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Exam3Lec6CancerGenetics Flashcards

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1
Q

How do you get cancer?

A

Mutation in regulatory proteins, can be inherited or arise through age/development

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2
Q

Almost all cancers require how many mutations?

A

MORE THAN ONE

remeber example with BRCA1
Just bc you have one mutation does not mean you will get cancer, you have incr chance

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3
Q

How can cancers can effect different cell functions?

A

Divide with not control
Stop cell death pathways (live forever) programmed cell death = apoptosis
Migration (angiogenesis)

Metastasis = Migrated to other organ

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4
Q

Family hx can indicate predisposition to cancer, may have ____ penetrance.

A

low

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5
Q

Research: about Rb-Raf-1 interaction disruptor RRD-251 induces apoptosis in metastatic melanoma cells and synergizes with decarbazine

A

RRD-251 = Inhibits melanoma cell proliferation.
and also Downregulates thymidylate synthase

RRD-251 is a drug that causes cell to die with RaF interaction, so it inhibits melanoma prolif and causes down regulation of thy synth\

SIMILAR TI VEMARFUNIB

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6
Q

In the case, RRD-251 leads to apoptosis. If RRD-251 resulted in G1 arrest, what would be the mechanism of that effect?

A

Prevents the binding of RAF kinase to Rb, cannot complete pw so arrested in G1

you are stuck at G1

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7
Q

How is RRD-251 different from PLX 4032, mentioned in the presentation?

A

-PLX 4032 is selective v600E mutation, RRD 251 is NOT

RRD not selective

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8
Q

What is the connection between methotrexate mechanism of action and RRD-251?

A

RRD 251 decreases thymidylate synthase, while methotrexate inhibits DHFR which provides the substrate for thymidylate synthase. BOTH inhibits thymine production and this DNA replication

both inhibit thymidylate synthase, but one straght up inhinits the enzyme, the other inhibits the substrate for thymidine synth (DHFR)

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9
Q

Review: Explain cell cycle

A

G1: prepare for replication
S: DNA replication
G2: prepare for mitosis
M: mitosis

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10
Q

Explain how the cell cycle can be regulated

A
  1. Peptide binds to a receptor ( this can be an integrin which is a full length protein like HLA)
  2. This activates MYC and RAS genes and activates synthesis of Cyclin D and it interacts with CDK4.
  3. RB is phosph (inactive) and E2F is free. E2F interacts with Cyclin E and A. This activates DNA replication
  4. The cell cycle can be blocked by P21, p27, p16, p14
  5. If p16 interacts with CDK4, RB is not phosph, if RB is not phosp so it brings in an HDAC=less interaction/
  6. In the event of DNA damage and cell stress, p53 causes cell arrest.

cell cycle can be blocked with anything that starts with a p
Remember RB removes the acetyl group inactivating E2F (Transactivator that binds in HAT)
HDAC=remove acetyl from lysine, leading to less + charge and less interaction

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11
Q

Dihydrofolate reductase gene (DHFR): has binding Site to what?

A

E2F, this means that E2F also participates in making thymine (thymidine synthase)

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12
Q

Explain the Control of cellular proliferation by retinoblastoma.

A

When the retinoblastoma protein (pRB) exists in the underphosphorylated state, it can block exit from G1 and progression of the cell cycle. (No replication)
IN other words
Rb is NOT phos phos, RB is free, it brings in a HDAC, it it closes genome

P16 commonly mutated in melonama
phos RB= inactive
E2F=activation
RB-E2F=no replication

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13
Q

Mutations in RB and P16 have the ____ effect

A

same

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14
Q

Explain the molecular basis of cancer

How do we get cancer?

A

Normal cell gets DNAdamage, usually you can repair it, if you fail to repair, you get mutations. These mutations can cause proliferative effects such as Increase oncogenes , Decrease Tumor suppressor genes , and Alter Apoptosis (avoid death). It can start to dicvide, do angio genesis, escape immunse system, basically it does anything to survive, grow and spread. Note that you can inherit mutatation that affect DNA repair such as Guanine methyl transferase (removes methyl from guanine if mutated.

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15
Q

Many cancers are due to failure in ____

A

DNA repair

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16
Q

For Papilloma and Herpes, what can we do to help treat this?

