Download Genetics Chapter 11 [4-20

Genetics Chapter 11: Cancer Genetics (page 212-221)
Cancer – uncontrolled cell growth
Neoplasm/tumor – mass of cancer cells
Tumorigenesis – formation of tumors
To grow as much as tumors do, you need more growth signals to be made, and inhibition of signals that
would prevent growth
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Normally, cells that do this would trigger apoptosis, but cancers somehow disable apoptosis
The growing tumor needs nourishment, so a new blood supply is gotten through angiogenesis (making
new blood vessels)
Malignant – invasive, invades nearby tissues
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Malignant is considered when it is able to invade and metastasize
If it can’t do those, the tumor is benign
Metastasis – spreads
Tumors are classified according to the tissue type they arise in
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Carcinoma – malignant epithelial tissue tumor, most common tumor
Sarcoma – connective tissue tumor
Lymphoma – lymphatic tissue tumor
Glioma – glial cell and CNS tumor
Leukemia – comes from hematopoetic cells
The cells that make up a tumor are all derived from a single ancestor cell, making them a single clone,
called monoclonal
Carcinogenesis – cancer development
The basic cause of cancer is damage to specific genes
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Usually, mutations in these genes accumulate in somatic cells over years, until a cell
accumulates enough errors to cause a tumor
Most of the genetic events that cause cancer happen in somatic cells
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Somatic cell mutations won’t be passed on to future generations
Cancer in germline cells can pass the cancer mutation on from one generation to the next
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Usually it just takes damage to one allele
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Since one is already damaged, the chances of getting another during life are good, so the
chances that person will get a tumor is good
o Also, all their cells received the mutation, so it just takes one cell getting one more
mutation to lead to tumor
The environment also affects cell growth, and is involved in cancer
Regulation of cell growth:
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Growth factors (like PDGF, EGF, and steroids) bind to cell surface growth factor receptors
o This triggers signal transduction
 Signal transducers include protein kinases (ex: src tyrosine kinase), mitogenactivated protein kinase (MAPK), and jun kinase (JunK)
 These work by tagging target proteins with a phosphate, called phosphorylation
 This all leads to regulating DNA transcription in the nucleus
 The target proteins regulate transcription factors that regulate genes that make
proteins for cell growth and proliferation
 Example genes: MYC, FOS, and JUN
After enough rounds of cell division, cells usually get signals that tell them to stop proliferating,
and to differentiate into specialized cells
o Works by turning off the cell growth genes, and turning on genes to prevent entry into
the cell cycle
Mutations to these genes for cell growth can lead to a cell that doesn’t stop proliferating
o Usually takes an accumulation of mutations to several genes to lead to progeny that do
this
Inherited retinoblastoma has tumors in both eyes, while sporadic retinoblastoma only has a tumor in
one eye
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Inherited – has an affected parent, and kids can get it
Sporadic – no risk of anyone else having it
Two hit model of carcinogenesis – idea that it takes two mutations at least to lead to inherited cancer:
1 mutation in the germline that’s passed on, and then another that converts the already mutated
progeny into a cancer cell
Constitutional mutation – mutation present in all cells of the body
In sporadic cases, both mutations would have to happen somatically in the developing fetus
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Makes it far more unlikely, and is why even if it does happen, like in sporadic retinoblastoma,
they only get one tumor, and not two, cause that’s even more unlikely to happen randomly
Retinoblastoma – first mutation is a germline mutation to RB1, that causes loss of function
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Now the progeny just need one more mutation to cause cancer
The second hit happens in the fetus when retinoblasts are rapidly dividing and proliferating
o This mutation actually removes the remaining normal gene, leaving behind just the
mutant allele, so it has to be expressed
o This shows that if you have the normal allele, even if the other is mutated, you won’t get
tumors
So retinoblastoma can only happen when there’s 2 mutations
Familial retinoblastoma starts you off with one right away, so it just takes one more to express it
Sporadic takes developing 2 mutations randomly, which is way less likely
Page 217 – table of tumor suppressor genes and DNA repair genes
3 classes of cancer causing genes:
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Tumor suppressors – normally inhibit cell proliferation
Oncogenes – activate proliferation
DNA repair genes
