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Transcript
Cancer Genetics
Cancer
• Disease characterized by uncontrolled cell growth
– This causes tumors
• Tumors may be benign or malignant
• Benign tumors grow in size but do not invade and destroy
surrounding tissue
– These may still be deadly
– Laryngeal papillomas for example can occlude the airway and cause
asphyxiation
• Cancer usually means malignant
– Malignancy means a cell is invasive
– Invasion destroys
• The internal cellular order of a tissue
• Membranes and barriers that define organs
Malignancy
• Invasion is prerequisite to malignancy
– Malignancy defined as the tendency to become worse,
or to progress in virulence
– Cells which are invasive tend to spread
• This is metastasis
• However an invasive tumor is not automatically metastatic
– Metastatic cells may migrate to other sites within the same
organ
– Cells or groups of cells may travel through the vasculature or
reticuloendothelial system to distant sites
• Initial mutation (initiation) alters
genes resulting in growth
• Progressive growth (influenced by
tumor promoters) creates more
cells, each with a certain probability
of mutating to more virulent state
– Rapidly growing cells more prone to
mutation than quiescent cells
– Mutations may occur in DNA repair
enzymes making other mutations more
likely
– Mutations may also lead to genomic
instability, fragmenting the genome
• Each break means another mutation
• Mutant cells arise within the
population of growing cells that are
able to break through into
surrounding tissues
The steps in
invasion
Effects of mutations
• Up regulation of positive signals for growth
• Down regulation of negative signals that suppress
growth
• Elimination of signals that might stimulate
immunological attack or apoptosis (programmed
cell death)
• Interference with the normal process of cell-cell
binding
• Production of proteins that result in degradation of
surrounding tissues
Tumor cell properties which may
change during tumor progression
•
•
•
•
•
•
antigenicity
growth rate
response to hormones
response to cytotoxic drugs
karyotypic abnormalities
capacity for invasion and metastasis
Germline versus somatic mutations that
result in cancer
• Germline
– Mutations in certain genes
• The mutation must not be so severe that it results in fetal death
– Heritable
• Variable penetrance depending on mutation
• Somatic
– Wider array of target genes
• Mutations that wouldn’t be tolerated during development can
occur in somatic cells
– Sporadic appearance
– Non-heritable
Environmental factors
• Experimentation and epidemiology indicate
that cancer is caused by mutagens
• Most mutagens are carcinogens and most
carcinogens are mutagens
– Exceptions include tumor promoters such as TPA
– This stimulates cell division without mutagenizing
• Identification of any particular agent is difficult
Unidentified environmental influences
• Japanese colon cancer rates rise and stomach cancer
rates fall when Japanese move to America
– Stomach cancer
• Helicobacter pylori?
• Stress?
– Colon cancer?
• Lifestyle – sedentary in US
• Environmental exposures?