A

We can use Gardasil whihc is a vaccination to help prevent tumor cells from escaping immunity.

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17
Q

Explain Ras Pathway

A

Tyrosine receptor signaling. Growth factor ligand causes the dimerization and autophosphorylation of tyrosines.

Bridging proteins (BRB2/SOS) bring the receptor into the vicinity of RAS, where it catalyzes guanine exchange on RAS.

The activated RAS associates with RAF1, a serine/threonine protein kinase,
and RAF1 then activates and phosphorylates MEK.

The MAP kinase cascade interacts with proteins that are translocated to the nucleus, where transcription factors are activated

An important transactivators is AP1. This encodes For interleukin 2 (IL2). Its an autocrine Growth factor for T cells [Common in T cell Leukemias]

v600E mutation= substitution of a glutamate mimics a phosphorylation activation process, because the glutamate residue has a carboxyl group, which like a phosphate group, has a strong negative charge
REMEMBER: BRAF V600E mutation can be tx by vemurafenib (PLX4032)

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18
Q

What is STAT3?

A

STAT3 is phosphorylated by by receptor associated kinase
Dimerizes, hides Phosphates, and translocate into nucleus
Binds to specific regulatory elements and causes transcription of genes important for S phase (replication)

similar to ras

STAT= Signal transducer and Activator of transcription

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19
Q

What is Burkitt’s Lymphoma?

A

The c-MYC gene wants to pro-proliferate so it translocated to Chomosome 14 which is close to IGH gene (H chain gens). We transcribef IGH alot leading to Burkitts Lymphoma.

In other words, The c-MYC gene is translocated downstream of the immunoglobulin heavy chain enhance (IGH). Expression of c-MYC is up-regulated by its position near the enhancer.

we translated an oncogene, whatever is next to that oncogene is going to be transcibed.

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20
Q

What is Chronic Myeloid Leukemia? (CML)

A

The ABL gene on chromosome 9 inserts into the BCR gene on chromosome 22 and creates an altered gene and protein ( this is called the philadelphia chromosome). This leads the CML

ABL and BCR fuse

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21
Q

Can we fuse BCR and ABL genes in different ways?

A

YES different parts of each gene are able to fuse to gether

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22
Q

What are 2 ways to get oncoproteins

A
  1. AA mutation like RAS/BRAF
  2. Chromosome translocation like
    BCR-ABL
    MYC + H enhancer
    NPM + ALK
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23
Q

What is Gleevec?

know this

A

It inhibits kinase activity of BCR-ABL fusion gene

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24
Q

Explain comparative genomic hybridization (CGH)

A

We are trying to find how much dna contents in tumor cells, so we are looking for unbalanced chromosome changes. An ex of this is double minutes, whihch is a small piece of chromosome that contains a high nunber of repeats. We also have HSR (homogeneously staining regions) by comparing the ratio. of the intesities of thetwo two fluorochromes along target chromosomes to indicate regions of DNA gain or loss.

detects HSR and double min.

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25
Q

What are the different results we can get with CGH?

A

If the tumor and the normal DNA are in the same amounts= intermediate color

If the tumor DNA is* over-represented* for a particular chromosome segment, the color will be green ( the blue one, in the pic.

Segment one of the chromosomes is under-represented in the tumor DNA, the color of that segment will be the color of the normal DNA

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26
Q

Does comparitive genomic hybridation detects reciprocal translocations?

A

NO these are balanced changes

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27
Q

Explain FISH with this pic

A

Fluorescence in situ hybridization with the probe MYCN.

A: Interphase nucleus with dmin and one HSR from patient 1.
B: Interphase nucleus with dmin and five HSRs from the same patient.
C: Metaphase cell with dmin and one HSR from patient 2.
D: Metaphase cell from the same case with dmin and two HSRs.

how we see dm and hsr

28
Q

What is Methotrexate?

A

Competitive inhibitor of DHFR
-DFHR is needed for thymine synthesis
-used in cancer and MS(multilpe sclerosis) to reduce T cell replication
-Tx with methotrexate is for individuals with **amplified DFHR genes **

29
Q

Causes of hereditary susceptibility to colorectal cancer. Single-gene mutations have been identified for HNPCC and FAP. Explain these mutations

A

Five mismatch repair genes have been identified in HNPCC.

