Human Genetics
Mariam55Cancer 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
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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Cancer can be inherited or acquired
cancer is genetic, and not usually inherited
however,
germline mutations are passed to offspring
cancer susceptibility as a heterozygote (10%)
mutation is recessive
present in every cell of the individual
cancer develops as acquired disease
second mutation (somatic) occurs to make homozygous
recessive phenotype due to “one-hit” mutation
non-susceptibility cancers require “two-hit” mutations
inherit Aa
somatic mutation aa
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“One-hit” cancers are more common
inherited susceptibility genes are recessive
all cells contain heterozygous mutation
only need some cells to acquire 2nd mutation
cells have to receive mutations in both alleles
cells only need one mutation because other mutation is already present
high penetrance, early-onset
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“One-hit” cancers are more common
dominant somatic mutations
occur sporadically
cancer susceptibility not needed for “one-hit”
single mutation causes disease
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Phenotype of cancer cells
stem cell-like appearance
changes in cell surface antigens
heritable mutations
transplantable
dedifferentiated
unusual growth
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Phenotype of Cancer Cells
lack of contact inhibition
invasive: squeeze into any space available
metastatic: move to new location in body
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Phenotype of Cancer Cells
induce angiogenesis
form new capillaries for blood flow
secrete hormones to stimulate own growth
aneuploid chromosomes
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Development of clinical cancer
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Origins of Cancer Cells
begins at the cellular level:
activation of stem cells to produce cancer cells
e.g., brain tumors
dedifferentiation
e.g., melanoma
increase in stem or progenitor cells
e.g., basal cell carcinoma
faulty tissue repair
e.g., lung mesothelioma
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Activation of stem cells to produce cancer cells
normal pathway of differentiation
cancerous pathway of non-differentiation
mutations can occur in stem cell to produce daughter cells that self-renew and/or specialized cells that self-renew
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Dedifferentiation reverses specialization
specialized cells lose phenotype of specialization
mutations accumulate to further lose phenotype of specialization stem-like
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Increase in stem or progenitor cells
in basal cell carcinoma, proliferation of basal stem cells increases chance of tumor formation
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Faulty tissue repair
in lung mesothelioma, asbestos or fiberglass irritates tissues
Identifying cancer mutations
driver mutations
provide selective growth advantage to cancer cell
proto-oncogenes or tumor suppressor genes
single-gene mutations or chromosome changes
~130 known genes
passenger mutations
byproduct of cancer (>99% of mutations in cancer)
no effect on cancer growth or spread
occur in cancerous and noncancerous cells
Driver mutations cause cancer
cumulative effect, 2 to 8 mutations
first mutation is the “gatekeeper”
enables a normal cell to divide slightly faster than others
clone of faster-dividing cells gradually accumulates
second mutation boosts the division rate
proportion of second mutation cells increases
tumors that are visible are >1 billion cells
Driver mutations cause cancer
driver mutations identified by:
comparing mutations in tumor cells
people at different stages of the same cancer
patients who respond to a drug and then relapse
Step-wise nature of cancer
Familial Adenomatous Polyposis (FAP)
affects 1 in 5,000 people in the U.S.
causes multiple polyps at an early age
cells do not apoptose, assemble into polyps
several mutations in cell cycle, apoptosis pathways
gatekeeper APC gene deletion
so β-catenin is not silenced; promotes mitosis
activation of oncogenes (e.g., K-Ras)
changes in TGF-β, p53, and other driver genes
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Mutations that Drive FAP Colon Cancer
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Evolution of a Cancer
simplistic view of genetic changes in cancer progression
complex view of cancer progression is more realistic–
cancer is an inherited form of genome instability
original cancer cell (gatekeeper mutated)
daughter cells with “private” mutations
natural selection of best reproducer cells
Chromosomes in cancer
rapid divisions do not allow repair
abnormal in number and/or structure
translocations, inversions, pieces missing or extra
translocation with
breakpoint effects
change expression of oncogene
duplication of copy number of
oncogene
deletion of tumor suppressor
gene
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Oncogenes can drive cancer progression
proto-oncogenes promote cell division
normal expression in cell cycle
misexpression function as oncogenes
activation (over-activation) associated with:
point mutation
chromosomal translocation
inversion
insertion
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Oncogene overexpression