Tumor suppressor genes – normally would block the uncontrolled cell proliferation that leads to cancer
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RB1 was the first discovered tumor suppressor gene
For tumor suppressor genes, heterozygotes usually will express the disease, even though a
heterozygote genotype is autosomal recessive and will not
o It’s because the chances of them getting that second mutation to make the cell
homozygous at some point are really high
o So the first hit is called an autosomal dominant trait, not because that genotype causes
cancer, but because it is super likely another mutation will happen and THAT will cause
cancer
Cell cycle for RB1 – page 218
o RB1 codes for the protein pRb
o Normally, pRb binds to the E2F transcription complex, which inactivates the complex
 E2F needs to be active in order to progress into the S phase, so if you inactivate
it, you stop the cell cycle
o pRb is inactivated when it gets phosphorylated by cyclin dependent kinases (CDKs) just
before the S phase of the cell cycle
o The cell then goes through the cell cycle until pRb is activated again by removing the
phosphate
o A loss of function mutation, deletion, or hypermethylation of the 5’ region of RB1 gene,
will permanently inactivate it, causing uncontrolled division
A lot of tumor suppressor genes code for CDK inhibitors, which inactivate CDKs, preventing
them from inactivating proteins that inhibit the cell cycle
Most tumor suppressor genes are known to cause germline mutations that can cause
inherited cancer syndromes
Oncogenes (aka cancer genes) – genes that can cause cancer
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Oncogenes originate from proto-oncogenes
Proto-oncogenes are genes that work in the 4 basic regulators of normal cell growth:
o Growth factors, growth factor receptors, signal transduction molecules, and nucleus
transcription factors
Mutations to proto-oncogenes turn them into oncogenes, whose excessively active product can
lead to unregulated cell growth and differentiation
When a cell proceeds from regulated to unregulated growth, the cell is said to have transformed
Unlike tumor suppressor genes, oncogenes are usually dominant in cells
o So only a single mutated copy of the oncogene is needed to cause a tumor
Also unlike tumor suppressor genes, oncogenes are activated by gain-of-function mutations,
gene amplification (increased #’s of the gene are made), hypomethylation of the oncogene’s 5’
region (increases transcription), or chromosome rearrangements that increase the oncogene’s
expression
o So adding a methyl to a gene silences it, and removing it expresses it
Germline oncogene mutations that cause inherited cancer syndromes are uncommon
o Instead, oncogenes are usually sporadic
Page 219 – differences between oncogenes and tumor suppressor genes
One way of getting oncogenes is from retrovirues
o Retroviruses use reverse transcriptase to transcripe its RNA into DNA, and then can
insert that DNA into a host chromosome
o Some retroviruses carry altered versions of growth-promoting oncogenes genes into
cells
RAS stands for Rat Sarcoma – an oncogene found in ¼ of cancers
o The RAS protein normally cycles between an active form bound to GTP, and an inactive
form bound to GDP
o Mutated RAS proteins can’t unbind GTP, so growth keeps happening
Philadelphia chromosome happens from translocation of the gene
o It moves the proto-oncogene ABL next to the BCR (B cell receptor) gene, which
enhances tyrosine kinase activity to cause myelogenous leukemia
ERBB2 (aka HER2/NEU) is the oncogene for the receptor to EGF (epidermal growth factor)
o It’s seen in up to 1/3 of breast cancers
Page 220 – table of oncogenes
DNA repair genes:
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Tumor cells usually have lots of mutations, chromosome breaks, and aneuploidy, a trait called
genomic instability
o Genomic instability can lead to activation of oncogenes, or deactivation of tumor
suppressor genes
Genomic instability can also lead to mutations to genes that work to repair these damages
Most DNA repair mutations are somatic and not inherited
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BRCA1 and BRCA2 mutations cause breast cancer by defective repair of double stranded
breaks in DNA, like from radiation
Aneuploidy can cause cancer by creating extra copies of oncogenes, or by deleting tumor
suppressor genes
Page 217 – table of DNA repair mutations
Even after a tumor cell has escaped regulation by tumor suppressors or DNA repair proteins, it must still
overcome the hurdle of the intrinsic limitation each cell has on how many times it can divide
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Usually, a cell can divide about 50-70 times, and then becomes senescent, and won’t divide
Each time a cell divides, the telomeres of chromosomes shorten slightly, because DNA
polymerase can’t replicate the tips of chromosomes
Once the telomere is reduced to a critical length, a signal is sent that causes the cell to become
senescent
Tumor cells overcome this by activating a gene that encodes telomerase, a reverse transcriptase
that replaces the telomere segments normally lost during cell division
Activation of telomerase is rarely present in animal cells, but very present in tumor cells