MCM 2-14 & 2-15 Cancer Genetics I & II Flashcards Preview

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Flashcards in MCM 2-14 & 2-15 Cancer Genetics I & II Deck (38)
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dominantly acting genes involved in unregulated cell growth and proliferation.

-appear in humans via viral transduction or activation of proto-oncogenes


describe proto-oncogones

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.


Li-Fraumeni Syndrome

familiar cancer syndrome (inherited)

associated with increased cancer risk of various phenotypes (depending on environmental factors) due to inherited mutation of p53


breast cancer

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

B. Smoking

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.


Familial forms of cancer usually occur earlier in life because only a single mutation is required for disease expression. tf


Familial cancers are usually due to mutations in tumor suppressor genes. Thus, this question is false for 2 reasons. First, TWO mutations in the specific tumor suppressor are required for disease expression. The statement says "ONLY a SINGLE mutation is required", so that is completely wrong. Just because one mutation is inherited doesn't mean that you discount it. It is one of the 2 mutations that are required for disease expression. Secondly, familial cancer requires mutations not only in the primary disease causing gene, but in several other genes as well (remember the cancer pathway from lecture). So, we are talking about 2 mutations in the primary tumor suppressor plus 2 mutations in 1-3 accessory tumor suppressors and single mutations in one or more proto-oncogenes. The point is that for cancer to occur, it is a complex process involving multiple genes and many mutations. To say that a single mutation is sufficient to cause any cancer is completely inaccurate. In familial cancer, one mutation is inherited but the second must occur at the somatic level. These cancers present relative early in life because the probability of the second mutation is high. If both mutations occur at the somatic level, the disease will occur later in life because it takes more time for both mutations to occur by chance.

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