virus integration next to proto-oncogene
transcription when virus is transcribed
retroviral insertion into genome
e.g., HPV in cervical cancer
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Oncogene overexpression
translocation into transcriptionally active area
moved next to an actively transcribed gene
glands synthesize hormones regularly
antibody genes are transcribed during infection
e.g., Burkitt lymphoma with Epstein-Barr virus and t(8;14)
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Oncogene overexpression
fusion proteins due to translocation
transcribed together, translates novel oncogenic protein
e.g., acute promyelocytic leukemia (APL) and t(15;17)
fusion of retinoic acid receptor and myl oncogene
acts as transcription factor
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Oncogene overexpression
fusion proteins due to translocation
transcribed together, translates novel oncogenic protein
e.g., chronic myelogenous leukemia (CML) and t(9;22)
Philadelphia chromosome bcr/abl fusion tyrosine kinase
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Oncogene overexpression
excessive response to growth factor
cell surface receptors and signalling
e.g., HER2 signalling in breast cancer
epidermal growth factor receptor (normally 20k-100k copies)
overexpressed on cell surface (1-2 million copies)
monoclonal antibodies to HER2 receptor can control proliferation by blocking extra receptors
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Tumor suppressor silencing
loss or silencing of a tumor suppressor gene
normally inhibits expression of pro-cancer genes
e.g., Wilm’s tumor gene
normally stops mitosis in developing fetus kidney tubules
suppressing gene allows continued mitosis, prenatal tumors
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Tumor suppressor silencing
loss or silencing of a tumor suppressor gene
normally inhibits expression of pro-cancer genes
e.g., Retinoblastoma and Rb gene
inherited susceptibility (“one-hit”) or somatic (“two-hit”)
autosomal recessive on chromosome 13
32
Rb protein normally sequesters proto-oncogene transcription factors (pro-mitosis proteins) in G1
absence of Rb allows mitosis to continue unchecked
this tumor originates in a cone cell of the retina
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DNA Repair Mechanisms
ataxia telangiectasia 2-6 fold cancer risk
xeroderma pigmentosum increased skin cancer risk
HNPCC increased colon cancer risk
p53 is a fail-safe
determines cell fate
repair DNA errors or die by apoptosis
> 50% of human cancers have abnormal p53
usually acquired mutations in somatic cells
inherited Li-Fraumeni syndrome
mutation in one copy of p53, susceptibility
very high risk of developing cancer
50% by age 30, 90% by age 70
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p53 cancers reflect environmental insults
Breast Cancer is a defect in repair
heterogeneous disease
familial form in BRCA1/BRCA2 genes
germline mutation and later somatic mutation
multiple exposures, two somatic mutations in same cell
sporadic form in BRCA1/BRCA2 genes
two somatic mutations in the same cell
at least 20 genes as gatekeepers
BRCA1/BRCA2 only in 15-20% of inherited cancers
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BRCA– Breast Cancer susceptibility
breast-cancer genes BRCA1, BRCA2
BRCA1 interacts with proteins, prevent DNA damage
mutant BRCA2 increases risk of other cancers
colon, kidney, prostate, pancreas, gallbladder, skin, stomach
autosomal dominant inheritance with decreased penetrance
BRCA1 incidence
1/833 of U.S. population
10% risk of disease
1/50 in Ashkenazi Jewish population
87% risk of disease
BRCA2 incidence and risk is similar
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Environmental Causes of Cancer
environmental factors contribute to cancer
interaction between genes and environment
mutating or altering the expression of genes
control of cell cycle, apoptosis, and/or DNA repair
population studies
associate disease “phenotype” with risk
e.g., study farmers with non-Hodgkin’s lymphoma
identify specific risks within the study group
translocations and pesticide use
Protection from cancer development
population studies to determine protection
noncancer “phenotype” associated with protection
e.g., dietary studies
mutations in driver genes that promote cancer growth
increased metabolites = increased risk of mutation = increased risk of mutation in important driver gene
Diagnosing and treating cancer
cancer is heterogeneous
no two cancer cells are the same
treatment
surgery can remove a solid tumor
radiation/chemotherapy
non-selective destruction of rapidly dividing cells
gene-based therapy
matched to tumor type
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Diagnosing and treating cancer
cancer is heterogeneous
categorized by body part, but genetically different
diagnosis through imaging is limited
tumors are very big if already visible
diagnosis through sequencing is specific
cancer exomes and genomes
cell-free tumor DNA (ctDNA) “liquid biopsy”
genetic information to stratify patients
appropriate treatment options for tumor types
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Cancer cells that look alike may be genetically distinct
columns represent individual tumors
rows represent individual genes
red represents increased expression
blue represents decreased expression
ALL=acute lymphoblastic leukemia; MLL=mixed lineage leukemia; AML=acute myelogenous leukemia