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ch 7 pt 2 Flashcards

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1
Q

genomic themes in carcinogenesis

A

nonlethal genetic damage, clonal expansion of a single precursor cells

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2
Q

4 classes of regulatory genes tend to be affected

A

growth-promoting proto-oncogenes, growth-inhibiting tumor suppressor genes, -genes that regulate apoptosis, -DNA-repair genes

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3
Q

complementary mutations occur in a stepwise fashion over time- resulting in?

A

cancer hallmarks, -driver mutations, -loss of fxn mutations

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4
Q

epigenetic modifications- include?

A

DNA methylation -histone modifications; dictate which genes are expressed- determines the lineage commitment and diff state of both normal and neoplastic cells

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5
Q

oncogene- what is it

A

any gene that may be related to the development of cancer

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6
Q

hallmarks of cancer

A

1- self-sufficiency in growth signals 2- insensitivity to growth-inhibitory signals 3- altered cellular metabolism 4- evasion of apoptosis 5- limitless replicative potential, 6- sustained angiogenesis 7- ability to invade and metastasize, 8- ability to evade host immune response

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7
Q

accelerate the features/hallmarks of cancer

A

genomic instability and cancer-promoting infl

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8
Q

immortality of cancer cells

A

evasion of senescence, -evasion of mitotic crisis, -self-renewal

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9
Q

oncogenes- roles

A

GFs, -GF Rs, -proteins involved in signal transduction, -nuclear regulatory proteins, -cell cycle regulators

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10
Q

act of EGF R tyrosine kinase

A

by point mutation -lung cancer

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11
Q

act of HER2 R tyrosine kinase

A

by gene amplification -breast cancer

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12
Q

act of JAK 2 tyrosine kinase -myeloproliferative disorders

A

by point mutation

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13
Q

act of ABL nonR tyrosine kinase

A

by chromosomal translocation- creates BCR-ABL gene -chronic myelogenous leukemia, acute lymphoblastic leukemia

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14
Q

BCR-ABL fusion gene

A

in CML (chronic myelogenous leukemia) and acute lymphoblastic leukemias, -ABL gene translocated from 9 to 22; BCR-ABL gene tyrosine kinase- constitutively active

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15
Q

increased expression of MYC

A

chromosomal translocation- Burkitt lymphoma, other hematologic malignancies, gene amplification- neuroblastoma

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16
Q

MYC- what is it?

A

proto-oncogene; belongs to the immediate early response genes- induced by RAS/MAPK signaling following GF stim; -tightly controlled; -all pathways that reg growth impinge on MYC

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17
Q

MYC- fxns

A

major transcriptional regulator of cell growth, act the expression of many genes involved in cell growth, -reprogram somatic cells into pluripotent stem cells; -act telomerase

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18
Q

MYC- assoc with?

A

Burkitt lymphoma (and other B and T cell tumors); -neuroblastoma; -many common carcinomas

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19
Q

MYC and burkitt lymphoma

A

chromosomal translocation- leads to increased MYC protein

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20
Q

CDK inhibitors

A

p21, p27, -INK4/ARF

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21
Q

inhibitors of mitogenic signaling pathways

A

APC, NF1, NF2

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22
Q

APC

A

gatekeeper of colonic neoplasia -inhibitor of WNT signaling -familial colonic polyps and carcinomas -carcinomas of stomach, colon, pancreas; melanoma

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23
Q

APC- mech

A

in resting colonic epit cells- B-catenin forms a complex containing APC- causes destruction of B-catenin; when colonic epit cells are stim by WNT- destruction complex is deact- B-catenin isnt destroyed- goes to nucleus- act genes for cell cycle progression

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24
Q

APC mutated/absent- mech

A

(occurs in colonic polyps and cancers); destruction of B-catenin cannot occur- B-catenin goes to nucleus- act genes for cycle progression

