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Genetics > Chapter 20: Genetics of Cancer > Flashcards

Chapter 20: Genetics of Cancer Flashcards

1
Q

Cancer is a genetic disorder at what level?

A

cellular

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2
Q
  • Mutations alter ?

- _% mutations are germ line mutations (hereditary)

A
  • gene expression

- 1%

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3
Q

What are four mutation sources for cancer?

A
  • spontaneous
  • radiation
  • tumour viruses
  • hereditary sources
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4
Q

What are the two types of tumours?

A
  • Benign

- Malignant

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5
Q

Neoplasm?

A
  • relentless growing mass which can be benign or malignant
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6
Q

Characteristics of a benign tumour?(6)

A
  • edges are encapsulated
  • no metastasis
  • no invasion
  • low growth rate
  • normal nuclei
  • not usually life threatening
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7
Q

Characteristics of a malignant tumour? (6)

A
  • edges are irregular
  • metastasis occurs
  • invasion occurs
  • high growth rate
  • variable/irregular nuclei
  • usually life threatening
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8
Q

Proliferation of cells is determined by what?

A
  • cell cycle and its check points
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9
Q

What are the cell cycles check points?

A
  • G1 to S
  • G2 to M
  • M checkpoint
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10
Q

Cell cycle checkpoints huh??

A
  • they occur at different points in the cycle and are control points with which the cell cycle is arrested if there is damage to the genome or cell cycle machinery. This allows damage to be repaired or if it is not the cell is destroyed.
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11
Q

G1?

A

prepares the cell for DNA replication and chromosome duplication in the S phase….

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12
Q

G1 to S checkpoint?

A

-determines whether the cell is able to or should continue into S phase…..the cell stays in G1 unless it grows large enough and the environment is favourable.

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13
Q

G2-M checkpoint??

A

unless all the DNA has replicated, the cell is big enough and the environment is favourable the cell cannot enter the mitotic phase of the cell cycle.

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14
Q

M checkpoint?

A
  • the chromosomes must attach properly to the mitotic spindle to trigger the separation of chromatids and the completion of mitosis.
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15
Q

Terminal differentiation?

A

cells that have lost the ability to proliferate; they have a finite lifespan; they are replaced by stem cells.

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16
Q

Cycle checkpoints are caused by what two things>

A
  • cyclins (proteins)

- enzymes ( cyclin-dependent kinases)

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17
Q

Regulation of the Cell Cycle:

- Growth factors??

A
  • growth factors are released: enhances proliferation—-> proto-oncogene
  • growth factors are molecules that stimulate cell division of a target cell and have specific effects because they bind to specific receptors on the target cells.
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18
Q

Give a run through of the interaction of growth factors with a cell. (cell cycle regulation)

A
  • GF binds to receptor (outside of cell/doesn’t enter the cell), activates receptor, signal is relayed through proteins in the cell, activates nuclear genes that encode for proteins that stimulate growth and division by affecting transcription factors.TF code for proteins that are released to stimulate cell division.
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19
Q

What about Growth inhibitory factors?

A
  • they do the same run through as growth factors.
    L> EXCEPT…..they activate nuclear genes that encode for proteins that INHIBIT growth and division.
    L> Transcription factors in this case code for proteins that inhibit cell division
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20
Q

What are the three classes of genes that are relevant with cancer?

A
  1. proto-oncogenes
  2. Tumour suppressor genes
  3. Mutator genes
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21
Q

Proto-oncogenes??
L> normally?
L> cancer?

A
  • Normal:
    L>normally they stimulate cell division
    L>proto-oncogene products are involved with stimulation of growth…ie growth factors, protein kinases, membrane associated g proteins

-Cancer:
L> mutant proto-oncogene (oncogene) are found in cancer cells, they are more active than normal or at inappropriate times.

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22
Q

Tumour suppressor genes???
L>normally?
L> cancer?

A

L>normally inhibit proliferation

L> in cancer cells they have lost their ability to inhibit proliferation ( division still occurs)

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23
Q

Mutator genes???
L> normally
L>cancer

A

L>normally ensure accurate replication and maintenance of the genome. (ensure DNA repair system is working accurately)
L> in cancer cells….they have lost this function and they make the cell prone to mutations in their genes…..( in either proto-oncogenes and tumour suppressor genes)

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24
Q

____ proto-oncogene mutation on a homologous pair of chromosomes is enough to cause an onocgene on that chromosome and to cause loss of cell division BUT you need more oncogenes to create a cancerous cell.

A
  • 1
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25
Q

Cancer cells can result from ____ or untimely synthesis of _____ in cells that do not normally produce them. Change can also be caused by an alteration in ______(v-onc) or mutation of ___.

