Genetics of the Cancer Cell and of the Tumor-Bearing Host: Oncogenes and Tumor Suppressor Genes...
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Transcript of Genetics of the Cancer Cell and of the Tumor-Bearing Host: Oncogenes and Tumor Suppressor Genes...
Genetics of the Cancer Celland of the
Tumor-Bearing Host:Oncogenes and
Tumor Suppressor GenesFolder Title: CxGenes(NoTP)
Updated: April 9, 2015
Biology of Cancer: What is Cancer LikeWhat is Cancer Like?
Why do we need to know about Cancer ? (Intro501)
What are cancers like as clinical diseases ? (Clinical)
What are incidence patterns of cancers like? (Epidemio)
How are cancers defined and classified ? (DefClass)
What do we study in cancer biology and cancer medicine? (Models)
When we study cancer cells, what features do we see? (CellProp)
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 (MetModels)
Biology of Cancer: Why is Cancer Like ThatWhy is Cancer Like That?
What accounts for the phenomenology of cancer 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 clinical oncology based on our understanding of what makes cancers “tick”?
Genetics in the Biology of CancerGenetics of What?
Genetics of the Host
Before the Cancer Starts
In Response to the Cancer After It Appears Promoting or protecting the cancer Interfering with therapy approaches
Genetics of the Cell that Gets TransformedPredisposing Factors in the Host
Genetics of the Cancer Cell
After Transformation - During Progression
Why Genetics Must Be Intimately Involved in the Biology of Cancer
Multiple Apparently Unrelated Causative Agents:• All Can Affect Genetics of Cells and of HostDefinition of Neoplasia: "Heritable Cellular Phenotype"Long Latent PeriodsProgressive Acquisition of the Full Neoplastic PhenotypeDiversity and Heterogeneity in NeoplasiasChromosomal Anaplasia• Chromosomal Anomalies and Cancer Progression• Specific Chromosomal Anomalies & Specific CancersSpecific Hereditary Diseases Linked to Specific CancersIncidence 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
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 HostGenome 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 CellGenome 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
Groups of Individuals with High Leukemia Risk: Genetic Associations
• Identical Twin of Child with Leukemia 1 in 5 (within weeks or months)• Bloom's Syndrome* 1 in 8
*Short stature, sun-sensitive skin (Fragile Chromosomes)
• Hiroshima Survivors at 1000 meters 1 in 60• Down's Syndrome (Trisomy 21) 1 in 95• Radiation-treated Patients with Ankylosing Spondylitis** 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 1
in 2,880
From Pitot, Fundamentals of Oncology, 3rd Edition, p. 117
Relationship Between Specific Genetic Diseases and Associated Neoplasms
Fanconi's Anemia (AR)
Bloom's Syndrome (AR)Xeroderma Pigmentosum(Autosomal Recessive)Retinoblastoma (Bilateral) (AD)Familial Polyposis Coli (AD)Gardner's Syndrome (AD)
Severe Combined Immune Deficiency (Sex-linked)
Acute Myelogenous Leukemia & Hepatocellular Carcinoma
Leukemia & Intestinal Cancers
Skin Cancers (Squamous cell carcinoma and Malignant Melanoma
Ocular Neoplasms & Sarcoma
Colon Carcinoma
Colon Carcinoma, Pancreatic, Thyroid, Adrenal, Bone, & Connective Tissue Neoplasms
Lymphoma, Leukemia, Sarcoma
AR = Autosomal RecessiveRed - 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(p53 Suppressor gene defect)
Figure 12.25 The Biology of Cancer (© Garland Science 2007) p. 499
Xeroderma Pigmentosum: Skin Lesions and Progression to Squamous Cell Carcinoma and Malignant Melanoma
Figure 12.26 The Biology of Cancer (© Garland Science 2007) p. 499
Age of Onset of Skin Cancers in X. Pigmentosum Patients vs General Population
Specific Chromosomal Abnormalities Associated with Specific Cancers
Chronic Myelogenous Leukemia
Human Breast Cancer
Burkitt's Lymphoma
Myelodysplasia and Acute Myelogenous Leukemia
Meningioma
Neuroblastoma
Reciprocal Translocation, 9&22
Her2Neu Amplification
Reciprocal Translocation, 8&14
Trisomy 8
Monosomy 22
N-Myc Amplification
Figure 4.6b The Biology of Cancer (© Garland Science 2007), p. 101
Amplification of HER2/Neu Gene Expression in Breast Cancer:
Relationship to Prognosis
Her2/Neu = growth factor receptor associated with cancer when mis-expressed.Therefore called a cellular onocogene.
Figure 4.11a 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 4.11b The Biology of Cancer (© Garland Science 2007) p. 107
Amplification of N-Myc Gene in Neuroblastoma: Relationship to Survival
This is a Turning Point Slide:It is inserted here to allow you to ask me
questions or to make observations
Are you here?
Any questions or other statements?
Chromosomal Anomalies and Expression of Oncogenes
9 to 22 reciprocal translocation (Switching pieces)Miss-expression of c-abl oncogene
8 to 14 reciprocal translocation
Reciprocal Translocation in Chronic Myelogenous Leukemia
The Philadelphia Chromosome
c-Sis and c-abl are endogenous cellular oncogenes like c-myc
c-sis and c-abl are endogenous cellular oncogenes
c-sis encodes platelet-derived growth factor beta chains
c-abl is a tyrosine kinase affecting cell differentiation, cell adhesion, and cell division
Figure 2.23b The Biology of Cancer (© Garland Science 2007) p. 49
Chromosome-specific Probe Analysis of Reciprocal Translocation (9 to 22) in Chronic Myelogenous Leukemia
Chromosome 9 (White); Chromosome 22 (Purple)
Figure 4.15a The Biology of Cancer (© Garland Science 2007) p. 113
Fusion Oncoprotein in Chronic Myelogenous Leukemia
c-abl is a tyrosine kinase affecting cell differentiation, cell adhesion, and cell division.
