Flashcards in MCM 2-14 & 2-15 Cancer Genetics I & II Deck (38)
dominantly acting genes involved in unregulated cell growth and proliferation.
-appear in humans via viral transduction or activation of proto-oncogenes
important housekeeping genes involved in cell proliferation and development
encode growth factors, cell surface receptors, and cell cycle regulators
precise effect on cell depends on what proto-oncogene is mutated. in general, the mutation of a proto-oncogene is a gain of function mutation that leads to tumorigenesis.
mutations act dominantly, only one mutated allele is neeeded for negative effects to manifest
most proto oncogene mutations result in
leukemias and lymphomas
describe tumor suppressors
genetic elements whose normal function including mediating cell-cell interactions, regulation of growth inhibitory substances, and cell proliferation.
the loss of inactivation of these allows the cell to display an alternate phenotype leading to neoplastic growth
mutation acts recessively, two mutated alleles are needed.
describe the inheritance pattern of oncogene mutations, tumor suppressor mutations, and DNA repair mutations
oncogone mutations - dominantly acting, only one mutated allele is enough to cause illness
tumor suppressors - recessive. two mutated alleles are needed for negative effects to manifest. Somatic mutations tend to have onset later in life as it takes time to acquire the mutations in the single cell. Inherited (familiar) mutations tend to have earlier onset
DNA repair genes - recessive mode of inheritance, can be inherited or acquired
DNA repair gene defects
defects in these genes leads to an inabiltiy to repair DNA defects/mutations, leading to increased genome instability, highetining the risk of widespread mutations that may effect tumor suppressors or proto-oncogenes
DNA repair gene defects can lead to what diseases?
lead to genome instability which causes chromosome breakage syndromes
xeroderma pigmentosum and HNPCC
Chronic Myelogenous Leukemia (CML)
common leukemia caused by oncogene activation
-first cancer associated with cytogenic marker (trnslatocation of chromsosomes 9 and 22)
-longer 9 and altered 22 (philadelphia chromosome)
discovery allows physicians to develope a drug that attacks the specific mutant protein that causes disease
loss of function mutation in the RB1 tumor supressor, leads to loss of mitotic checkpoint between G1 and S leading to uncontrolled growth.
common RB1 mutation is deletion, generally the first abnormality looked for when screening for Rb1 mutations
unilateral (one tumor) disease is sporatic (random), while bilateral (multiple tumors in one or both eyes) is inherited.
autosomal recessive inheritance, but which high rate of sporatic mutation of second allele in those with inherited mutant allele.
familiar cancer syndrome (inherited)
associated with increased cancer risk of various phenotypes (depending on environmental factors) due to inherited mutation of p53
familiar OR sporatic, due to mutations in homo recombination or DNA repair defects
BRCA1,2 are two genes that are associated with DNA repair defects and occur in 90% of familiar cases.
because familiar cases are less than 10%, BRCA 1 and 2 account for only 5-9% of breast cancers. In most cases the sporatic mutations are predominant, there are multiple mutations involved.
describe clonal expansion
cancer tumors tend to be clonal. cell metabolism/proliferation triggers the cell into a different pathway. these mutations are often deleterious, but some will survive and form a new cell line.
how are cancers named?
by primary tissue of organ
a primary cancer which has metastasized to a secondary area is known by the primary classification (aka, breast cancer that spread to the liver). The cancer cells in the liver will be breast cancer cells.
constitutional vs acquired anomalies
constitutional findings - present in zygote, basic genetic constitution. Anything that happens to this DNA after this point are acquired changes
Acquired changes- occurs to DNA afterwards, this is normal, and often get cleared up by maintenance enzymes in the cells. But when not cleared, can sometimes lead to cancer
driver vs passenger
driver - the mutation immediately involved with cancer or changes in cell leading to cancer
passenger - mutations which have not been seen in direct correlation, may be random
a cancerous karyotype which is badly mutated, can be difficult to determine which mutation lead to the cancer, and which is a side effect of the genomic instability cause by the primary mutation
Primary driver genes are classified into
mutations of genes involved in cell death or proliferation
mutations of genes involved in genomic integrity or expression
Point - there are many targets in the cell, many points where errors can occur and cause cancer.
proteo-oncogenes can be subject to many different types of mutations. What effects does this have?
this leads to many different possibly changes in the product that is formed.
regulatory mutation may cause excess protein to be created
while translocation mutations may create a new novel protein
normal vs abnormal findings of FISH in CML
normal - two red and two green, showing we have two distinct copies of chromosome 17 and 15
abnormal - 1 green, 1 red, and two yellow as a result of the mutual translocation between the two chromosomes
using microsattelites to find repeats suggesting a defect in mismatch repair what what type of testing?
indirect testing, we are not looking for mutation itself but looking for the effects of the mutation
Proto oncogene summary
dominantly acting, acquired, chromosome translocation, amplification, point mutation
primary target - leukemias/lymphomas
gain or change of function
tumor supressor summary
recessive - 1 mutation is enough
deletions, chromosomal gain/loss, gene mutation
-primary target -solid tumors
-loss of function mutation
describe cancer evolution
series of mutations that occur, generally in a stepwise fashion, leading to cancer and possibly metastasis. Each step is a mutation in a particular "Gatekeeper" gene, and must have all of these mutations in a single cell.
we are most concerned about the first step or "Trigger step" which often causes the cascade. This trigger step is already present in those who have inherited the mutation on one allele.
how do we determine if a patient is getting better or worse
we must take a baseline at the time of diagnosis
people with downs syndrome are more susceptible to leukemia. Why or why not?
The trisomy 21 constitutional karyotype that they are born with.
how do we determine if a bone marrow transplant is succssful
should do mixed sex
example) female donor, male recipient
after clearing out the patients cells with radiation, graft the female donors cells in
a suceessful transplant will show very few circulating XY (if any) and a majority of XX in the male patient
an unsuccessful tranplant will show few XX in the male and many XY via FISH
Genetics and Cancer summary
mutations may be inherited and/or acquired
somatic mutation is usually required for disease expression
disease is due to multistep process at somatic cell level
inherited cancers summary
carrier parent has 50% chance of passing mutation
second mutation occurs at somatic level
risk is correlated to number and degree of affected relatives
inherited mutation -> increased RISK of acquiring disease, it is not guaranteed.
Primary genetic causes of cancer can be linked to
many disease now have
new technologies are proving..
oncogenes/protooncogenes and tumor suppressor gene mutations
clinical testing available
new diagnostic methods and new treatments
Which of the following is NOT a risk factor for cancer?
A. Trisomy 21
C. Exposure to ultraviolet light
D. A constitutional translocation
E. All of the above ARE risk factors.
A-C are definitely risk factors for cancer. A constitutional translocation is NOT. Constitutional translocations are inherited, usually as completely benign elements in a person's chromosome complement. It may not be know the translocation even exists until it is detected as a result of a meiotic error. A translocation may arise de novo in a zygote, and again will be benign unless the breakpoints interrupt an important gene. The only type of translocation that was presented as a risk factor for cancer were acquired translocations that occurred in a clone of abnormal cells.