A
  • excessive growth
  • growth factors
  • growth factor genes
  • cellular proto-oncogene
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26
Q

Oncogenes are more ______ or active at ____.

A
  • active than normal

- inappropriate times

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27
Q

Oncogenes can be caused by a tumour____.

A
  • tumour virus
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28
Q

What are the two types of tumour viruses that can induce infected cells to proliferate and produce tumours?

A
  1. RNA tumour viruses

2. DNA tumour viruses

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29
Q

In terms of mutations what are the four kinds that can occur to bring about an oncogene?
L> how many are required for a proto-oncogene to be mutated into an oncogene ?

A
  1. deletion/point mutation
  2. gene amplification
  3. X rearrangement
  4. tumour virus
    - a single mutation on a proto-oncogene can cause an oncogene on that chromosome
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30
Q

With RNA tumour viruses explain their oncogenes?

A
  • they carry oncogenes that are altered forms of normal host genes.
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31
Q

Explain the infection process of an RNA tumour virus.

A
  • infects cells, ssRNA genome is converted into a proviral dsDNA which than integrates into a chromosome of the host and creates RNA virus progeny.
  • *** reverse transcriptase is what converts the ssRNA into ssDNA! then replication occurs making it ds
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32
Q

Retroviruses typically have three protein coating genes that are transcribed by host RNA _____ to get in new hosts and out of old ones to get into another. What are they?

A
  • polymerase II
    1. gag
    2. pol
    3. env
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33
Q

RNA Retrovirus genes:

1. Gag?

A
  1. encodes the precursor protein that cleaves to produce virus protein particles
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34
Q

RNA Retrovirus genes:

2. pol?

A
  1. encodes precursor protein that cleaves to produce reverse transcriptase ( to convert ssRNA to dsDNA - proviral) and integrase ( to integrate proviral DNA into chromosome of the host)
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35
Q

RNA Retrovirus genes:

3. env??

A
  1. encodes precursor to the envelope glycoprotein
36
Q

Retroviruses infect the cell, RNA genome released from the viral particle and then _____ encoded by _____ transforms the ssRNA into proviral dsDNA and it is then integrated into the a host cells chromosome which the now virus infected genome is transcribed to produce ____viral RNA genomes and viral ____.

A
  • reverse transcriptase
  • pol
  • progeny
  • proteins
37
Q

Oncogenic retroviruses carry oncogenes that give the retrovirus what ability?

A
  • the ability to transform the cells they infect. They go through the SAME life cycle as the non-oncogenic retroviruses.
38
Q

In oncogenic retroviruses what is the specific oncogene it carries called?

A
  • v-onc (only in tumour viruses)
39
Q

What is an example of a RNA tumour retrovirus that was mentioned in lecture?

A
  • Rous Sarcoma Virus
    L> it causes a sarcoma
    L> carries the oncogene called src (v-src)
40
Q

Transducing Retrovirus : explain the process of picking up a hosts genes and transducing of them.

A
  • picks up either host oncogenes or proto-oncogenes with their genome when packaged.
  • These oncogenes can be transduced ( DNA taken up by other viruses) and brought to other cells. This occurs when there is a loss of the gag,pol and env genes that cause the provirus to connect to the cellular genes.
41
Q

Whats the story of the retroviruses progeny that take the transduced oncogenes?
(basically think about how these genes will be expressed?)

A
  • All viral progeny then have all or part of a cellular gene and express the gene in infected cells. If the cellular genes picked up contain oncogenes, the retrovirus becomes oncogenic. If the cellular genes picked up contain pro to-oncogenes, the increased expression can cause oncogenesis.
42
Q

Do the oncogenes taken up in retroviruses have a role in the life cycle?

A
  • NO

- the genes may replace other genes required fro the viral life cycle.

43
Q

Whats the story for retroviruses that do take up oncogenes in regards to their ability to replicate?(if no solution?)

A
  • most cannot replicate
    L> the addition of the oncogene to the genome causes the loss of some genes required for the cell cycle.
    L> solution: introduction of a helper virus….
    L> they allow the defective retrovirus o produce progeny by supplying the gene products necessary for the life cycle to continue.
44
Q

The Rous sarcoma virus (RSV) RNA genome and integration of the proviral DNA into the host ______ chromosome. What gene is associated with this virus?

A
  • chicken

- src

45
Q

Explain the process the RNA goes through with a Retrovirus ( RSV)!

A

RSV genome RNA
L>reverse transcription =
RSV proviral DNA
L> ligate ends to form circular viral dsDNA =
Circular proviral DNA
L> make cut in viral DNA and staggered nicks in cell DNA = beginning of viral DNA integration
Viral ends become joined to the ends of the cell’s DNA by recombination
L> gaps are filled in=
integration of viral DNA completed
— short direct repeats in cell DNA = proviral

46
Q

What are two ways for retroviruses to cause cancer?