• Overall risk dependent on both exposure and genetic
predisposition
Carcinogens
• Mutagens = carcinogens generally
• Works against specific genetic background
• Two step experimental induction of cancer
– Initiation = mutagenesis
– Promotion = mitogenesis
• Common carcinogens act as both
initiators and promoters
– Polycyclic aromatic hydrocarbons –
cigarette smoke; soot; tobacco
– Alkylating agents – mustard gas
– Industrial agents – benzene; vinyl
chloride; asbestos
– Metals – arsenic
– Drugs – cyclophosophamide; DES
– Food additives – Nitrosamines
– Natural substances – Aflatoxin B1
• Promoters
– Are not mutagens but provoke cell
division by activating positive growth
signals
– TPA (PMA)
Carcinogens
(and UV, ionizing
radiation, …)
• These are an uncommon
cause of cancer
– HTLV I and II – STD’s
• Retroviruses found in patients
leukemia
– HTLV I Adult T-Cell
leukemia/lymphoma
– HTLV II Hairy Cell leukemia
• Infection only rarely results in
disease
• Rare forms of leukemia
• These are integrative viruses
– It’s genome inserts into
chromosomal DNA as a
necessary step in viral
replication
– The integration site is
therefore mutated
– Promoters on the virus can
up-regulate transcription
from proximal host genes
Human tumor viruses
Viruses II
• Hepatitis B virus – may be
STD’s
– Chronic form may result in
hepatocellular carcinoma
• Herpes virus – may be
STD’s
– EBV provokes unregulated
growth in people chronically
infected with Plasmodium
• Burkitt’s lymphoma
– Kaposi’s sarcoma results
from KSHV
• HPV 16 and 18 – STD’s
– Cervical cancer
• Unregulated expression of
oncogenes E6 and E7
provoke tumors
• De-regulation is a result of
integration of the virus such
that molecules that regulate
expression of E6 and E7 are
destroyed
– Other HPV
• Eg HPV-1 common warts;
HPV-11 laryngeal warts
• Exist as episomes – not
integrated
• Benign tumors (warts) that
may regress or be recurrent
• Almost never progress to
malignancy
Human
papillomavirus
Types of Cancer
• Epithelial tissue
– Carcinoma
• Most common form of solid tumor in humans
• Stem or basal cells are mutated
• Not as common among animals
• Connective tissue
– Sarcoma
• These are more common in animals and are often
virally caused in them
• Others named for the cell type of origin
– Glial cells – glioma
– Melanocytes – melanoma
– Neuroblastoma (from sympathetic nervous
tissue – most common in children), etc.
Leukemia
• Abnormal proliferation and development of
hematopoietic cells in bone marrow and blood
– This results in the expansion of cells that circulate in the
vasculature
– Often in the form of blast cells, or undifferentiated cells of
hematopoietic origin
– Classification
• Acute or chronic
• Lymphogenous or myelogenous
– Suffixes -cytic verus -blastic refers to the maturity of the
proliferating cell
– A blast is a more immature form of a cell
• Leukemic or aleukemic
– Aleukemic means there is no abnormal increase of cells in the blood
Lymphoma
• Cancer of the lymphoid tissue
– Usually malignant
– Named according to the predominant cell type
within the tumor or the discoverer
• Burkitt’s lymphoma
– A B-cell proliferation confined to the lymphoid tissues
– Also properly described as a "B-Cell lymphoma"
Types of cancer genes
Cancer
Gene type
Transmission, effect
How
discovered
Cell types
involved
Oncogenes Dominant, positive
acting (gain of
function)
Retroviral
Somatic,
origins,
sometimes
transfection germline
Tumor
Dominant or
Suppressor recessive, negative
genes
acting (loss of
function)
Pedigrees
mainly
Somatic
and
germline
Cancer is a genetic disease
• Cell division accomplishes replacement of dead or sloughed
cells
– Most cells are programmed to die as a result of normal terminal
differentiation
• Apoptosis
• Sloughing
• Genes affecting growth control may either turn cell division
off or turn it on
– Germline mutations may result in predisposition
• Often are Tumor suppressor genes
– These are negative controls on cell growth
» Restrict cell division
» Provoke apoptosis
– Somatic mutations may result in uncontrolled growth
• Oncogenes
– These are positive signals to grow or inhibitory signals against apoptosis
– Viral oncogenes interact with cellular cancer genes
Cell cycle
• In G0 a cell imposes
control on cell growth
• Restriction points on
DNA synthesis also
exist in G1, S and G2
phases
• In order to enter G1, a
positive signal to divide
must be received
• Negative effects on
growth are thereby
relieved
Families
• How positive signals changed?
– Hormone – autocrine loop
• Cell overproduces a signal that tells itself to grow
– Sis – Platelet Derived Growth Factor beta subunit – Stomach
cancer
– HST – FGF – Glioma
– Growth Factor Receptors
• RET – Rearranged during Transfection – Multiple Endocrine
Neoplasia (MEN)
• Erb B – (First identified in avian erythroblastosis virus)
– ERBB1 – EGFR homolog – glioblastoma – but viral oncogene
– ERBB2 – (NEU) EGFR family – responsiveness to chemotherapy
in breast cancer – amplified in 20-30% breast cancers - over
expression confers taxol resistance in breast cancer
– B3/B4 – no cancer connections
Positive acting Cancer Genes –
Growth factor receptors
• Cells grow and differentiate under control
of external signals
• Why would a cell divide?
