Human Genetics
Mariam55Multifactorial and Acquired Cancer Traits
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Cancer is a genetic disease
abnormal growth that invades and spreads
lifetime risk of one in three
deregulation of cell cycle
inherited cancer susceptibility genes
environmental exposure
tumor genome sequencing
genetic changes that cause and/or accompany cancer
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Cancer is a cellular disease
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Cancer is a cellular disease
cellular pathways affected by cancer mutations
cell fate
dedifferentiation
cell survival
oxygen availability (angiogenesis)
preventing apoptosis
genome maintenance
less resistance to reactive oxygen species (ROS) and toxins
faulty repair of DNA and chromosomes
alternative mRNA splicing
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Cancer as a clinical disease
irregular mitosis results in a tumor
cell escapes normal control over its division rate
abnormal proliferation of cells
benign tumor (not clinical “cancer”)
does not spread or “invade” surrounding tissue
solid with clear margins
malignant tumor (clinical “cancer”)
infiltrates and damages nearby tissues
metastasis is a spread to other tissues
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Cancer is an acquired genetic disease
carcinogens
substances that cause cancer
often also mutagens that damage DNA
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Cancer is an acquired genetic disease
changes in cancer-related genes
cell cycle related genes
proto-oncogenes mutated to oncogenes (~100 genes)
acts as autosomal dominant negative, “one-hit”
tumor suppressor genes knocked out (~30 genes)
acts as autosomal recessive, “two-hit”
DNA repair genes
allow other mutations to persist
accumulation of mutations more severe phenotype
inherited susceptibility
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Cell Cycle genes in cancer
check points allow cell cycle to proceed
timing, rate, and number of cell divisions
protein growth factors
signaling molecules from outside the cell
transcription factors within the cell
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Cell Cycle genes in cancer
faulty check points allow cell cycle to proceed
mutations in tumor suppressors or oncogenes
even if conditions are not met
no apoptosis = damaged cell divides
spindles not assembled or attached = improper segregation and/or chromosome loss or gain
DNA damage not repaired = mutations passed to offspring cells
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Cancer reprograms cells
progression of mutations
normal cells differentiate into cell types
limited growth
cancer cells de-differentiate into stem cells
unlimited growth
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Telomere shortening normally ages cells
loss of telomere length leads to apoptosis
normal, due to end-replication problem
all cells have ~50 cell cycles until death
telomerase activation repairs telomeres
only in certain types of immortalized cells
cancer cells can turn telomerase on
mutation in TERT gene or dedifferentiation
telomeres extended, cells live past 50 cycles
not susceptible to apoptosis anymore
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