A
  1. if it is a transducing retrovirus and the v-onc is expressed
  2. Insertional mutagenesis
47
Q

Explain insertional mutagenesis!

A
  • occurs if proviral DNA integrates near a proto-oncogene.
    L> expression of the proto-oncogene is under control of retroviral promoter and enhancer sequences. These sequences do not regulate based on environmental signals in the cell as in normal proto-oncogene regulation…. therefore over expression of the proto-oncogene occurs (more protein products than wanted at the moment) and causing the cell to enter a tumorous state.
48
Q

DNA tumour virus:

-how are the oncogenic?

A
  • because they induce ell proliferation by transforming cells to a cancerous state through the action of an oncogene ( 1 or more) in its viral genome.
49
Q

DNA tumour virus:

Do they contain cellular genes?

A
  • NO

- they are already DNA

50
Q

DNA tumour virus:

-Do they always induce a cancerous state?

A
  • no……the virus produces protein that activates DNA replication in the host cell.Using host cell proteins, the viral genome is replicated, transcribed…producing progeny viruses in large numbers and causing cell lysis and death. Viruses are released and can infect other cells.
51
Q

DNA tumour virus:

-Is it rare for the viral DNA to be replicated? If not explain why!

A
  • NO. it is rarely not replicated
    L> if it does not replicate:
    L> the DNA is integrated into the hosts DNA. If the viral protein that activates DNA replication in the host is synthesized through this the protein transforms the cell into a cancerous state ( causing the dormant cell to proliferate, Go to S phase)
52
Q

What are tumour suppressor genes?

A
  • their products (proteins) have the ability to suppress uncontrolled cell proliferation (division).
53
Q

What is the consequence of the loss of tumour suppressor genes?
L>how many mutational events are needed

A
  • it is correlated with tumour formation (mutation prevents gene product form preventing them)
    L>two mutational events are needed(recessive mutations)
54
Q

TP53 codes for??

A
  • P53 which is a transcription factor! this is a common TSG mutation…. in 50% of cancers P53 is involved
55
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:
- Two mutational events are required.
L> what are the two types of this cancer.

A
  1. Sporadic

2. Hereditary

56
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:

- Sporadic version

A
  • two mutations occur in somatic cell later in the patients life.
    L> two wild type ( RB+) copies of the gene in the beginning mutate to two mutant (RB). RB+/RB+ mutates to RB/RB in ONE cell. Mutations occur at different times…
    RB+/RB+—–> RB/RB+——> RB/RB
57
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:

- Hereditary version?

A
  • one mutation is inherited (RB) causing a predisposition to the cancer while the second mutation occurs in somatic cell. RB+/RB heterozygote mutates to RB/RB.
58
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:
- Hereditary version?
L> explain loss of heterozygousity
L> why does this disease seem dominant?

A

Loss of heterozygosity occurs because the cell generally accumulates the second mutation and causes the tumour. ( tumour formation requires only a mutational event in the remaining wild type in any one of the cells in that tissue) This probability of this occurring is high making the disease look dominant.

59
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:
- Hereditary version?
L> With this disease there is basically no heterozygote because the mutation almost always occurs …making it homozygous recessive? Explain LOH

A
  • LOH:
    L> an arm containing it or the entire chromosome containing normal TSG lost, mutated copy is duplicated and now you have two copies of the recessive, mutant TSG allele.
60
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:

  • Hereditary version?
  • Explain the two hit hypothesis
A
  1. First Hit: point mutation that inactivates on copy of a TSG (usually born with this). No cancer develops because there is a normally functioning TSG allele on the other chromosome
  2. Second Hit: loss of functioning TSG occurs ( deletion), and individual develops cancer.
61
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:
- Tumour suppressor gene on chromosome __ codes for __, which is involved with regulating cell cycle ( G1-S checkpoint) and involved in regulation of _____.

A
  • 13
  • pRB
  • E2F transcription factor
62
Q

Retinoblastoma (Childhood cancer) tumour suppressor gene:
- E2F explain it.
L> phosphorylation and (un) interacting with pRB

A
  • phosphorylation pRB+ E2F= transcription factors cause transcription in DNA synthesis, unphosphorylation pRB+ E2F= inhibitor for TF.
  • when RB/RB (mutant), pRB is unstable and does not bind to E2F and activates DNA synthesis.
63
Q

TP53 Tumour Suppressor Gene:

-When two mutant alleles??

A
  • it is involved with 50% of all human cancers
64
Q

TP53 Tumour Suppressor Gene:

- normally??