– It receives an external signal
– It responds to that signal with division
• The signal is a growth factor
– E.g. Epidermal Growth Factor
• Must have a specific receptor to respond
– Epidermal Growth Factor Receptor
Nuclear
• N-myc
– related to v-myc and c-myc
• Avian myelocytomatosis virus
• DNA binding protein
– amplification in neuroblastomas
• Myb
– related to v-myb
• Avian myeloblastosis viral oncogene
• DNA binding protein
– malignant melanoma, lymphoma, leukemia
• Fos
– related to v-fos
• Finkel murine osteosarcoma
• transcription factor of AP-1 complex
– Human osteosarcoma
DNA repair enzymes
• These are not oncogenes per se
• They do not participate in cellular proliferative
signals
• Instead they act to enhance the mutability of
the genome
• This in turn increases the chances for
mutagenesis of cancer genes
Family History Flags of Hereditary
Cancer
•
•
•
•
•
Cancer in 2 or more relatives
Early age of diagnosis
Multiple primary tumors
Bilateral or multiple rare tumors
Existing mutation predisposes to cancer
Multistep evolution in cancer
Proto-oncogenes
•
•
•
•
Induce telomerase activity
Block apoptosis
Stimulate proliferation
Increase blood supply
Tumor Suppresor Genes
• Gatekeepers: regulation of cell cycle; growth
inhibition by cell-to-cell contact
• Caretakers: Repair DNA damage
• Maintain genome integrity
Oncogene-caused cancer exemples
- Amplification of the same gene as a cause of
oncogene-caused cancer (can be diagnosed by
FISH)
- Chromosomal translocations as a cause of
oncogene-caused cancer (Brc/Abl novel fusion
gene that confers growth and survival advantage
to Chronic Multiple Myeloma is a result of
translocation)
- Common idea – overexpression or gain-offunction of oncogenes in cancer
Hereditary Syndromes of Oncogenes
• MEN2 – predisposition to thyroid cancer, GOF
germline mutations
• Different mutations in RET gene (cell surface
receptor tyrosine kinase)
• Different outcomes so genetic testing is
important
Loss of second allele in cancer
Knudson hypothesis
Hereditary Syndromes of Tumor
Suppresor Genes
• Retinoblastoma – Rb1 (gate-keeper gene)
• Familial Adenomatous Polyposis (FAP)
• Hereditary Nonpolyposis Colorectal Cancer
Syndrome
• Hereditary Breast/Ovarian Cancer Syndrome
Knudsen two hit model for
Retinoblastoma
• Model for heritable cancer
• Rb-1 travels in families
• Single hit in germline
predisposes for
Retinoblastoma
– results in heterozygosity for
all cells
• Second hit in Rb necessary
to lose cell cycle control
– This results in a Loss of
Heterozygosity
– Specific mechanisms for the
second hit
Knudsen two hit model
• Rb travels in families
• Leukocoria is initial presentation
– Usual red reflection in an eye on
photography is white
• Disease can be treated in
bilateral form by removal of
eyes
– Radiation and chemotherapy can
eliminate tumors without loss of
eyesight
• Cancer will reemerge in other
tissues later in life
– Notably as osteosarcoma
Normal Colon and FAP colon
Normal function of APC protein
Specific FAP phenotypes associated
with specific APC mutations
• FAP is caused by germline LOF mutations in
APC gene
Colorectal tumor DNA sample gel electrophoresis with
microsatellite instability
Cell signaling in TGFbeta (defective in
some cancers)
Hereditary Breast/Ovarian Cancer
• BRCA 1 / 2 genes
• Associated with defective DNA repair complex
that repairs breaks and cross-links in DNA