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25
NF1
inhibitor of RAS/MAPK signaling; neurofibromatosis type 1; neuroblastoma, juvenile myeloid leukemia
26
NF2
merlin; cytoskeletal stability, Hippo signaling pathway; -neurofibromatosis type 2; -schwannoma, meringioma
27
inhibitors of cell cycle progression
RB
28
RB
tumor suppressor gene; -binds E2F TFs in its hypophosphorylated state- prevents G1/S transition; -retinoblastoma, osteosarcoma carcinomas of breast, colon, lung
29
inhibitors of pro-growth programs of metabolism and angiogenesis
VHL
30
VHL
(Von Hippel Lindau) protein; -inhibitor of hypoxia-induced TFs (HIF1alpha); -renal cell carcinoma
31
VHL- mech
encodes a component of ubiquitin ligase that degrades hypoxia-induced factors (HIFs- TFs that alter gene expression in response to hypoxia)
32
germline loss-of-fxn of VHL; -autosomal dominant
von Hippel Lindau syndrome; -high risk of renal cell carcinoma and pheochromocytoma
33
acquired loss-of-fxn of VHL
sporadic renal cell carcinoma
34
inhibitors of invasion and metastasis
CDH1 (cadherin)
35
CDH1 (cadherin)
cell adhesion, inhibition of cell motility; familial gastric cancer; gastric carcinoma, lobular breast carcinoma
36
enablers of genomic stability
TP53
37
TP53
tumor suppressor; -acts thru p21 to cause cell cycle arrest; -causes apoptosis- induces BAX; -regulated neg by MDM2; -li-fraumeni syndrome; -most human cancers
38
DNA repair factors
BRCA1, BRCA2
39
BRCA1, BRCA2
repair of dbl-stranded breaks in DNA; -familial breast and ovarian carcinoma; chronic lymphocytic leukemia
40
WT2
Wilms tumor-1; -TF; -Familial Wilms tumor; -Wilms tumor, certain leukemias
41
2 hit hypothesis of oncogenesis - assoc with?
RB gene; -especially interaction with E7 protein of HPV
42
role of RB in regulating G1-S checkpoint
GFs- act cyclins D/E- hyperphosphorylated RB- cant bind to E2F- transcriptional act.; -growth inhibitors- CDK inhibitors (p16/INK4a)- inact cyclins D/E- hypophosphorylated RB- binds to E2F- blocks transcription
43
antiproliferative effect of RB- in cancers- mechanisms:
loss-of-fxn mutations affecting RB; -gene amplifications of CDK4 and cyclin D genes; -loss of cyclin-dependent kinase inhibitors (p16/INK4a); -viral oncoproteins that bind and inhibit Rb (E7 protein of HPV)
44
p53- mech
central monitor of stress in the cell; act by anoxia, inappropriate signaling by mutated oncoproteins, or DNA damage; -DNA damage sensed by complexes containing kinases of the ATM/ATR family- phos p53- liberating it from inhibitors such as MDM2; -active p53 upreg expression of proteins such as cyclin-dep kinase inhibitor p21- causes cell-cycle arrest at G1/S- allows time for DNA repair; if DNA damage cannot be repaired- p53 leads to apoptosis/senescence
45
mech's used by tumor cells to avoid apoptosis
intrinsic pathway; -extrinsic pathway
46
apoptosis- intrinsic pathway
DNA damage- p53 response- BAX- cytochrome c- APAF-2- caspase 9; (lesions most common in this pathway)
47
apoptosis- extrinsic pathway
FASL to FAS (CD95)- FADD- caspase 8
48
in 85% of follicular B-cell lymphomas
anti-apoptotic gene BCL2 is overexpressed due to a 14;18 translocation
49
RB- 2 hit hypothesis- familial cases
2 hits are required to produce retinoblastoma; -1 defective copy in germline (1st hit) and 1 normal RB allele; Retinoblastoma develops when the normal RB allele is mutated (second hit); -2nd hits are inevitable in some retinoblasts- autosomal dominant trait
50
RB- 2 hit hypothesis- sporadic cases
both normal RB alleles must undergo somatic mutation in the same retinoblast (2 hits)
51
p53- therapeutic implications
tumors with wild type TP53 alleles- most likely killed by therapy; -mutated TP53 alleles- not killed by therapy; -testicular teratocarcinomas and childhood acute lymphoblastic leukemias (have wildtype TP53 alleles)
52
mutated TP53- therapeutic implications
lung cancers, colorectal cancers; resistant to chemotherapy
53
intrinsic features characteristic of malignancy
angiogenesis; -invasion and metastasis; -evasion of host defenses
54
angiogenesis- triggered by?
hypoxia- thru HIF-1alpha on VEGF
55
regulates angiogenesis
p53- induces syn of angiogenesis inhibitor thrombospondin-1; -RAS, MYC, MAPK- upreg VEGF expression
56
invasion and metastasis- 4 steps
loosening of cell-cell contacts; -degradation of ECM -attachment to novel ECM components -migration of tumor cells
57
cell-cell contacts- lost by?
inact of E-cadherin
58
basement memb and interstitial matrix degradation- mediated by
proteolytic enzymes secreted by tumor cells and stromal cells -MMPs and cathepsins
59
many tumors arrest in what?
1st capillary bed they encounter
60
organ tropism of tumors
due to expression of adhesion or chemokine R's whose ligands are expressed by endo cells at the metastatic site
61
genes that promote epit-mesenchymal transitions
TWIST and SNAIL; -important metastasis genes in epit tumors
62
evasion of host defense- tumor ag's
products of mutated proto-oncogenes, tumor suppressor genes, overexpressed proteins, tumor ags produced by oncogenic viruses, oncofetal ags
63
immunosuppressed pts- increased risk for
cancer caused by oncogenic DNA viruses
64
tumors can avoid immune system in immunocompetent pts- how?
selective outgrowth of ag-negative variants; -loss of reduced expression of histocompatibility ag's; -immunosuppression mediated by certain factors by tumor cells (TGF-B, PD-1 ligand, galectins)
65
oncofetal ags
proteins expressed at high levels on cancer cells and in normal developing (fetal) tissues
66
antitumor effector mech's
CTL, NK cells, macrophages

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