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Pathology > 6.10 caner genes > Flashcards

6.10 caner genes Flashcards

1
Q

oncogene activation by normal expression of a protein with altered function

A

ras, abl

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2
Q

oncogene activation by overexpression of a normal protein

A

myc

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3
Q

overexpression can come from

A

amplification, translocation next to active promoter, insertion of viral promoter

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4
Q

Chronic myelogenous leukemia translocation

A

translocation of abl gene from chromosome 9 to chormosome 22, sitting right next to the BCR locus –> under this promoter the tyrosine kinase encoded by abl is overexpressed –> chronic myelogenous leukemia

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5
Q

gleevec

A

specific tyrosine kinase inhibitor that is encoded by abl, since specific to the cancer cells no side effects

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6
Q

burkitts lymphoma mutation

A

translocation of myc gene from chromosome 8 to chromosome 14, sidding beside the Ig gene

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7
Q

amplifcation of N-myc

A

n-myc produces double minutes, and amplification can turn cover a large region of the chromosome that can be morphologically picked up

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8
Q

what can you add for membranes to fuse together

A

propylene glycol - used to fuse immortal cell and specific bcell to make monoclonal antibody

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9
Q

what phenotype do normal and malignant fused cells give you

A

normal phenotype - something on the normal chromosome suppresses the malignant phenotype bc if that chromosome is kicked out you’ll see the malignant phenotype

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10
Q

Retinoblastoma inherited form

A

multiple, deletions in all cells

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11
Q

Retinoblastoma spontaneous form

A

single, deletions only in tumor

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12
Q

Rb inheritance

A

one allele inactivated at birth, 2nd inactivated by somatic event

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13
Q

Rb function

A

phosphorylation regulates activity –turns it off, when unphosphorylated the Active Rb gene sequester factors necessary for entering the cell cycle – tumor suppressors

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14
Q

Viral proteins and Rb

A

viral proteins interfere with Rb gene

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15
Q

hypophosphorylated Rb

A

binds E2F transcription factors, and that complex binds DNA preventing transcription

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16
Q

Rb is released from E2F when

A

CDK4 and 6 hyperphosphorylate Rb, releasing E2F, allowing several genes to be transcribed

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17
Q

If Rb is absent or not functional

A

all the genes normally inhibited by E2F will be constitutively expressed

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18
Q

E2F/DP1/Rb complex inhibits transcription by

A

recruiting histone deacetylase, that makes chromatin more compact — when the complex is released, histone deacetylase is released allowing for the transcription of genes

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19
Q

Rb can by phosphorylated by

A

CDK4-cylinD or CDK2-cyclinE

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20
Q

some genes under the control of E2F/DP1/Rb complex

A

Cyclin A, E, CDK1

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21
Q

loss of Rb gene

A

knock out mice do not survive and undergo apoptosis in several organs, No Rb leads to apoptosis in many cells but not in retinoblasts

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22
Q

mutations equivalent to losing Rb gene

A

mutation sin cyclinD, CDk4, CDK6, p16

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23
Q

several other pathways fo growth converge at the Rb gene product such as

A

TGF beta, transforming proteins of oncogenic viruses binding hypophosphorylated Rb, p53

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24
Q

TGFbeta inhibits cell proliferation by

A

upregulating p27 and p15 (CDK inhibitors) –> defects give rise to cancer

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25
Q

p53 works by

A

upregulating CDK inhibitor p21, and inducing apoptosis in cells genetically damaged if repair does not occur

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26
Q

most common mutation found in 50% of human tumors

A

p53

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27
Q

p53 is activated by

A

hypoxia, DNA damage

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28
Q

p53 binds DNA and transcriptionally upregulates

A

p21 (G1 arrest), GADD45 (DNA repair) and bax (apoptosis)

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29
Q

Li-Fraumeni Syndrome

A

inherited one mutant allele of p53, 25fold increased incidence of malignant tumors by the age of 50

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30
Q

how is Li-Fraumeni syndrome different from Rb mutations

A

LF patients have a large variety of tumors, develop tumors at a young age, and have multiple primaries

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31
Q

How does hypoxia selecto for mutated p53

A

hypoxia (along with chemo and radiation) activates p53, and the cells die, so in areas of hypoxia where the cell survives, we know that that cell having a mutated p53 is selected bc it did not die

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32
Q

p53 and chemotherapy/irradiation

A

if p53 negative, chemo cannot induce apoptosis so this means resistance to therapy

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33
Q

protein similar to p53

A

p73

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34
Q

BRCA 1 and 2 breast cancer rates

A

80% of familial and 3% or sporadic; also associated with ovairian cancer

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35
Q

functions of BRCA 1 and 2

A

BCRA 1 - regulation of estrogen and androgen receptors, Both - homologous recombination involved in repair of dsDNA breaks in association with RAD51, close association with genes involved at halting DNA synthesis at checkpoints if DNA damage present, While BRCA not involved in may breast cancers could be analogous to Rbp

36
Q

what would accomplish the same thing as BRCA mutation

A

any damage in the dsDNA repair system - Ub, D2, Rad51, Chek2, ATM, ACEFG

37
Q

Adenomatous polyposis coli

A

APC gene loss results in the formation of thousands of polyps in the colon with 100% chance that one or more will become malignant

38
Q

APC gene

A

APC in cytoplasm where it degrades beta-catenin

39
Q

Beta catenein

A

moves to the nucleus and upregulates transcription of a number of growth promoting genes

40
Q

Mutation resulting in the same thing as a nonfunctional mutation of APC gene

A

mutation in beta catenin preventing APC binding, also mut in WNT receptor turning it on all the time inducing dissociation of the APC and beta catenin

41
Q

a mutation in APC gene alone

A

will not cause cancer, but this is one critical hit

42
Q

NF 1 loss

A

induces type 1 neurofibromatosis, multiple neurofibromas with some malignant transformation - increased risk of acute myeloid leukemia - due to loss of GTPase activity ras is always on

43
Q

NF 1 function

A

downregulate ras - it is a GTPase activating protein

44
Q

Colon cancer has deletion of

A

region on chromosome 18 that functions to ragulate axon outgrowth - no known as dependence receptor, signals one way without langand and another way with ligand.

