BASIC ONCOLOGY

Jhade Lotus Peneyra MD FPCP FPSMO

 TOPIC OBJECTIVE

• To discuss the major characteristics of the

disease known as cancer, including an
overview of its etiologic agents, its
diagnosis and clinical manifestations
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History:
 Before the microscope: aggregates of mucus

 Middle 19th century: arose from normal cells of tissue of origin

• caused by viruses
• cancer in chimney sweepers
• studies of x-rays
• cigarette smokers with lung cancer
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History:

 1970’s : study of retroviruses (oncogenes); study of

families with genetic predisposition (tumor suppressor
genes)
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• CHARACTERISTICS:

 Loss of contact inhibition

 Abnormal elaboration of growth factors
 Genetic activation for tumor formation
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• CHARACTERISTICS:

 Loss of tumor suppressors

 Bizarre irregular appearances
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CANCER CELLS NORMAL CELLS
Frequent
mitoses

Normal
cell

Nucleus

Few
Blood vessel mitoses

Abnormal
heterogeneous cells

Loss of contact inhibition Oncogene expression is rare

Increase in growth factor secretion Intermittent or co-ordinated
growth factor secretion
Increase in oncogene expression
Presence of tumor
Loss of tumor suppressor genes
suppressor genes
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• Basic qualities:
 CLONALITY (MUTATION)
• Disease of the genes

• Arises through a series of somatic alterations in

DNA

• Nearly all cancers originate from a single cell

(neoplasia vs hyperplasia)
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• CLONALITY
 5-10 accumulated mutations necessary for a
cell to progress to a malignant phenotype
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• Tumor progression model:

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• CLONALITY
 2 major classes of cancer genes

• Directly affect cell growth

• Do not directly affect cell growth
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• CLONALITY

 ONCOGENES
 TUMOR SUPPRESSOR GENES

• Controlling cell division (cell birth)

• Controlling cell death (apoptosis)
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• CLONALITY
 ONCOGENES
• Normally tightly regulated

• Single allele and acts dominantly

• Increased activity of the gene product
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• CLONALITY
 TUMOR SUPPRESSOR GENES
• Normally restrain cell growth (gatekeeper genes)

• Both allelles must be inactivated

• Recessive mechanism
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• CLONALITY
 ONCOGENES
• Inside retroviruses genome capable of causing CA
in animals
• Targets of mutation/ aberrant regulation in human
CA
• Proto-oncogenes: normally expressed in
proliferation and differentiation
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ONCOGENE FUNCTION ASS’TD CA
SIS Platelet-derived GF
ERB1 Epidermal GF
FMS CSF-1 Rc
KIT Stem cell GF Rc
MET Hepatic GF Rc Papillary Renal CA
HER2 NEU/ERB2 Heregulin receptor Breast, Ovary, Bladder,
Glioblastoma CA
RET Neutrotrophic GF Medullary thyroid CA
ERBA Thyroid hormone Rc
RAS (H,K,N) GTPase Lung, pancreas, bladder,
colon, rectum CA
BCR-ABL Cytoplasmic TK CML
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ONCOGENE FUNCTION ASS’TD CA
RAF Cytoplasmic TK

SRC Cytoplasmic TK

FOS Transcription factor

JUN Transcription factor

MYC Transcription factor Burkitt’s lymphoma,

neuroblastoma, lung CA
BCL6 Transcription factor Large cell lymphoma
BCL2 Pro-apoptosis Prostate CA, lymphoma
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• CLONALITY
 ONCOGENES

Normal growth & differentiation are controlled by growth factors

bind to receptors on cell surface

signals generated by these receptors are transmitted inside the

cell thru signaling cascades

affect the transcription factors in the nucleus

 GROWTH FACTORS AND
ONCOGENES
i o n
la t
mu Paracrine (Adjacent
sti
r i ne cells)
u toc
A
Growth Growth Factor
Factor and Receptor
Synthesis
Growth Factor
Receptor

