Cancer Genetics

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Cancer Genetics
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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

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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

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The steps in invasion

• 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

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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

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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

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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 wouldnt be tolerated during
  development can occur in somatic cells
• Sporadic appearance
• Non-heritable

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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

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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

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Carcinogens

• Mutagens carcinogens generally
• Works against specific genetic background
• Two step experimental induction of cancer
• Initiation mutagenesis
• Promotion mitogenesis

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Carcinogens(and UV, ionizing radiation, )

• 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)

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Human tumor viruses

• These are an uncommon cause of cancer
• HTLV I and II STDs
• 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
• Its 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

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Viruses II

• Hepatitis B virus may be STDs
• Chronic form may result in hepatocellular
  carcinoma
• Herpes virus may be STDs
• EBV provokes unregulated growth in people
  chronically infected with Plasmodium
• Burkitts lymphoma
• Kaposis sarcoma results from KSHV

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Human papillomavirus

• HPV 16 and 18 STDs
• 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

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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.

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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

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Lymphoma

• Cancer of the lymphoid tissue
• Usually malignant
• Named according to the predominant cell type
  within the tumor or the discoverer
• Burkitts lymphoma
• A B-cell proliferation confined to the lymphoid
  tissues
• Also properly described as a "B-Cell lymphoma"

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Types of cancer genes
Cancer Gene type Transmission, effect How discovered Cell types involved
Oncogenes Dominant, positive acting (gain of function) Retroviral origins, transfection Somatic, sometimes germline
Tumor Suppressor genes Dominant or recessive, negative acting (loss of function) Pedigrees mainly Somatic and germline
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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

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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 S, a positive signal to divide
  must be received
• Negative effects on growth are thereby relieved

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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

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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

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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

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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

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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

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Multistep evolution in cancer
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Proto-oncogenes

• Induce telomerase activity
• Block apoptosis
• Stimulate proliferation
• Increase blood supply

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Tumor Suppresor Genes

• Gatekeepers regulation of cell cycle growth
  inhibition by cell-to-cell contact
• Caretakers Repair DNA damage
• Maintain genome integrity

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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-of-function
  of oncogenes in cancer

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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

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Loss of second allele in cancer
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Knudson hypothesis
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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

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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

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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

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Normal Colon and FAP colon
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Normal function of APC protein
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Specific FAP phenotypes associated with specific
APC mutations

• FAP is caused by germline LOF mutations in APC
  gene

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Colorectal tumor DNA sample gel electrophoresis
with microsatellite instability
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Cell signaling in TGFbeta (defective in some
cancers)
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Hereditary Breast/Ovarian Cancer

• BRCA 1 / 2 genes
• Associated with defective DNA repair complex that
  repairs breaks and cross-links in DNA