Transcript CxGenes(NoTP)

Genetics of the Cancer Cell
and of the
Tumor-Bearing Host:
Oncogenes and
Tumor Suppressor Genes
Folder Title: CxGenes(NoTP)
Updated: April 16, 2014
Biology of Cancer: What 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 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”?
Why Does All of This Matter?
Age Group and Lifetime Risk of Developing Invasive Cancers
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
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 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
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
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, 3rd 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)
Retinoblastoma (Bilateral) (AD)
Familial Polyposis Coli (AD)
Gardner's Syndrome (AD)
Leukemia & Intestinal Cancers
Severe Combined Immune
Deficiency (Sex-linked)
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 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
(p53 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 Chromosomal Abnormalities
Associated with Specific Cancers
Chronic Myelogenous
Leukemia
Reciprocal Translocation, 9&22
Burkitt's Lymphoma
Reciprocal Translocation, 8&14
Myelodysplasia and
Acute Myelogenous
Leukemia
Trisomy 8
Meningioma
Monosomy 22
Specific Genetic Anomalies Generating Cancers:
Oncogenes and Suppressor Genes
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 4.6b The Biology of Cancer (© Garland Science 2007), p. 101
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 4.11a The Biology of Cancer (© Garland Science 2007) p.
107
Amplification of N-Myc Gene in Neuroblastoma: Relationship to Survival
Figure 4.11b The Biology of Cancer (© Garland Science 2007) p.
107
Turning Point Slide Coming Up
17%
1
17%
2
17%
3
17%
4
17%
5
17%
6
Chromosomal Anomalies and Expression of
Oncogenes
Reciprocal Translocation in Chronic Myelogenous
Leukemia
The Philadelphia Chromosome
c-Sis and c-abl are endogenous cellular oncogenes
like c-myc
Chromosomal
Translocations:
Oncogenes as Fused Partial
Normal Genes
The Philadelphia
Chromosome
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
Chromosome-specific Probe Analysis of Reciprocal Translocation (9 to 22)
in Chronic Myelogenous Leukemia
Chromosome 9 (White); Chromosome 22 (Purple)
Figure 2.23b 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 4.15a The Biology of Cancer (© Garland Science 2007)
p. 113
Reciprocal Translocation (8 to 14)
in Burkitt’s Lymphoma: Activation of myc oncogene
The effect of immune-activation
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 4.13a 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
Figure 4.13b The Biology of Cancer (© Garland Science 2007
p. 109)
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 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
• Of Entire Chromosomes
• Of Parts of Chromosomes
• Of Specific Genes
Additions
• Aberrant Chromosome Replication: Trisomy & Aneuploidy
• Amplifications and Repeats
Turning Point Slide Coming Up
The picture below is showing one kind of genetic anomaly in cancer. What kind
of anomaly is it showing? What is happening here?
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 Ling Cx, Ductal Breast Cx
17p
17q
Small-cell Lung Cx, Colorectal Cx,
Breast Cx, Osteosarcoma
Neurofibroma
18q
Colorectal Cx
From: JNCI, 83:92 (1991)
Chromosomal Deletions Associated with Specific Neoplasms
What's Missing?
5q
APC
Familial Polyposis Coli, Colorectal Cx
11q
WT1
Wilm's Kidney Tumor, Breast Cx,
Rhabodmyosarcoma, Bladder Cx
13q
Rb1
Retinoblastoma, Osteogenic Sarcoma
Small-cell Lung Cx, Ductal Breast Cx
17p
p53
17q
NF1
Small-cell Lung Cx, Colorectal Cx,
Breast Cx, Osteosarcoma
Neurofibroma
18q
DCC
Colorectal Cx
From: JNCI, 83:92 (1991)
Chromosomal Deletions Associated with Specific Neoplasms
What 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)
Rb1 Gene Chromosome 13
Wilm's Tumor (AD)
WT1 Gene Chromosome 11
Colon Carcinoma
APC (5), DCC (18), p53 (17)
APC Polyposis Coli
Hereditary Non-Polyposis nMLH1 (3), nMSH2 (2) (DNA repair gene products
Breast Cancer
Linked with Ovarian
Not ovarian-linked
BRCA1 (17) ( involved in DNA repair
BRCA2 (13)
see p. 510)
Multiple malignancies
Li Fraumeni Syndrome (p53)
Figure 7.4b The Biology of Cancer (© Garland Science 2007)
Figure 7.4c The Biology of Cancer (© Garland Science 2007)
Figure 7.5a The Biology of Cancer (© Garland Science 2007)
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?
Figure 2.17 The Biology of Cancer (© Garland Science 2007)
p. 40
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
A-Form
Expressed
B-Form
Expressed
Tissue Cells are Mosaic for
Forms A or B of G6PDH
(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 G6PDH,
Not both!
Figure 2.18c The Biology of Cancer (© Garland Science 2007)
p. 41
Monoclonality of Plasma Cell Tumors
Figure 2.19a The Biology of Cancer (© Garland Science 2007)
p. 42
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 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)
3 Turning Point Slides Coming Up