Post
receptor signal Gene Activation
transduction
pathways
Oncogenes
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• CLONALITY
 ONCOGENE
• Mechanisms of activation
 Point mutation
 DNA amplification
 Chromosomal rearrangement
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• CLONALITY
 ONCOGENE
• Mechanisms of activation
 Point mutation
• Precise substitutes at residues that normally
downregulate protein activity
• RAS gene mutation in 85% of pancreatic CA pts,
50% in colon CA pts
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• CLONALITY
 ONCOGENE
• Mechanisms of activation
 DNA amplification
• Increase in the DNA copy number
• Chromosomal/ extrachromosomal alterations (HSR or
dmins)
• Extend to hundreds or thousands of base pairs
• More than one oncogene may be amplified
• Predictor of poor prognosis
• HER2/ERBB2 (breast CA) and NMYC (neuroblastoma)
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• CLONALITY
 ONCOGENE
• Mechanisms of activation
 Chromosomal rearrangement
• Heterogenous and complex (loss of TSGs) in solid
tumors (RET gene, (10;17)(q11.2;q23) Papillary
thyroid CA)
• Simple translocations in liquid tumors (Philadelphia
chromosome ABL-BCR 9;22 in CML)
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• CLONALITY
 TUMOR SUPPRESSOR GENES
• Mechanisms of inactivation:
 Point mutations
 Large deletions (LOH)
 Gene silencing
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• CLONALITY
 TUMOR SUPPRESSOR GENES
• Mechanisms of inactivation:
 Point mutations
• Seen in the coding region leading to truncated
protein products (nonfunctional)
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• CLONALITY
 TUMOR SUPPRESSOR GENES
• Mechanisms of inactivation:
 Large deletions
• Loss of a functional product
• Entire gene or chromosome arm
• Lead to loss of heterozygosity in tumor DNA
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• CLONALITY
 TUMOR SUPPRESSOR GENES
• Mechanisms of inactivation:
 Gene silencing
• In conjunction with promoter hypermethylation
• Epigenetic change (does not involve a change in the
DNA sequence)
• VHL gene silenced in renal cell CA
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• CLONALITY
 CARETAKER GENES
• Affect the ability of the cell to maintain integrity of its genome

• If deficient, increase rate of mutations in all genes

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• CLONALITY
CANCER-PROMOTING EFFECTS OF EGFR (HER1) DYSREGULATION
• Plays a key role in many processes important for the growth and survival of
cancer
 Cell proliferation
 Growth
 Migration
 Invasion
 Angiogenesis
 Decreased apoptosis
• Expressed or overexpressed in a variety of tumor types
 NSCLC
 Cancers of the kidney, breast, head/neck, stomach, colon/rectum,
esophagus, prostate, bladder, pancreas, and ovaries
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• CLONALITY
CANCER-PROMOTING EFFECTS OF HER2 DYSREGULATION

• Overexpressed in a variety of tumor types

• Cancers of the breast, ovary, lung, thyroid gland, stomach, colon, pancreas,
and oral cavity
• Once HER2 tyrosine kinase is activated, it triggers signal transduction
pathways resulting in a variety of biological effects that promote the growth
and progression of cancer
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• CLONALITY
GENETIC MUTATIONS

• Angiogenesis may be stimulated by certain genetic mutations, not by

hypoxia

 Loss of certain tumor suppressor genes (e.g., VHL, p53, and PTEN)
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• AUTONOMY (PROLIFERATION)

 Cancer cells are able to proliferate outside the

normal control mechanisms

 Due to damage on genetic apparatus

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• AUTONOMY
 Uncontrolled growth can be stimulated by:
• Secretion of growth factors
• Increased growth factor receptors
• Independent activation of certain enzymes or
protein production pathways
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• AUTONOMY
 Cancer cells acquire mutations in cell cycle
regulatory genes
• Regulatory G1 checkpoint
 Normally, damaged cells activate a suicide
pathway
 In cancer, death pathways are damaged
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• AUTONOMY
 CELL CYCLE:

• M - shortest phase (30 mins to 1hr); cell division

and resulting 2 daughter cells

• G1 - 18 to 30hrs; cell determines readiness to

commit to DNA synthesis
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• AUTONOMY
 CELL CYCLE:

