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Block 1 Week 4 > Cancer Genetics 2 > Flashcards

Cancer Genetics 2 Flashcards

1
Q

Karyotypes of most cancers?

A
  • typically abnormal karyotypes
  • altered chrom. number (aneuploidy)
  • chrom translocations & deletions
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2
Q

Two mechanisms that cause cancer?

A

1) Non-Genotoxic Mechanism (Non-Mutagenic Carcinogens)
2) Genotoxic Mechanism
Exogenous Mutagens (Pro-mutagens and Mutagens):

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3
Q

Non-Genotoxic Mechanism

Non-Mutagenic Carcinogens

A
  • carcinogens that don’t alter DNA
  • most are tumor promoters
  • molecules that lead to inflammation/tissue damage, this can increase proliferation
  • benefits neighboring mutated cells
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4
Q

Genotoxic Mechanism?

Exogenous vs Endogenous Mutagens

A
  • Pro-mutagens & Mutagens that alter DNA
    exogenous: tobacco smoke; UV light
    endogenous: failure in normal cell processes; ex DNA repair, replication, metabolism, maintenance
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5
Q

What genes contribute to cancer?

A
  • 291 genes

- most common are chromosomal translations creating chimeric genes

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6
Q

What are the two types of cancer?

A

1) tumor suppressor genes

2) oncogenes

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7
Q

tumor suppressor genes

A
  • recessive; require two mutated genes to develop cancer
  • LOSS OF FUNCTIOn
  • these genes usually active and repress cell cycle; when deactivated loose breaks of cell cycle, proliferate uncontrollable
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8
Q

oncogenes

A
  • dominant; gain of function
  • 1 mutant allele can lead to cancer
  • these genes start as healthy functioning protoncogenes; when unhealthy state changed to oncogenes
  • over activation/ hyperactivation
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9
Q

main difference between tumor suppressor genes and oncogenes?

A

-cancer from oncogenes due to hyper activation; cancer from tumor suppressor genes due to inactivation (turning off)

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10
Q

tumor supressor genes (TSG) & inheritence?

A
  • follow pattern of autosomal dominant inheritence
  • if have affected parent; have 50% chance of offspring receiving one mutated gene that predisposes them to cancer
  • still require a 2nd somatic mutation to acquire cancer; due to TSG being recessive
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11
Q

why tumor suppressor genes considered single gene Mendelian disorders?

A

-because one mutant copy can be inherited, typically family members are also exposed to same env so ended up looking like strict inheritence

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12
Q

What are tumor suppressor genes typical role in healthy cells?

A

1) TSG act as brakes to stop cell proliferation
2) restrain inappropriate cell growth & division
3) stimulate cell death
4) involved inDNArepair (prevents accumulation of mutations)

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13
Q

What happens to tumor suppressor genes in cancer?

A
  • tumor suppressor genes are shut off
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14
Q

Characteristics of autosomal dominant inheritence?

A

1) Multiple generations affected
2) Males & females affected equally
3) Male to male transmission
4) offspring affected parent has 50°/o chance being affected,50% being unaffected

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15
Q

Retinoblastoma

A
  • malignant tumor of retina that occurs in children
  • due to malfunctioning in tumor suppressor gene Rb
  • can see in retina due to light refraction from camera
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16
Q

Two forms of retinoblastoma?

A

1) hereditary (40%)

2) non hereditary (sporadic) (60%)

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17
Q

hereditary retinoblastoma?

A
  • autosomal dominant, 90% penetrance
  • bilateral; 3 tumors per person
  • diagnosed ~15 months
  • already have 1 mutated rb gene, takes less time to get random somatic mutation & damage healthy rb gene
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18
Q

non-hereditary retinoblastoma

A
  • no familial association
  • unilateral; 1 tumor
  • diagnosed ~30 months
  • takes longer to develop 2 spontaneous somatic mutations so diagnosed later
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19
Q

how many mutations required for rb tumor production? frequency of these mutations?

A
  • is recessive at cell level, requires 2 mutated genes

- somatic mutations occur at low spontaneous frequency

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20
Q

what chromosome is rb gene on?

A
  • chromosome 13
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21
Q

Hereditary vs sporadic retinoblastoma on pedigree?

A
  • hereditary (mendelian) see in most generations, autosomal dominant transmission
  • sporadic skips generations then randomly appears
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22
Q

what is rb role in the cell?