A
  • when no mutations in it are present it encodes the protein p53 which its function is regulated by phosphorylation….it binds to E2F
65
Q

TP53 Tumour Suppressor Gene:

L> when does p53 permit cell division and when does it not?

A
  • when it is phosphorylated and binds with E2F it progresses through cell division
  • when it is unphosphorylated and binds with E2F, cell division is inhibited and prevents the cell from entering S phase.
66
Q

TP53 Tumour Suppressor Gene:

- what can p53 also activate besides E2F?

A
  • BAX gene which blocks function of BCL-2 protein (repressor of apoptosis ) and cell goes through programmed cell death.
67
Q

TP53 Tumour Suppressor Gene:

- If there is a mutation what occurs with p53 in regards to BAX gene?

A
  • no active p53 can be produced, BAX gene does not activate and the cell will proceed through cell cycle and not go through cell death.
68
Q

Breast Cancer Tumour Suppressor Genes:

- what are the two types?

A
  • BRCA1 and BRCA2
69
Q

Breast Cancer Tumour Suppressor Genes:

- when can you be tested for the two TSG’s?

A
  • if the cancer is a prominent familial feature
70
Q

Breast Cancer Tumour Suppressor Genes:

- BRCA1 and BRCA2 are located on what chromosomes?

A
  • Chromosome 17q21

- Chromosome13q12-13

71
Q

Breast Cancer Tumour Suppressor Genes:

-What are the BRCA1 and BRCA2 gene products usually involved with normally and what occurs when they are mutated?

A
  • DNA damage repair( does not get repaired), transcription regulation( not regulated, proteins that help regulate cell division are not formed) and addition of ubiquinone to make proteins for degradation.
72
Q

Breast Cancer Tumour Suppressor Genes:

- what has BRCA1 been specifically associated with?

A
  • with high risks/ susceptibility to overran cancer
73
Q

Mutator genes are normally involved with what?

A
  • DNA replication and repair
74
Q

When mutator genes are mutated what occurs?

A
  • these genes will increase instances of mutations in other genes. Normally mutator gene products help fix mutations on other genes and when it becomes mutated, damage in DNA increases (because nothing is being fixed)
75
Q

Give an example of a cancer involved with mutator genes and the four mutator genes involved!
L> how are these genes similar to E.coli and yeast genes ?

A
  • cancer: Hereditary nonpolyposis colon cancer
  • genes: hMSH2, hMLH1, hPMS1 and hPMS2 ( 4 human mutator genes associated with this cancer)
    L> they are similarly involved in mismatch repair pathway (homologous genes!)
76
Q

What is 5- TTAGGG-3 ??

A
  • the repetitive sequence at the end of human chromosomes ( human telomere sequence)
77
Q

What happens to telomeres after each cell division?

A
  • they shorten
78
Q

What does telomerase do to the telomere?

A
  • it extends the telomere for a finite amount of cell divisions ( can only divide a certain amount..ex: epithelial cells: 75x), so cells can only go through so many cell cycles.
79
Q

Replicative senescence??

A
  • stopping the cell from dividing after its finite number of times it can go through the cell cycle has been reached, caused by changes in telomere structure.
  • cell division is inhibited
80
Q

Colorectal Cancer (FAP) is said to have a _____ nature.

A

multistep

81
Q

Multistep Nature of Colorectal Cancer (FAP):

-1.Cancer cells provide own _____, avoid _____ and promote _____.

A
  • growth signals, apoptosis(PCD), angiogenesis (formation of new blood vessels)
82
Q

Multistep Nature of Colorectal Cancer (FAP):

-2.Explain hypomethylation !

A
  • not enough methyl groups, keeps cell division going…basically being in chromatin form when it shouldn’t be. ( hypomethylation= not enough methyl groups on DNA= MORE GROWTH).
83
Q

Multistep Nature of Colorectal Cancer (FAP):
- 2.Hypomethylation:
L> what occurs when methyl groups are added ?

A
  • when added to DNA (methylating) it causes your DNA to turn off.
84
Q

Multistep Nature of Colorectal Cancer (FAP):
- 3.cancer cells shut down _____ and ____ occurs because the first protein products that cause apoptosis are formed in the ____.

A
  • mitochondria
  • fermentation
  • mitochondria
85
Q

Multistep Nature of Colorectal Cancer (FAP):

- 4.Explain this multistep nature in terms of mutations!

A
  • most cancers require an accumulation of mutations in a number of genes
  • This multistep nature involves mutations that convert proto-oncogenes to oncogenes and inactivate TSG’s ( which involves the breaking down of multiple mechanisms that regulate growth and differentiation, no backup plans to prevent the uncontrolled nature of cancer).

Genetics (14 decks)

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