• S - 16-20hrs; DNA synthesis; genetic material is

replicated, no re-replication is permitted

• G2 - 2-20hrs; fidelity of DNA replication is

assessed and errors are corrected
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• AUTONOMY
 Hallmark of cancer is deregulation of the mechanisms
controlling cell cycle

 Orderly phase progression is due to:

• Cyclins (A,B,D,E)
• Cylclin-dependent kinases (1,2,3,4,5,6,)
• Cyclin-dependent kinase inhibitors
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QuickTimeª and a
Animation decompressor
are needed to see this picture.
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• AUTONOMY
 Critical regulators:
• G0 = cell commit to and complete mitosis

• G1 - S checkpoint
 Phosphorylation state of retinoblastoma (pRB) tumor supressor
gene
 CDK4 or CDK6 + D-type cyclins forming G1-specific kinase
 Active CDK2 + cyclin-E results in full pRB phosphorylation
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• AUTONOMY
 CDK inhibitors
• Kinase inhibitory proteins (KIP)
• Inhibitor of CDK4 (INK4)

 KIP inhibit cyclin + CDK activity (G1 arrest)

• Senescence, differentiation, DNA damage
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• AUTONOMY

 Loss of function of pRB as guardian of G1

restriction point - occur in human CA

 INK4a - commonly deleted in human CA

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• AUTONOMY
 p 53
• Guardian of the genome
• Sequence-specific transcription factor
• Bind to mdm2 oncogene product (normal low
levels)
• With DNA damage, p53 is phosphorylated by
several kinases in the DNA damage checkpoint
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• AUTONOMY
 p53
• Activates genes leading to cell cycle arrest (p21Cip1/Waf1) or
apoptosis (pro-apoptotic Bcl-2 family members)

• Myc promotes abberant G1/S transition results to p53-

induced apoptosis
 Mediated by ARF (upregulated by Myc and E2F) w/c binds to
mdm2 and releases p53
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• AUTONOMY
 p53
• BUT:
• Genetic alterations that bypass p53 tumor-
suppressor pathways - found in human CA
• Inactivation results to survival of cells with oncogenic
mutations and clonal expansion w/in the tumor (w/out
activation of physiologic death pathways)
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• AUTONOMY
 GROWTH RATES:
• Doubling time
 Mean length of time for division of all tumor cells present
 Time in which tumor doubles its mass and number of its
cells
 Important indicator of cancer aggressiveness
 Clinical disease progression, imaging studies to measure
size progression
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• AUTONOMY
 GROWTH RATES:
• Doubling time
 30 doubling times to reach 1 cm tumor
 1cm tumor = 109 cells
 Cancer can exist for a long time in an occult form
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number of
cancer cells

10 12

diagnostic
10 9 threshold
(1cm)

time

undetectable detectable
cancer cancer
limit of
host
clinical
death
detection
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• AUTONOMY
 Gompertzian growth pattern:
• LAG phase - cell number is small, growth factors not enough

• LOG phase - explosive increase, growth factor secretion

maximal, (+) angiogenesis, sensitive to chemotherapy

• PLATEAU phase - growth declines, outsripping of blood

supply, chemotherapy not effective, cells die or go to G0
 TRANSFORMATION TO
MALIGNANT DISEASE
 

Transformation to malignant disease may occur over many years

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• DYSPLASIA
 Abnormalities in growth patterns and
morphology
• May closely resemble normal cells (low grade)
• May appear to be almost indistinguishable from
cancerous cells (high grade)
 Considered to be a premalignant condition
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 What Determines Whether
Cancer Develops?
• Number of dysplastic cells
• How altered the cells have become
• What initiators and promoters are involved
• How long these stimuli have been applied
• Dysplasia does not necessarily precede
cancer
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• ANAPLASIA (LOSS OF DIFFERENTIATED

FUNCTION)

 Cancer cell loses the normal function of tissue of origin

 Cancer cell exhibit abnormal, bizarre looking cells
• Large nuclei, prominent nucleoli, increased chromatin
• Increased / abnormal mitosis
• Aneuploidy
• Partial / complete loss of normal architecture
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• METASTASIS & INVASION