A
  • gatekeeper from G1–>S
  • unphosphorylated/inactive, binds E2F1 trxn factor & prevents cell cycle progression
  • phosphorylated/active, unbinds E2F1 trxn factor & cell cycle progresses
  • tumor suppressor gene
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23
Q

What phosphorylates rb?

A
  • cyclin D/ CDK4 (mitogen sensor)

- cyclin E/CDK2

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24
Q

What happens when lack 2 copies of Rb on chromosome 13?

A

-no cell cycle arrest; unregulated growth

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25
Q

cancer hallmarks retinoblastoma has?

A

1) self-sufficiency in growth signals
2) insensitivity to antigrowth signals

since rb is absent, doesn’t respond/require either

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26
Q

Why is retinoblastoma just in the eyes?

A
  • in development cone precursors express cancer related proteins that enable proliferation/suppress apoptosis
  • if loose rb, cone cells now loose the breaks and easy to develop retinoblastoma
27
Q

Familial Adenomatous Polyposis (FAP)

A
  • autosomal dominant genetic syndrome
  • develop thousands of benign polyps in colon
  • polyps progress to malignant adenocarcinomas
  • is affected by APC gene
28
Q

WNT signaling pathway

A

-have 19 WNT signals/ligands that bind to WNT transmembrane receptors extracellulary
-in colon controls proliferation
since colon is subject to high cell turnover & proliferation

29
Q

B-Catenin

A
  • bifunctional protein
    1) cytoskeleton function: anchors E-cadherin to cell membrane so it can act with E-cadherin of neighbor cell to form tight junctions
    2) Trxn function: normally destroyed & no trxn occurs; when active allows trxn to occur
30
Q

No WNT ligand/signal and B-catenin?

A

-when no ligand present, the destruction complex (including APC) bind and destroy B-catenin and no cell proliferation occur

31
Q

When have WNT ligand/signal and B-catenin?

A

-when ligand present, destruction complex is not functional & B-catenin is able to go into nucleus, bind TCF, and activate trxn

32
Q

APC protein and WNT pathway?

A

-APC is required for the destruction complex, if is mutated/destroyed then destruction complex cannot function and B-catenin is unregulated and able to continuously activate cell proliferation

33
Q

What does B-catenin associate with in the nucleus and what is its role?

A
  • associates with TCF which is a repressor trxn factor

- w/o B-catenin prevents trxn, once B-catenin translocates into nucleus and binds, activates trxn

34
Q

What are two ways that B-catenin can activate proliferation?

A

1) APC destroyed so no destruction complex, B-catenin always active & free to imitate trxn
2) WNT signal constantly released/ bound causing permanent destruction of APC complex

35
Q

What type of gene is APC?

A
  • a tumor suppressor gene, when have it; blocks trxn

- when loose this gene we cause cell proliferation

36
Q

Loss of APC has what cancer hallmarks?

A

1) self sufficiency in growth signals
2) insensitive to anti growth signals
since you loose APC it no longer responds to signals!

37
Q

Lynch Syndrome (LS) or Hereditary nonpolyposis colon cancer (HNPCC)?

A
  • have a normal looking karyotype because is due to mutations in DNA mismatch repair not genetic material fuck ups
  • autosomal dominant, has high risk of colorectal & endometrium cancer
  • early polyps but don’t increase numbers like in FAP
  • high frequency of inheritence
38
Q

Mechanism of LS/HNPCC?

A
  • mutation in MLH1 endonuclease, can ID DNA damage but can’t open DNA for exonuclease to come in and fix mismatch
  • accumulate mismatches, as cell replicates mismatches will propagate and turns into point mutation
39
Q

LS/HNPCC cancer hallmarks?

A

1) loss of genomic stability

40
Q

Li-Fraumeni (cancer family)

A
  • syndrome, caused by germline transmission of mutations in p53
  • autosomal dominant familial cancer
  • affected family members get diverse types of cancers
  • Cancer occurs at early age, survivors of 1st cancer develop a second independent tumor of a different type
41
Q

p53?

A
  • mutations in this gene cause Li-Fraumeni (ATG–> AGC)
  • an important regulator of cell proliferation and apoptosis
  • Loss of p53 function is advantageous to some cancer cells
42
Q

What is the most common mutation that causes malfunctioning in p53?