Two of these MMR genes are responsible for a majority of cases, and genetics laboratories that offer
HNPCC testing examine only these two genes: M**LH1 and MSH2. **

HNPCC= Failure of MMR in the gene that creates mutated protein of the transforming growth factor beta 2 (TGFBR2); TGFBR2 activates RB to stop proliferation (mutated RB)

MMR= Exonuclease activity

30
Q

It was found that One in 40 Ashkenazi Jews carries a BRCA1 or BRCA2 mutation, demonstrating a founder effect. What are the functions of BRCA1 and BRCA2?

A

BRCA1 functions in several cellular processes that are important for controlling cell growth such as activation of kinetochore protein

BRCA 2= Recombination repair, double strand break, one strand of DNA invades the neighboring , forming triple helix

31
Q

What is mutated to cause ovarian cancer?

A

Both BRCA 1 AND BRCA 2, but Most genetic causes of ovarian cancer are associated with BRCA1 mutations (70%). Unlike breast cancer, familial clustering does not appear to occur in ovarian cancer families

32
Q

What is the role of P53 with cancer?

A

P53 mutation–> abnormal cells divide unchecked

The whole purpose is to stop cell growth. It increases p21and GADD45 which then inhibites CDK, so no replication occurs.

It also activates BAX which is a Proapoptotic and is upregulated by p53. Get this gene, the cell kills itslef (Make pores–>cytochrome C from mito (suicide)

33
Q

What inhibits p53 death?

A

BCL2, if theres an incr in P53, BCL2 will decr.

know this

34
Q

How does telomerase relate to cancer?

A

Telomerase binds to the 3’ end of a parental strand-the terminal sequences of the chromosome-and provides a template (ACCCCAAC) for synthesis in the 5’–>3’ direction.

The newly extended sequence serves as the template for synthesis on the opposite strand
CANCER CELLS HAVE LARGE AMOUNTS OF TELOMERASE (keeps adding this so it doesnt die)

35
Q

Telomerase has a ____ template and undergoes ____ synthesis which means its a ____ polymerase.

A

RNA, DNA, DNA

36
Q

Explain clustering program: mRNA expression

A

Profiling of 26 breast carcinomas.
Each vertical column represents one carcinoma, and each horizontal row represents the data for a gene identified at the left.

Red circle, increase in expression
Green circle, decrease in expression
black circle, no difference in expression between normal and carcinoma cells.

mRNA can be used a a cancer “fingerprint”

Discovery based, no hypothesis to guide experiment

37
Q

Which of the following is a potential oncoproteoin?
P16
MLH1
RAS
Rb

A

Ras

p16-stops rb from being phos
mlh1: mmr
rb: corepressor

38
Q

Which of the following function to tether HDACs to gene regulatory sequences?
P16
MLH1
RAS
Rb

A

Rb

39
Q

Treatment of pt with methotrexate can lead to ____ of the DHFR gene
amplification
duplication
mutation
translocation

A

amplification

competitive inhibitor

40
Q

In the above figure, which of the following genes would most likely not be activated?
cyclin
histone genes
MYC
p21

there is not figure for this, just name what they act with for each

A

cyclin-acts with CDK4
histone genes
MYC- cyclin D synthesis
p21- repressor (stops cell cycle)

41
Q

Which of the following proteins is activated in a pro-growth signaling pathway?
BRCA2
p16
p53
STAT3

A

STAT3

BRCA2-recomb repor
p16-inhibition of cell cycle
p53-inhibition of cell cycle

42
Q

Which of the following proteins is most closeely connected with double stranded break repair.
BRCA2
p16
p53
STAT3

A

BRCA2 (also rad51)

43
Q

Cancer results from mutations that can be acquired by ____________ with a very high penetrance; can represent a predisposition to cancer, with a low penetrance; or can be acquired during _____________.

A

inheritance, somatic cell development

44
Q

Mutations that lead to cancer mostly affect __________ pathways that regulate cell ___________.

A

signaling, division

45
Q

_____________pathways leading to cell division can begin with receptor ___________ or receptor clustering. The receptors can either be bound to a kinase protein or can have intrinsic __________ activity, as in the case of the receptor ________ kinase class of receptors.