 Spread of tumor from the primary organ to other
sites / tissues

• Benign neoplasms - unregulated growth without

invasion
• Malignant neoplasms - cancer; invade and spread to
other sites
 Carcinoma ( epithelial)
 Sarcoma (mesenchymal)
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• METASTASIS & INVASION

 3 MAJOR FEATURES:

• Cell adhesion to basement membrane

• Local proteolysis of the membrane

• Movement of the cell through the rent in the

membrane and ECM
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• METASTASIS & INVASION

 Cancer cells become invasive by:
• Alteration of the surface biochemical structure of
cancer cells

• Increased motility of cancer cells

• Elaboration of lytic substances by cancer cells

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• METASTASIS & INVASION

• Decreased mutual adhesiveness of cancer cells

• Loss of mutual growth restraint between cancer cells

and normal tissue
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• METASTASIS & INVASION

 SOME PATTERNS OF METASTASIS:
• Mechanical theory

 Incidence / number of metastases due to function of the

number of cells, size of cells, cell grps gaining access to
the circulation
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• METASTASIS & INVASION

 SOME PATTERNS OF METASTASIS:
• Soil theory

 Determined by the environment of the various organs

 Certain tumors can thrive at a particular site or soil
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• METASTASIS & INVASION

 SOME PATTERNS OF METASTASIS:
• Intrinsic cellular factors theory

 Individual tumor cells have properties that determine

pattern
 Subpopulation of cells w/ high metastatic potential
 Selected out during tumor progression
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• METASTASIS & INVASION

 SOME PATTERNS OF METASTASIS:
• Immunologic surveillance

 Dissemination is due to a defect in the immunologic

defense
 Evasion of the immune system by downregulation of
MHC class I /II molecules; induction of T cell tolerance,
inhibition of normal dendritic cell and/or T cell function
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• METASTASIS & INVASION

 Bone metastasis:
• Tumor cell -stromal cell interactions activate
osteoclasts and inhibit osteoblasts
• Bisphosphonates are effective inhibitors of
osteoclast function
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• METASTASIS AND INVASION

 PROCESS OF METASTASIS:
1. Escape from the primary tumor to circulation
2. Survival in the circulation
3. Arrest at new site
4. Escape from the circulation
5. Migration into interstitial space at the new site
6. Initiation of new vessel formation
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• METASTASIS & INVASION

 TUMOR ANGIOGENESIS
• Recruitment of blood vessels and vascular
endothelial cells

• Angiogenic switch : critical element

 The ability of the tumor to promote the formation of new
capillaries from host vessels
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• METASTASIS & INVASION

 TUMOR ANGIOGENESIS

• STIMULI:
 Hypoxia
 Inflammation
 Genetic lesions in oncogenes/ tumor suppressor genes
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• METASTASIS & INVASION

 TUMOR ANGIOGENESIS
• Tumor blood vessels are not normal (VEGF)

• Tumor blood flow is variable (Loss of p53)

• Tumor blood vessels have high vascular permeability

(Interstitial HPN)

• Tumor blood vessels lack perivascular cells (no vasoactive

control)
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ANGIOGENESIS
• Important in normal reproduction, development, menstruation, and tissue
repair
• Normally short-lived (i.e., days or weeks)
• Usually suppressed in adults
• Depends on the balance of
 Proangiogenic factors
• Vascular endothelial growth factor (VEGF)
• Fibroblast growth factor (FGF)
• Platelet-derived growth factor (PDGF)
 Anti-angiogenic factors
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• PRO-ANGIOGENIC FACTORS:
 VEGF is a key regulator of angiogenesis
 Binds to its receptors (VEGFR-1 and VEGFR-2) on blood
vessel endothelial cells
 VEGFR-2 responsible for endothelial growth signaling (and
cancer-associated angiogenesis) via activation of the
RAF/MEK/ERK signal transduction pathway
 Can also activate the PI3 kinase and the phospholipase C-
PKC pathways
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RAF/MEK/ERK PATHWAY
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PARACRINE EFFECTS OF VEGF
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•FGF
-Potent growth factor that stimulates angiogenesis
-Binds to its receptor (FGFR) on blood vessel endothelial cells
-Stimulates endothelial cell proliferation, migration, and survival
-Not as specific for blood vessel endothelial cells as VEGF
-Affects many other cell types (fibroblasts, smooth muscle cells, neurons)
-Important in the development and function of the nervous system, eyes, skeleton,
and other organ systems
•PDGF
-Targets pericytes, fibroblasts, and smooth muscle cells
-Important in both tumorigenesis and angiogenesis
-Expressed by capillary endothelial cells and mediates its angiogenic effect via
these receptors
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ANTI-ANGOGENIC FACTORS:
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BLOOD VESSEL ENDOTHELIAL CELLS: ROLE IN ANGIOGENESIS