A
  • most p53 mutations are single AA substitutions
  • almost always occur in a few well-defined locations in the p53 gene
  • some mutations are DOMINANT NEGATIVES
43
Q

Dominant negative mutations

A

-when have an altered gene product that acts antagonistically to the wild-type allele

44
Q

p53 and dominant negative mutations?

A

-if p53 tetramer has 1 subunit w/ dominant negative mutation, the tetramer is not functional

45
Q

p53 in healthy individual?

A
  • damage is detected, p53 activated, binds dan then:
    1) can modify cell cycle
    2) can repair DNA damage
    3) can signal for apoptosis
46
Q

p53 mechanism when mutated?

A

-DNA damage occurs, p53 isn’t activated, no apoptosis, accumulation of mutant cells, damage and mutations begin to accumulate

47
Q

loss of p53 has what cancer hallmarks?

A

1) insensitivity to antigrowth signals
2) genomic instability
3) evasion of apoptosis

48
Q

Oncogenes & mutations that cause them?

A
  • operate as dominant gain of function mutations
  • require only one mutated gene to be cancerous
  • mostly somatic mutations (not germline/inherited)
  • these mutations cause hyper activation of the gene or gene products
49
Q

3 ways you can go from proto-oncogenes to oncogenes?

A

1) Deletion or point mutation in coding sequence
2) Gene amplification
3) Chromosome rearrangment

50
Q

Deletion or point mutation in coding sequence & oncogenes?

A
  • have hyperactive protein made in normal amounts
  • ex: RAS
  • can’t turn off the protein (RAS) so have constant cell proliferation
51
Q

Gene amplification & oncogenes?

A
  • have a normal protein, but is greatly overproduced

- usually due to excessive trxn making extra mRNAs that turn into extra proteins

52
Q

Chromosome rearrangment & oncogenes? (2 ways)

A

1) nearby regulatory DNA sequence causes normal protein to be overproduced
2) proto-oncogene DNA is fused to actively trxned gene which causes fusion protein to be overproduced OR causes the fusion protein itself to be hyperactive

53
Q

oncogenes and inheritence?

A
  • until recently assumed all oncogenes were somatic; never inherited
  • Paton Raus discovered retrovirus (RSV) that can be passed from human to human (hen to hen)
54
Q

Paton Raus discovered what? How?

A
  • the first oncogene
  • isolated RSV (Rous Sarcoma Virus ) from hen tumor, put in other hen and found it caused tumor to develop
  • the hen cells infected w/ RSV virus were “transformed”
55
Q

What does it mean when say cells are transformed?

A

-cells change from normal shape/configuration to changing their appearance and proliferated abnormally

56
Q

How does RSV direct tumorigenesis?

A
  • SRC gene present in virus also present in hen/human cells
  • w/o virus, it is a proto-oncogene in humans. Has beneficial role
  • w/ virus changed into oncogene (hyperactive gene) which leads to cancer
57
Q

Who discovered how RSV direct tumorigenesis?

A

Bishop & Varmus

58
Q

How other oncogenes identified?

A
  • done by Bob Weinberg
  • DNA isolated from bladder cancer, introduced into immortalized but not transformed mouse cells
  • causes occacional colonies of transformed (rapid growth) cells
  • Among clones he found RAS
59
Q

immortalized cells mean?

A
  • cells had lost their clock of how many times they can divide before dying
  • but ARE NOT transformed/ not cancerous
60
Q

RAS? in proto-oncogene form?

A
  • example of an oncogene
  • located near membrane; activated by growth factors that bind to receptor & modify affinity of RAS from GDP to GTP -once have GTP Ras is activated & can activate trxn factors like MAPk to enable progression of cell cycle
61
Q

How RAS go from proto-oncogene to oncogene?

A
  • single nucleotide substation (G–>T) changes glycine–> valine,
  • caused change in affinity for GTP
  • RAS can no longer hydrolyze GTP to GDP, RAS is constantly activated responding to growth factors
62
Q

Consequences of RAS being activated indefinelty?

A
  • means RAS can activate it’s downstream proteins at all times
  • causes many trxn factors & modulators of several responses (including the cell cycle) to be engaged at all times
  • alters many molecules explains why directly linked to so many cancer
63
Q

Ras has what hallmarks of cancer?

A
  • self-sufficiency in growth signals

- point mutations in RAS genes cause constitutive activation of signaling pathways normally regulated by growth factors

Block 1 Week 4 (7 decks)

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