A

signal transduction, dimerization, catalytic, tyrosine

46
Q

__________ phosphorylates and thereby inactivates Rb. p16 inhibits CDK4 activity and is often found mutated in ___________.

A

CDK4, certain cancer (melanoma)

47
Q

Oncogenes can be due to mutations that lead to amino acid substitutions, such as the ________ mutation in BRAF in melanoma; and oncogenes can be generated by translocations and gene _______________. Gene amplification comes in two structural forms, homogeneously staining regions or _______________.

A

V600E, fusion, double minutes

48
Q

Rb, an important tumor suppressor protein, recruits _____________ to E2F complexes that are present in genes such as the ___________ genes and DHFR.

A

HDAC, pro-proliferation

49
Q

The result of inhibiting the DHFR enzyme with the drug, methotrexate, is _______________ of the DHFR gene, leading to high level expression of the DHFR enzyme.

A

amplification

50
Q

T-cell receptor clustering, due to binding to HLA on another cell, leads to ________ activation and ultimately the transcription of the __________ gene, which encodes an autocrine factor for T-cell division.

A

RAF kinase, IL-2

51
Q

In some cases, the lack of DNA repair pathway provides an opportunity to treat a cancer with DNA damaging agents that a normal cell, with its normal DNA repair pathway, will tolerate, but a cancer cell, with its lack of DNA repair will not. This is the case for the enzyme, methyl guanine transferase, which is _____________ in some cancer cells.

A

silences/hypermethylated

52
Q

Several late stage developments in cancer are considered to be metastasis, ______________, which leads to new blood vessels in the tumor; and evasion of the _______ system by cancer cells.

A

angiogenesis, immune

53
Q

The papilloma virus vaccine should reduce the rates of _______________.

A

CANCER

54
Q

The V600E mutation in BRAF in melanoma is similar to a ________________ event.

A

phosphorylation/ activation

55
Q

Gleevec is specific for the ______________ fusion protein in CML.

A

BCR-ABL

56
Q

The IgH locus, when recombined next to the MYC gene, leads to large amount of MYC ________________.

A

protein (Burkett’s lymphoma)

57
Q

Comparative genomic hybridization is a technique whereby the expansion or _________ of a genetic region in cancer can be localized. A modern addition to this approach is to use a DNA ____________, where the genome can be subdivided into highly short segments, for precise localization of the difference between cancer DNA and normal DNA.

A

elongation, microarray

58
Q

____________ is the repair process defective in hereditary nonpolyposis colon cancer.

A

MMR

59
Q

The MMR repair process employs and exonuclease, which makes sense given the need for this process to eliminate __________ DNA, which will have a free end close to the MMR repair complex.

A

recently synthesized

60
Q

BRCA1 and BRCA2 are defective in hereditary breast cancer, which is not ________ penetrant. BRCA1 functions in several processes related to cancer, and BRCA2 functions in recombination repair, also termed, _____________ repair, which requires the process of ________, whereby the broken DNA uses neighboring “host” DNA as template. BRCA2 specifically facilitates the _____________ process part of recombination repair.

A

DNA, DS break, strand invasion, strand invasion

61
Q

TRUE or FALSE. p53, p21, FAS receptor, FAS ligand and caspases all function to facilitate apoptosis, in the event of failure of DNA repair or other normal, cellular processes. p53 in particular is commonly defective in cancer, that is, a p53 defect will facilitate continued growth even in the absence of DNA repair.

A

truw

62
Q

p53 is a transcriptional activator of the ______ gene, p21 is a CDK inhibitor.

A

p21

63
Q

TRUE OR FALSE Chromosome ends are replicated by the specialized DNA polymerase, telomerase, which includes both polypeptide and RNA components. The RNA component serves as a template for replication of the chromosomal end sequences.

A

true

64
Q

mRNA expression profiling can distinguish ____________ of tumors and contribute to a _____________ approach to additional cancer research.

A

fingerprints, discovery based

65
Q

For tumor suppressor genes to be relevant to cancer, both alleles must be lost. In most cases, a mutation renders one allele inactive, and the _________ process, involving nondisjunction of _______ chromatids in __________ leads to the loss of the second allele.

A

loss of heterozygosity, sister, mitosis

Genetics (12 decks)

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