Line the inside (lumen) of a blood vessel
Have specific receptors for growth factors that influence their migration and
proliferation in support of angiogenesis
Form new blood vessels in response to stimulation by VEGF, FGF, and
other pro-angiogenic factors
Stimulate endothelial cells in existing blood vessels to proliferate,
degrade their basement membrane, migrate, and form new blood vessels
Form tubes, become capable of handling blood flow, and mature into new
blood vessels
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• CARCINOGENESIS

 Multi-stage process that begins with a cell exposed to

a potential carcinogen resulting to genetic damage
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• CARCINOGENESIS
 INITIATION

• Initial stage
• Rapid and genotoxic, irreversible
• Mutant DNA
• If exposure stops, can still be cleared by immune system
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• CARCINOGENESIS
 PROMOTION

• Second stage
• Continued exposure results to formation of a mass
• Longer period of time
• Independent of the genetic apparatus (epigenetic)
• Potentially reversible in early stages
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• CARCINOGENESIS
 PROMOTION

• Epigenetic modification :
 Change in the genome that does not involve a change in the
DNA sequence
 Role is unclear
 General decrease in level of DNA methylation is commonly
seen in CA
 Reprogramming the expression of a large number of genes in
CA
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• CARCINOGENESIS
 CLINICAL CANCER

• Third stage
• Continued exposure to carcinogens
• If untreated, leads to metastasis and death
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• CARCINOGENESIS
 ETIOLOGY:

Environment Genes

Cell

CANCER
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• CARCINOGENESIS
 ETIOLOGY:
1. Occupational
Arsenic, Asbestos, Benzene, Mustard gas, Vinyl chloride

2. Lifestyle
Low consumption of vegetables, increased nitrates, high
fat diet, low calcium, mycotoxins, sexual promiscuity, Hepa B
infection

5. Multifactorial
Tobacco & alcohol & asbestos
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• CARCINOGENESIS
 ETIOLOGY:
4. Viruses

- contain a strip of DNA or RNA that acts as oncogene

- stimulate the infected cell to proliferate for it to replicate itself
- resulting cell produces abnormal growth factors w/c stimulate
tumor growth
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• CARCINOGENESIS
Viruses Neoplasia
DNA VIRUSES
HPV 16, 18, 32,34 Warts, anogenital CA, cervical CA
Herpes simplex virus-2 Cervical CA
EBV NPCA, Burkitt’s lymphoma
Cytomegalovirus Kaposi’s sarcoma
Hepa B, Hepa C virus HCC
Herpes simplex virus -6 B-cell lymphomas
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• CARCINOGENESIS
Viruses
RNA viruses
Human T cell leukemia virus-I
Human T cell leukemia virus-II
Human immunodeficiency virus-III
Neoplasia
T cell leukemia/ lymphoma
Hairy cell leukemia
Lymphoma/ Kaposis sarcoma
 ONCOGENIC VIRUSES

• Vast majority of viral infections do not cause cancer

• A few viruses have been implicated as cancer-causing (oncogenic)
• The final common pathway of carcinogenesis is the interaction of the
virus with the host DNA

QuickTimeª and a
Animation decompressor
are needed to see this picture.
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• CARCINOGENESIS
5. Chemical carcinogens

- most important induction agents in human

cancers
- electrophilic reactants arising through
metabolism
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• CARCINOGENESIS
5. Chemical carcinogens NORMAL CELLS

