. B Growth Factor e. g. sis Platelet-derived growth factor G Protein e. g. ras Intra-cellular signaling to nucleus to drive cell cycle entry Transcription Factors e. g. myc Nuclear control of DNA replication

What happens if you over-express one of these oncogenes? What happens if a virus moves or activates an endogenous normal oncogene? (“c-sis” means it is a normal cellular oncogene; “v-sis” means that the normal cellular sis oncogene that has been incorporated into the retroviral genome as an RNA copy coding for the DNA oncogene information) What happens if you mutate one or more of these oncogenes to produce a mutant onco-protein? What happens if an oncogene is fused with other DNA sequence information that it doesn’t need and shouldn’t have? What happens if we get a fusion protein including an oncoprotein?

Chromosomal Anomalies and Expression of Oncogenes Translocations and the Creation of Fusion Proteins 9 to 22 reciprocal translocation (Switching pieces) Miss-expression of c-abl oncogene The Philadelphia Chromosome Generation of a Fusion Protein Involving the abl Protein 8 to 14 reciprocal translocation Reciprocal Translocation in Chronic Myelogenous Leukemia Miss-expression of c-myc gene Over-expression of myc protein “downstream” of a gene for antibody heavy chains

Chromosomal Translocations: Oncogenes as Fused Partial Normal Genes The Philadelphia Chromosome “Philadelphia” chromosome: Truncated (cut-off) version of normal chromosome 22 Where did the missing piece of chromosome 22 go?

When the piece of chromosome 22 moved, what did it take with it? ? ?

c-sis and c-abl are endogenous cellular oncogenes c-sis encodes plateletderived growth factor beta chains c-abl is a tyrosine kinase affecting cell differentiation, cell adhesion, and cell division bcr = break-point region

Chromosome-specific Probe Analysis of Reciprocal Translocation (9 to 22) in Chronic Myelogenous Leukemia Chromosome 9 (White); Chromosome 22 (Purple) See Figure 2 -26, Chapter 2, p. 62 2 nd Edition 2014 Figure 2. 23 b The Biology of Cancer (© Garland Science 2007) p. 49

Fusion Oncoprotein in Chronic Myelogenous Leukemia c-abl is a tyrosine kinase affecting cell differentiation, cell adhesion, and cell division. Figure 4. 15 a The Biology of Cancer (© Garland Science 2007) p. 113 Also see Figure 4. 16(A) 2 nd Edition p. 125

Reciprocal Translocation (8 to 14) in Burkitt’s Lymphoma: Activation of c-myc oncogene from Chromosome 8 by translocation to Chromosome 14 The effect of immune-activation by exposure to infectious disease: Epstein-Barr Virus Myc overexpression or mis-expression in cancers, affects the cell cycle, apoptosis, differentiation, cellular metabolism and genomic stability. Myc proteins are potent transcription factors involved in 80% of human cancers. See slides 16 and 17

Reciprocal Translocation (8 to 14) in Burkitt’s Lymphoma Figure 4. 13 a The Biology of Cancer (© Garland Science 2007) p. 109

Antibody heavy chain constant region gene

Myc Oncogene (Chromosome 8) Expression Controlled by Fusion with Immunoglobulin Heavy Chain Gene (Chromosme 14) in Burkitt’s Lymphoma Abnormal Chromosome 14 Figure 4. 13 b The Biology of Cancer (© Garland Science 2007 Abnormal positioning of c-myc oncogene next to Ig. H gene for antibody heavy chains leads to over -expression of cmyc p. 109)

Table 4. 5 Weinberg 2 nd Edition p. 126 Fusion Proteins (Like bcr/abl) in Specific Human cancers

Translocations and Deregulation of Genes and Gene-products Supporting Cancer Table 4. 4, Weinberg 2 nd Edition, p. 122

Some Questions to Ask About Reciprocal Translocation: 1. There are paternally and maternally inherited chromosomes. Does it matter which of the two chromosomes is the translocation “donor” and which of the two is the translocation “recipient”? 2. Are there cases of translocations involving the X or y chromosomes? If so, is the incidence and/or pathobiology of the resulting cancer different in girls vs boys?

3 Turning Point Slides Coming Up Remember that you can also ask questions or make observations for my attention when these slides are open.

Suppressor Genes in Cancer

Genetic Aberrations in Cancer: What Can Go Wrong? Inherent or Induced Initial non-Random Genetic Instability Progressive Random Genetic Instability Point Mutations and Failure to Repair DNA Translocations and Inversions of Chromosomal Material • To Where? • Next to What? Activated? , Repressed? Amplified? • Fused to What? Mis-regulated? Deletions If cancers are caused by • Of Entire Chromosomes oncogenes, how can loss • Of Parts of Chromosomes of genes lead to cancers? • Of Specific Genes Additions • Aberrant Chromosome Replication: Trisomy & Aneuploidy • Amplifications and Repeats

Genetic Aberrations in Cancer: What Genes are Messed Up? • What gene has been mutated, amplified, derepressed, activated, fused and mis-regulated, repeated? • What is it product, and what does that product normally do? Cancer. Genes or Oncogenes • What gene has been inactivated, repressed, lost? • What is its product, and what does that product normally do? Suppressor Genes or Anti-Oncogenes

