082614 molecular oncogenesis

Question 1

cancer gene targets are?

Answer 1

protooncogenes (activation)
tumor supp. genes
antiapoptosis genes
apoptosis genes
DNA repair genes

Question 2

protooncogene

Answer 2

normal regulatory gene of cell growth

encodes proteins that are growth factors, growth factor receptors, singal transducers, transcription factors, cell-cycle regulators

tight regulatory control

Question 3

oncogene

Answer 3

protooncogene that’s altered

genes involved in autonomous, unregulated cell proliferation

constitutively expressed

Question 4

how can growth factor receptors play a role in cancer?

Answer 4

normally they are transiently activated, leading to dimerization and tyrosine phosphyrltation

can have abnormal constitutive activation–overexpression or mutations

Question 5

ex of growth factor receptors that are encoded by oncogenes

Answer 5

ERB B2 gene (HER2/Neu)

c-KIT gene

Question 6

how does targeted drug therapy target ERB B2 growth factor receptor amplification in breast cancer?

Answer 6

herceptin attaches cancer cell with receptor and tells immune system to target the cancer cell

also, herceptin can stop the cancer from sending to itself signals to grow and divide

Question 7

how to target c-KIT mutations in cancer?

Answer 7

c-KIT is a growth hormone receptor

can use a tyrosine kinase inhibitor

Question 8

what is the single most common abnormality of oncogenes in tumors?

Answer 8

point mutation in RAS

Question 9

what mechanism is reduced in the point mutation of RAS?

Answer 9

GTPase activity

Question 10

c-ABL gene

Answer 10

encodes signal transducing protein that is not receptor linked

protein has tyrosine kinase activity that is normally TRANSIENT

Question 11

what is the philadelphia chromosome?

Answer 11

abnormality in chromosome associated with chronic myelogneous leukemia and acute lymphoblastic leukemia

due to abl gene translocation from chromosome 9 to 22, which renders its expression constitutive

Question 12

myc oncogene

Answer 12

encodes a transcription factor

normally as protooncogene would have transient increase in expression

the oncogene has mutated forms that lead to continued expression (c-myc) or amplification (numberous gene copies: n-myc)

Question 13

how does c-MYC play a role in Burkitt lykmphoma?

Answer 13

the gene translocates from chromosome 8 to 14, causing it to be constitutively turned on because it is now located by the heavy Ig chain gene

Question 14

how does n-MYC gene play a role in disease?

Answer 14

it gets amplified in neuroblastoma

Question 15

how is cyclin D1 involved in tumorgenesis?

Answer 15

is overexpressed in mantle cell lymphoma

due to translocation from chromosome 11 to 14, the Ig heavy chain locus

if cyclin D overexpressed, will cause activation of CDKs and phosphorylation of Rb protein which will cause cell cycle to keep going

Question 16

Two hit hypothesis

Answer 16

loss of fxn of something like tumor suppressor gene would need mutations in both alleles for oncogenesis

Question 17

RB gene

Answer 17

encodes a tumor suppressor protein that is a cell cycle regulator

mutations in RB cause failure of E2F regulation, so you get uncontrolled E2F activation and unregulated cell growth, leading to retinoblastoma

Question 18

APC gene

Answer 18

gene involved in destruction of beta-catenin

tumor suppressor gene

if mutated (two hits), beta catenin accumulates and complexes with TCF, a transcription factor, to stimulate growth factor transcription

Question 19

APC gene disease ex

Answer 19

familial adenomatous polyposis-APC mutations

Question 20

p53

Answer 20

tumor suppressor gene

function normally is to, after DNA damage, arrest the cell in the cell cycle or repair DNA or initiate apoptosis

Question 21

ex pf p53 gene disease

Answer 21

Li-Fraumeni syndrome-inherit a mutated p53 allele (tumor suppressor gene)

increased risk of developing cancer by age 50

Question 22

5 types of protooncogenes

Answer 22

growth factors
growth factor receptors
signal transducers
transcription factors
cell-cycle regulators

Question 23

what is an ex of pro-apoptotic protein?

Answer 23

Bax

Question 24

ex of anti-apoptotic protein?

Answer 24

Bcl-2

Question 25

how does BCL-2 play a role in oncogenesis?

Answer 25

prevents cells from apoptosis

t(14;18) in follicular lymphoma; get overexpression (this is a lower grade tumor b/c it’s not to die vs being told to grow

Question 26

types of specific DNA alterations in cancer

Answer 26

see slide with table

Question 27

what are direct and indirect acting carcinogens

Answer 27

direct: highly reactive electron deficient compounds that react with DNA, RNA, protein (don’t require processing)
indirect: metabolized by cytochrome P450 system

Question 28

initiator vs promoter compounds

Answer 28

initiator is a CHEMICAL that causes permanent DNA mutations (includes direct and indirect acting)

promoter is a nontumorigenic chemical that boosts the proliferation of mutated cells (REVERSIBLE effect), with examples such as hormones and alcohol

Question 29

polycyclic aromatic hydrocarbons’ role in lung cancer, bladder cancer, and laryngeal cancer

Answer 29

found in tobacco smoke, combustion of coal

is an INITIATOR

Question 30

how do viruses cause oncogenesis

Answer 30

viral genome integrates into host DNA–can get overexpression of viral proteins that affect host cell growth or disruption of protooncogene

can stimulate host inflammatory response with subsequent regeneration, which has the potential for insults to DNA and tumorgenesis

Question 31

how can EBV infection contribute to Burkitt lymphoma?

Answer 31

in an immunosuppressed pt, there’s lack of T cells regulating B cells so B cells proliferate and aren’t checked

Question 32

how do hepatitis viruses cause oncogenesis

Answer 32

chronic liver injury leads to regeneration

HBx protein of hep B activates growth genes and inhibits p53

Question 33

how does H. pylori cause oncogenesis

Answer 33

host inflammatory response contributes to carcinogenesis(regeneration, metaplasia, dysplasia, carcinoma)

polycloncal expansion of lymphocytes in MALT can select for clonal population with additional mutations (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue)