Cancer Of The Breasts, Ovaries, Or Colon (Molecular Bio)

Front 1

True or False:
Most forms of breast cancer occur sporadically due to mutations in somatic cells?

Back 1

TRUE: most forms of breast cancer do occur sporadically due to mutations in somatic cells.

Front 2

What percentage of patients with breast cancer have a mutation in either BRCA1 or the BRCA2?
a) 2%
b)5%
c)10%
d) 15%

Back 2

b) 5%

Front 3

How is breast cancer treated?

Back 3

Typically with surgery, radiation, chemotherapy and adjuvant drug therapy.

Front 4

I'd describe ovarian cancer as particularly virulent upon diagnosis. What's one reason why this is an apt description?

Back 4

Because at dx the disease is often already at an advanced stage. After dx, 5-year survival is only 35%.

Front 5

What is the typical treatment for ovarian cancer?

Back 5

Surgery and chemotherapy with platinates and taxanes (taxanes stabilize the microtubules).

Front 6

True or False:

About 10% of all patients with ovarian cancer have hereditary ovarian cancer and most of this is due to a BRCA2 mutation?

Back 6

False. Most of the 10% is due to a BRCA1 mutation.

Front 7

What is the BRCA1 protein's normal role/function?

Back 7

It is a tumor suppressor involved in DNA repair.

Front 8

What triggers the BRCA1 protein to work?

Back 8

Several proteins lead to the activation of certain kinases in response to DNA damage. These kinases then phosphorylate BRCA1 to activate it.

Front 9

How, exactly, does BRCA1 go about its activity once activated?

Back 9

BRCA1 complexes with BARD1. This complex has E3 ubiquitin ligase activity and thus plays a role in DNA repair and the control of the cell cycle (read: not all ubiquitin leads to degradation of a protein).

Front 10

Where on the BRCA1 gene does pathogenic mutation often occur?

Back 10

On the part that's important to the binding of E2.

Front 11

Describe the role BRCA1 plays in homologous recombination repair.

Back 11

DNA double-strand breaks due to stalled replication or from drug-induced interstrand cross links (i.e. platinum drugs, nitrogen mustards, or psoralens) are resected by an enzyme on one strand so that the base-paired strands of the fragments have unequal lengths(i.e. there is an overhang). The overhang then invades the homologous chromosome, which is used as a template for synthesis of the missing DNA region.

Front 12

Relative to BRCA1 and BRCA2 mutation, mutation of which offers a higher risk of cancer development?

Back 12

BRCA1.A woman with a BRCA1 mutation has a 70% lifetime chance of having breast cancer and a 35% lifetime chance of ovarian cancer. These are slightly lower for BRCA2 mutations.

Front 13

What is BRCA2s role/function?

Back 13

Like BRCA1, it too is involved in DNA repair. Though it is not yet known how.

Front 14

Describe the pathogenesis of heritable breast and ovarian cancer.

Back 14

1)A pt inherits 1 good and 1 bad BRCA allele from their 'rents.2)Cells in the breast or ovaries lose or inactivate the 1 good copy.3) W/out BRCA, cells accumulate mutations and become tumors.

Front 15

Are breast tumors w/BRCA1 mutations usually estrogen receptor negative or positive and what's the significance of it?

Back 15

They are estrogen receptor negative. So they do not have estrogen receptors and are not affected by treatments that impact estrogen in the body.

Front 16

Are breast tumors with a BRCA2 mutation estrogen receptor positive or negative? What's the significance of that?

Back 16

They are estrogen receptor positive, so they do respond to the presence of estrogen.

Front 17

What is/are the name/s of the treatment/s used for the positive estrogen receptors of BRCA2 mutations and what does/do it/they do?

Back 17

It's Tamoxifen (a selective estrogen receptor modulator) and aromatase inhibitors (which diminish the production of 17 beta-estradiol & estrone which, in turn, stops the production of estrogen. Thus depriving the tumor of estrogen).

Front 18

In sporadic ovarian cancer up to 80% of tumors have lost BRCA1 function due to spontaneous genetic alterations. What is the the most prevalent alteration of those found?

Back 18

Hypermethylation; which accounts for 25% of these alterations

Front 19

True or False:
Concerning tumors of the ovaries, loss of 1 parent's allele plus duplication of the other parent's allele is less common among patients who carry a BRCA1 or BRCA2 mutation than those who are wild-type (i.e. have the typical, normal allele)?

Back 19

False. It is MORE common.

Front 20

What are the 2 main, general causes of colon tumors?

Back 20

1) Large-scale alterations of chromosomes
2) Defective DNA mismatch repair

Sidenote: 80-85% have unstable chromosomes.