Chromosomal Deletions Associated with Specific Neoplasms: Cancer Suppressor Genes 5 q Familial Polyposis Coli, Colorectal Cx 11 q Wilm's Kidney Tumor, Breast Cx, Rhabodmyosarcoma, Bladder Cx 13 q Retinoblastoma, Osteogenic Sarcoma Small-cell Lung Cx, Ductal Breast Cx 17 p 17 q Small-cell Lung Cx, Colorectal Cx, Breast Cx, Osteosarcoma Neurofibroma 18 q Colorectal Cx

Chromosomal Deletions Associated with Specific Neoplasms What's Missing? 5 q APC Familial Polyposis Coli, Colorectal Cx 11 q WT 1 Wilm's Kidney Tumor, Breast Cx, Rhabodmyosarcoma, Bladder Cx 13 q Rb 1 Retinoblastoma, Osteogenic Sarcoma Small-cell Lung Cx, Ductal Breast Cx 17 p p 53 17 q NF 1 Small-cell Lung Cx, Colorectal Cx, Breast Cx, Osteosarcoma Neurofibroma 18 q DCC Colorectal Cx From: JNCI, 83: 92 (1991)

Chromosomal Deletions Associated with Specific Neoplasms What do the missing proteins usually do in the cell? 5 q APC Colon Crypt Stem Cell Migration and Maturation (Control of b-catenin degradation) 11 q WT 1 Transcription Factor 13 q Rb 1 Cell Cycle Entry 17 p p 53 Transcription Factor; Cell Survival 17 q NF 1 Deactivates RAS pathway 18 q DCC DNA Repair? From: JNCI, 83: 92 (1991)

Human Cancers with Strong Hereditary Predispositions in Sub-Groups of Patients The Role of Suppressor Proteins Retinoblastoma (AD) Rb 1 Gene Chromosome 13 Wilm's Tumor (AD) WT 1 Gene Chromosome 11 Colon Carcinoma APC (5), DCC (18), p 53 (17) APC Polyposis Coli Hereditary Non-Polyposis n. MLH 1 (3), n. MSH 2 (2) (DNA repair gene products Breast Cancer Linked with Ovarian Not ovarian-linked BRCA 1 (17) ( involved in DNA repair BRCA 2 (13) see p. 510) Multiple malignancies Li Fraumeni Syndrome (p 53)

Retinoblastoma and the Loss of the Rb 1 Suppressor Protein Function

Loss of Rb 1 Gene Function Leads to Incidence of Many Different Types of Cancers in Addition to Retinoblasoma Figure 7. 5 a The Biology of Cancer (© Garland Science 2007)

Mutation or loss of the one functional RB gene in one heterozygotic cell will allow that cell to escape cancer suppression

Clonal Origins of Human Cancers (Chapter 2, pages 50 – 53, 2 nd Edition, 2014) Do cancers arise from a single cell being transformed, or from multiple cells being transformed? Sometimes only one? Sometimes more than one? at the same time? at different times? How can we tell?

Clonal Origins of Spontaneous Cancers Determination of Clonality Immunoglobulin products of plasma cell leukemias Unique T-Cell receptor genes in T-Cell leukemias X-Linked Isoenzyme Markers Results of Clonal Analysis Monoclonal: CML, Lymphomas, Most carcinomas Polyclonal: • Some neoplasms linked to heredity • Spontaneous leukemias in inbred leukemic mice • High dose carcinogen-induced fibrosarcomas in mice • Virally-induced cancers

Distinct different enzyme isoforms coded on the X-chromosomes. e. g. Glucose-6 -phosphate dehydrogenase. Only one X-chromosome expressed in each cell female cell A-Form Expressed B-Form Expressed Tissue Cells are Mosaic for Forms A or B of G 6 PDH (Glucose-6 -phosphate Dehydrogenase). Express one or the other but not both

Monoclonality of Tumors from Women Heterozygous for X-linked Glucose-6 -Phosphate Dehydrogenase For Monoclonal Tumors get one form or the other of G 6 PDH, Not both! Figure 2. 18 c The Biology of Cancer (© Garland Science 2007) p. 41

3 Turning Point Slides Coming Up

Turning Point Slide Coming Up

If Cancer is fundamentally a condition arising from Genetics of the host and of the Cancer Cells, what would we expect to see? Groups at risk for specific cancers Association of genetic diseases with cancer Familial cancers Specific genetic anomalies and specific cancers Specific cancer genes Loss of genes associated with cancers Gain of genes associated with cancers Alterations in genes associated with cancers Chromosomal effects and cancers Inability to repair DNA associated with cancers Defective apoptosis involving genes controlling apoptosis Defective senescence involving genes controlling cell immortalization

Cancer-Associated Syndromes with Dominant Inheritance • Retinoblastoma (bilateral). Controls E 2 F transcription factor and cell cycle entry) • Wilm's Tumor (bilateral childhood kidney cancer) • Family Cancer Syndrome (p 53) • Adenomatous polyposis coli (APC gene controlling b-catenin degradation • Neuroblastoma (N-Myc amplification and Telomerase activity? See p. 383) • Gardner's Syndrome • Multiple Endocrine Adenomatosis • Basal Cell Nevus (basal cell skin cancer) (loss of “patched signaling receptor (PTCH)