45
Q

colon cancer gene and knock out mice

A

complete knock out is fatal, but heterozygous knockout shows no tumors_.so the model doesn_t really work in mice

46
Q

colon cancer dependence receptor

A

no ligand signals apoptosis. With ligand signals something else

47
Q

INK4a/ARF locus

A

p16 (p16INK4a) the CDK4 inhibitor is coded in this region

48
Q

mutations associated with 50% of pancreatic cancer, esophageal, bladder cancer, and tumors of the head and neck

A

p16INK4a

49
Q

p16INK4a in cervical cancer

A

inactivated by hypermethylation, not mutated

50
Q

NF2 codes for

A

merlin that binds to actin and CD44 (TM protein that affects binding of cell to ECM) and affects ability of cells to maintain stable cell to cell junctions

51
Q

cancers associated with NF2

A

schwannomas, meningiomas, ependymomas

52
Q

what gene do we think is involved in metastasis

A

NF2 - rmember ability to maintain cell-cell junctions, so loss of this makes sense that it would contribute to metastasis

53
Q

70% of HNPCC (colon cancer) is associted with

A

type 2 TGFbeta receptor mutation

54
Q

in the same pathway as TGFbeta what contributes to 50% of pancreatic cancer

A

SMAD4 gene that codes for a portion of growth inhibitory signaling

55
Q

VHL and cancer

A

von Hippel Lindau gene mutations associated with hereditary renal cell cancer, pheochromocytomas, and angioblastic tumors of CNS

56
Q

VHL gene product function

A

ubiquinates hypoxia inducible factor 1 (HIF1) causing degradation. HIF1 norally induces VEGF and PDGF for growth.

57
Q

PTEN and cancer

A

phosphate and tensin homologue mutated in endometrial Ca and GBMs

58
Q

PTEN function

A

normally inhibits PI3K/AKT actions promoting cell survival –> so this mutation causes higher levels of PTEN to get cancer

59
Q

Cadherins

A

promote cell to cell adhesion, mutated in stomach and esophageal cancer, facilitates metastatic capacity

60
Q

WT1 and 2

A

Wilms tumor

61
Q

WT1

A

transcription factor for genes involved in renal and gonadal differentiation

62
Q

WT2

A

unkonwn but in Beckwith-Wiedermann syndrome

63
Q

other candidate tumor supressor genes

A

KLF6, Patched, TGFbeta system and p21 –> all suspected bc of observed chromosome deletions in certain tumors

64
Q

Bcl-2

A

protects cells from apoptosis

65
Q

Bax

A

induces apoptosis

66
Q

Bcl2 fn

A

Bcl2 lives outside the mitochondria and blocks movement of cytochorme c

67
Q

Bax fn

A

bax facilitates movement of cytochrome c

68
Q

overexpression of Bcl2 is associated with

A

B-cell lymphoma – translocated to IgG promoter similar to Burkitt’s

69
Q

HNPCC is associated with

A

mismatch repair

70
Q

Xeroderma Pigmentosum is associated with

A

Excision repair - mostly see benign tumors but some can become malignant

71
Q

Telomerer shortening and cell death

A

teleomeres shroten with each replication and when they get too short it is percieved as a dsDNA break and p53 inhibits entry into S phase. The two ends try and join and the apnormal chromocomes become dicentric that are pulled apart at anaphase inducing new dsDNA breaks. the resulting genomic instability causes eventual mitotic catastrophe and scenscense

72
Q

Telomerase

A

tumor cells can reactivate telomerase and become immortal – during the crisis stage of dicentric chromosomes.

73
Q

slide 124

A

be aware

74
Q

Epigenectic mechanisms - tumor cell DNA

A

tumor cell DNA is generally hypomethylated and there is promoter specific hypermethylation

75
Q

region scilenced by promoter methylation in colon and gastric cancer

A

CDKN2a locus coding for p14 and p16. similarly with BRCA1 in brease cancer.

76
Q

Histone modifications

A

paly important roles in depression of stem cell like genes

77
Q

hyper and hypo methylation

A

hyper –scilencing, hypo –activating

78
Q

metabolic changes in cancer cells

A

shift to glycolysis in the face of adequeate oxygen (Warbur effect).

79
Q

reasoning for the Warburg effect

A

growth advantage for hypoxic tumor cells, dec O2 demand, more O2 for each cell. Lacktic acid fermentation of blocking pyruvate from entering aerobic metabolism alows for shunting fo these carbons to synthesis of molecules other than DNA that are needed for division. Normal cells respond to O2 deprevation with autophagy, tumor cells do not.

80
Q

miRNA

A

suppress translation –when there is too much, tumor suppressor translation might be affected –when there is too little, oncogene translation might be allowed –> both ways lead to cancer

81
Q

in the sequence of events loss of p53 is a

A

late event

82
Q

sequence of events

A

sequence matter, APC initiates, p53 loss allows progression

83
Q

potential gate keepers are

A

APC, Rb, NF1 –there are few of them and they are tissue specifice

84
Q

Care takers are

A

BRCA1 and 2, p53 – enhances mutations of all genes

85
Q

p53 mutation is resistant to

A

Chemo theramy

86
Q

mutation in BRCA mutation

A

radiation induces dsbreaks so dna repair enzymes are sensitive to irradiation

Pathology (26 decks)

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