Front 21

What is lynch syndrome and what, generally, causes it?

Back 21

It's a hereditary predisposisition to malignancy that is explained by a germline mutation in a DNA mismatch repair gene. It is autosomal dominant.

sidenote: Only 3% of all people with colon cancer have Lynch Syndrome.

Front 22

What is FAP and how is it caused?

Back 22

FAP (Familial adenomatous polyposis)is a type of tumor caused by a mutation in the APC gene(which is a tumor suppressor gene).

sidenote:1:15 Ashkenazi Jewish people have FAP, giving them a 15% lifetime risk of developing colon cancer. Whereas for non-Ashkenazi Jewish people w/FAP, there is a 100% risk by age 40.

Front 23

What is a key FAP symptom?

Back 23

The APC mutation often leads to hundreds of thousands of polyps; usually starting in puberty.

Front 24

Describe how APC normally functions.

Back 24

When there is no Wnt protein bound to the cell surface receptor, APC is free to degrade Beta-Catenin found in the cytosol. When a Wnt protein IS bound to the cell surface, the APC protein is inhibited from degrading Beta-Catenin. The Beta-Catenin then is free to bind to the DNA as a transcription factor; stimulating transcription.

Front 25

What inhibitor can reduce the number of polyps formed?

Back 25

COX2

Front 26

What is the sequence of events leading from the APC gene mutation to colon cancer?

Back 26

1)Mutation of APC gene (deletion of function), 2)mutation in the KRAS gene (a ras protien that activated raf and p14K in response to growth factors; proto to oncogene), 3)mutaion in the DCC(deleted colon cancer) gene(a tumor suppressor of essentially unknown function), 4)mutation in the TP53 gene(codes for p53, a tumor suppressor) and 5) other mutations.

Front 27

What 2 proteins are REQUIRED for normal DNA mismatch repair?

Back 27

MLH1 and MSH2

Front 28

Describe what happens when APC is non-functional (i.e.mutated).

Back 28

Beta-Catenin is free to act as a transcription faction to stimulate transcription ALL of the time. Regardless of whether Wnt is bound to the surface receptor or not. This leads tumor formation.

Front 29

What is the function of the MSH2-MSH6 complex?

Back 29

It is required for repair of single-nucleotide mismatches and extra or missing nucleotides in mononucleotide tracts.

sidenote: MLH1 is also needed in this process (it acts as an endonuclease in this process).

Front 30

True or False: Even if you have a dysfunctional MLH1, as long as you have a functional MSH2 you will display at least SOME repair of DNA mismatches.

Back 30

False. "Patients who have either no functioning MSH2 or no functioning MLH1 display no mismatch repair at all."

Front 31

True or False: MSH6 is only required for MMR (mismatch repair) in mononucleotide tracts, not in dinucleotide tracts.

Back 31

True.

Front 32

True or False:
In Lynch syndrome, cancers occur at an unusually late age.

Back 32

False. It occurs at an unusually EARLY age. The average is 44 years old.

Front 33

Define "Classic Lynch Syndrome."

Back 33

This is when the patient has both an MLH1 and a MSH2 mitation so that there is no MMR.

sidenote:This is the case in 90% of those who have Lynch Syndrome.

Front 34

True or False:
In Lynch Syndrome where there is only a mutation in MSH6, there is only reduced MMR.

Back 34

True. Patient still retains some MMR functioning.

Front 35

What causes microsatellite instability?

Back 35

Defective MMR primarily leads to microsatelite instability.

Front 36

What do high MSI (microsatelite instability) and low MSI correspond to?

Back 36

High MSI is when there are 2 or more loci deletions or expansions found in the tumor and low MSI is when there is only 1.

sidenote: if all loci are stable, a tumor is said to have notmal MMR.

Front 37

Name one gene that has a microsatellite that defective MMR can affect.

Back 37

TGFBR2, BAX, or MSH6.

Front 38

True or False:
In patients w/an acquired defect in MMR, the promoter for MLH1 is hyperacetylated; which means that the MLH1 gene is not transcribed.

Back 38

False. In this case, the MLH1 is hypermethylated.
This lack of MLH1 means that there is no DNA MMR.

Front 39

Describe, generally, they typical treatment for colon cancer.

Back 39

Surgery. Many patients receive adjuvant chemotherapy involvingleucovorin, oxaliplatin, irinitecan, capecitabine and 5-fluorouracil.

Front 40

Which type of patient with colon cancer may be HARMED by taking 5-flurouracil?

Back 40

Patients who have tumores w/microsatelite instability (in at least 2 of 5 loci).

i.e. those with dysfunctional MMR mechanisms.