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tumor genes Flashcards

1
Q

what are the types of cancer?

A

carcinoma, sarcoma, myelomas, leukemia, lymphomas, mixed types

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2
Q

how is cancer developed?

A

multistep process:
cells gradually become malignant through progressive alterations –> multiple abnormalities accumulate –> selection for grwoth advantage

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3
Q

what are the stages of tumor development?

A

tumor initiation–> tumor progression (growth advantage, survival, invasion, metastasis)

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4
Q

what are the causes of cancer?

A

carcinogens, tumor promoters

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5
Q

what are the characteristic properties (name 8) of cancer cells?

A

1.lack density dependent inhibition of proliferation
2. reduced requirements of growth factors
3.less regulated cell-cell, cell-matrix (loss of E-cadherin)
4.not sensitive to contact inhibition
5. secrete proteases and growth factors –> invasion, angiogenesis
6.dont differentiate normaly
7.do not undergo apoptosis
8.unlimited DNA replication, overexpression of telemorease

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6
Q

what are proto-oncogenes?

A

normal cell genes from which oncogenes originated
often proteins of a signal transduction pathway that controls cell proliferation –> growth factor receptors (protein-tyrosine kinases)

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7
Q

which signaling pathways/oncogenes play a role in cancer if they are mutated?

A

1.NOTCH- NICD
2. IL receptor- JAK/STAT
3. growth factor: ErbB2/HER2 receptor – RAS – either activates PI3K/Akt/mTor (inhibited by PTEN) or Raf/Mek/ERK/MAPk
4. WNT- frizzled- beta catenin-APC

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8
Q

what types of mutation occur in cancer?

A

point mutation (RAS)
abnormal chromosomes: translocation, duplications, deletions (c-myc, c-abl)

LOF in transcription factors
GOF in kinases, receptor mutations, ligand mutations

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9
Q

what are the properties of oncogenes?

A

can encode transcription factors normally induced by growth factors

proto-oncogene proteins have normal roles in growth factor stimulated signal transduction pathways

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10
Q

what are tumor suppressor genes?

A

normally they inhibit cell proliferation and tumor development

in many tumors, both genes are lost or inactivated –> contribution to an abnormal proliferation of tumor cells

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11
Q

how is retinoblastoma inherited?

A

inherited as dominat autosomal, either hereditary or sporadic

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12
Q

what causes retinoblastoma?

A

Rb1 gene encodes pRB protein

loss of pRB can lead to cancer

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13
Q

what is the function of pRB?

A

suppresses cell division in absence of mitotic signals
prevents transition from G1 to S phase

hypophosphorylated pRB: binding and inhibition of E2F –> cell cycle arrest

pRb hyperphosphorylation by CDK: release of E2F

in cancer cells disrupted pRB function results in aberrant cell proliferation

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14
Q

what are the types of retinoblastoma and what are their characteristics/mutations?

A

bilateral: both eyes –> germline mutation or sporadic

unilateral: one eye –> somatic mutation

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15
Q

what is the two hit model in regards to retinoblastoma?

A

first hit: inheritance of one defective Rb gene

second hit: only one successive genetic alteration in one of the retinal cells

tumor formation requires two genetic alterations

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16
Q

what is loss of heterozygosity (LOH)?

A

Loss of an entire chromosome by chromosome non-disjunction and recombination of the mutant allele

17
Q

why are mutant tumor suppressor genes transmitted through the germline while ocogenes are usually not?

A

oncogene is dominant at the cellular level and disruption of normal tissue development in the embryo –> embryo dies

tumor suppressor genes are recessive at the cellular level and normal embryonic development

18
Q

why can the RET oncogene be transmitted through the germline?

A

expression is limited to a small set of tissue, delayed expression of ret during embryogenesis

19
Q

what are examples of tumor suppressor genes

A

pRB
p53
APC

20
Q

what is p53 and what is the function of p53?

A

tumor suppressor
is frequently inactivated in cancer
is a transcription factor

FUNCTION:
hinders proliferation of damaged cells
prevents genome mutations

21
Q

what is the interaction between oncogenes and tumor suppressors?

A

tumor suppressor genes inhibit regulatory pathways stimulated by products of oncogenes

22
Q

which regions of p53 can be mutated?

A

Transactivation domain
proline rich domain
DNA binding domain (cancer hotspot mutations)
tetramerization domain
Lysine rich domain

change of conformation: the mutations are dominant negative

23
Q

what is the mechanism of p53 action?

A

transactivation of target genes by tetratmeric p53

24
Q

how is p53 controlled?

A

through negative feed back loops

1.active p53 if tetramers are formed
2.transactivation of various genes (mdm2)
3.production of mdm2 protein
4.mdm2 binds p53 in the nucleus–> inactivation of p53
5.export to the cytoplasm and mdm2 mediated ubiquitination of p53
6.p53 degradation

25
Q

what activates p53?

A

activation of DNA damage sensing kinases leads to p53 stabilisation and acivation

26
Q

what are the paradigms of tumor suppression?

A

two hit paradigm
haploinsufficiency
quasi suffiency
obligate haploinsufficiency

27
Q

what is haploinsufficiency?

A

a single copy of a wild type allele at a locus in heterozygous combination with a mutated allele –> although wild-type allele still produces the normal product, the total product is sufficient for induction of cancer

e.g. p53

28
Q

what is quasi sufficiency?

A

tumor suppression is impaired after subtle downregulation of expression without loss of eveb one allele

e.g. pTEN

29
Q

what is obligate haploinsufficiency?

A

is more tumorigenic than complete loss of the TSG usually due to the activation of fail-safe mechanisms following the complete loss of TSG expression

30
Q

what is the function of APC?

A

tumor suppressor protein

loss of APC function leads to unregulated dividing cells

is component of Wnt/frizzled signaling pathway

31
Q

what are the types of mutation in APC?

A

germline and somatic
framehsift and nonsense mutations

c-terminally truncated protein

32
Q

what are somatic mutations?

A

most changes in DNA usually happen during our lifetime

33
Q

germline mutations?

A

inherited DNA from parents that greatly increase risk of developing certain cancer

34
Q

what are driver mutations?

A

confer grwoth advantage on cancer cells

causally implicated in oncogenesis

35
Q

what are passenger mutations?

A

without functional consequences for oncogenesis
no growth advantage on the cancer cell

Pa1o (3 decks)

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