Reciprocal Translocation (8 to 14) in Burkitt’s Lymphoma:
Activation of c-myc oncogene from Chromosome 8by translocation to Chromosome 14
The effect of immune-activationby 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
Figure 4.13a The Biology of Cancer (© Garland Science 2007) p. 109
Reciprocal Translocation (8 to 14) in Burkitt’s Lymphoma
Figure 4.13b The Biology of Cancer (© Garland Science 2007 p. 109)
Myc Oncogene (Chromosome 8) Expression Controlled by Fusion with Immunoglobulin Heavy Chain Gene (Chromosme 14) in Burkitt’s Lymphoma
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?
Genetic Aberrations in Cancer:
What Can Go Wrong? Inherent or Induced Initial non-Random Genetic InstabilityProgressive Random Genetic InstabilityPoint Mutations and Failure to Repair DNATranslocations and Inversions of Chromosomal Material• To Where?• Next to What? Activated?, Repressed? Amplified?• Fused to What? Mis-regulated?Deletions• Of Entire Chromosomes• Of Parts of Chromosomes• Of Specific GenesAdditions• 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?
CancerGenes 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
5q Familial Polyposis Coli, Colorectal Cx
11q Wilm's Kidney Tumor, Breast Cx, Rhabodmyosarcoma, Bladder Cx
13q Retinoblastoma, Osteogenic Sarcoma Small-cell Lung Cx, Ductal Breast Cx
17p Small-cell Lung Cx, Colorectal Cx, Breast Cx, Osteosarcoma
17q Neurofibroma
18q Colorectal Cx
From: JNCI, 83:92 (1991)
Chromosomal Deletions Associated with Specific NeoplasmsWhat's Missing?
5q APC Familial Polyposis Coli, Colorectal Cx
11q WT1 Wilm's Kidney Tumor, Breast Cx,Rhabodmyosarcoma, Bladder Cx
13q Rb1 Retinoblastoma, Osteogenic SarcomaSmall-cell Lung Cx, Ductal Breast Cx
17p p53 Small-cell Lung Cx, Colorectal Cx,Breast Cx, Osteosarcoma
17q NF1 Neurofibroma
18q DCC Colorectal Cx
From: JNCI, 83:92 (1991)
Chromosomal Deletions Associated with Specific NeoplasmsWhat do the missing proteins usually do in the cell?
5q APC Colon Crypt Stem Cell Migration and Maturation (Control of b-catenin degradation)
11q WT1 Transcription Factor
13q Rb1 Cell Cycle Entry
17p p53 Transcription Factor; Cell Survival
17q NF1 Deactivates RAS pathway
18q DCC DNA Repair?
From: JNCI, 83:92 (1991)
Human Cancers with Strong Hereditary Predispositions in Sub-Groups of Patients
Retinoblastoma (AD)
Wilm's Tumor (AD)
Colon Carcinoma APC Polyposis Coli Hereditary Non-Polyposis
Breast Cancer Linked with Ovarian Not ovarian-linked
Multiple malignancies
Rb1 Gene Chromosome 13
WT1 Gene Chromosome 11
APC (5), DCC (18), p53 (17)nMLH1 (3), nMSH2 (2) (DNA repair gene products)
BRCA1 (17) ( involved in DNA repair
BRCA2 (13) see p. 510)
Li Fraumeni Syndrome (p53)
Clonal Origins of Human Cancers
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 ClonalityImmunoglobulin products of plasma cell leukemiasUnique T-Cell receptor genes in T-Cell leukemiasX-Linked Isoenzyme Markers
Results of Clonal AnalysisMonoclonal: CML, Lymphomas, Most carcinomasPolyclonal:• Some neoplasms linked to heredity• Spontaneous leukemias in inbred leukemic mice• High dose carcinogen-induced fibrosarcomas in mice• Virally-induced cancers
A-FormExpressed
A-FormExpressed
B-FormExpressed
B-FormExpressed
Tissue Cells are Mosaic for Forms A or B of G6PDH(Glucose-6-phosphate Dehydrogenase).Express one or the other but not both
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
Figure 2.18c The Biology of Cancer (© Garland Science 2007) p. 41
Monoclonality of Tumors from Women Heterozygous for X-linked Glucose-6-Phosphate Dehydrogenase
For Monoclonal Tumors get one form or the other of G6PDH, Not both!
Figure 2.19a The Biology of Cancer (© Garland Science 2007) p. 42
Monoclonality of Plasma Cell Tumors
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 cancersAssociation of genetic diseases with cancerFamilial cancersSpecific genetic anomalies and specific cancersSpecific cancer genesLoss of genes associated with cancersGain of genes associated with cancersAlterations in genes associated with cancersChromosomal effects and cancersInability to repair DNA associated with cancersDefective apoptosis involving genes controlling apoptosisDefective senescence involving genes controlling cell immortalization
Cancer-Associated Syndromes with Dominant Inheritance
• Retinoblastoma (bilateral). Controls E2F transcription factor and cell cycle entry)
• Wilm's Tumor (bilateral childhood kidney cancer)• Family Cancer Syndrome (p53)
• 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)