INITIATORS INITIATED CELLS

CHEMICAL TUMOR CELLS

CARCINOGEN

PROMOTERS CLONES
INACTIVE
METABOLITES
GROSS TUMORS
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TYPE MOA EXAMPLE

GENOTOXIC
Electrophil,organic Ethylene imine,ether
DIRECT-ACTING
cmpd,genotoxic interacts
w/ DNA
Vinyl chloride
PRO-CARCINOGEN Require conversion by Benzo(a)pyrene,chromiu
metabolic activation m, dimethylnitrosamine
nickel
INORGANIC Not directly genotoxic,
CARCINOGEN DNA changes by
selective alteration in
fidelity of DNA replication
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TYPE MOA EXAMPLE

EPIGENETIC
Affects mesenchymal Polymer or metal foils,
Solid-state carcinogen
cells, physical form vital, asbestos
unknown MOA,increase
cell cycling
Hormone Alters endocrine system Estradiol,
balance & differentiation, Diethylstibesterol
promoter
Immunosuppressors Alters endocrine balance
& differentiation, Azathioprine,
promoter antilymphocytic serum
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TYPE MOA EXAMPLE
EPIGENETIC
Not Phorbol esters pyrene,
Co-carcinogen
genotoxic/carcinogenic; catechol ethanol SO2
but enhances effects of
other agents
Butylated hydroxy
Cytotoxin Not anisole, nitrol-tiacetate
genotoxic/carcinogenic, carbon tetrachloride
overdose kills cells

Promoter Not Phorbol esters, phenol,

genotoxic/carcinogenic bile acids, sodium
but enhances effects of saccharin
other agents
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• CARCINOGENESIS
6. Radiation

- sunlight
-artificial sources of UV light
- x-rays
- radiochemicals
- nuclear fission
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• CARCINOGENESIS
6. Radiation

- mutations in the host cell is a possible

mechanism for transmitting irreversible
changes of gene expression to cell progeny
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• CARCINOGENESIS
7. Genetic Predisposition
- predisposing loss-of-function mutation in one allele of a
tumor suppressor gene or caretaker gene
- the tumors show a loss of the remaining normal allele due
to somatic events

- Knudson hypothesis: (2-hit hypothesis)

Hereditary: Ist hit = inherited susceptibility gene
2nd hit = after conception mutation
Non-hereditary: 1st hit = somatic cell mutation
2nd hit = environmental causes / random mutation
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• CARCINOGENESIS
 KNUDSON HYPOTHESIS:

It was later found that carcinogenesis (the development of malignancy) depended both on the activation of
oncogenes (genes that stimulate cell proliferation) and deactivation of tumor suppressor genes (genes that
keep proliferation in check). A first "hit" in an oncogene would not necessarily lead to cancer, as normally
functioning tumor suppressor genes (TSGs) would still counterbalance this impetus; only damage to TSGs
would lead to unchecked proliferation. Conversely, a damaged TSG (such as the Rb1 gene in
retinoblastoma) would not lead to cancer unless there is a growth impetus from an activated oncogene.
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SYNDROME GENE INH TUMORS
Ataxia telagiectasia ATM AR Breast CA
Cowden syndrome PTEN AD Breast, Thyroid
FAP APC AD Int. adenoma, Colorectal CA
Familial Wilms Tumor WT1 AD Pediatric renal CA

Hereditary BRCA1/2 AD Breast, ovarian, colon,prostate

breast/ovarian CA
Hereditary RB1 AD Retinoblastoma, osteosarcoma
retinoblastoma
HNPCCA MSH2/MLH1/ AD Colon, endometrial,ovarian,
MSH6/PMS2 stomach,small bowel,ureter CA

Juvenile polyposis SMAD4 AD GI,Pancreatic CA

Li-Fraumeni TP53 AD Sarcoma, Breast CA
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SYNDROME GENE INH TUMORS

MEN type 1 MEN1 AD Parathyroid,endocrine, pancreas,pituitary

MEN type2a RET AD Medullary thyroid CA,Pheochromocytoma

Neurofibromatosis type NF1 AD Neurofibroma, neurofibrosarcoma,brain

1 tumor
Neurofibromatosis type NF2 AD Vestibular schwannoma,meningioma,
2 spine
Von Hippel-Lindau VHL AD Kidney, cerebellum,pheochromocytoma
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QUESTIONS?