Carcinogenesis

Question 1

List at least 5 of 7 properties of malignant cancer cells

Answer 1

1. unresponsive
2. Dedifferentiated
3. Invasive
4. Metastatic
5. Clonal in origin
6. Anchorage Independence
7. Growth factor Independence

Question 2

How are malignant cancer cells unresponsive?

Answer 2

they are unresponsive to normal signals for proliferation control.
–> ability to proliferate indefinitely (immortalization!)

Question 3

What is senescence?

Answer 3

The normal finite lifespan of a cell

Question 4

How are malignant cancer cells de-differentiated?

Answer 4

lack many specialized structures/functions (with rounded morphology)

Question 5

How are malignant cancer cells invasive?

Answer 5

Loss of contact inhibition (ability to grow over one another)

Question 6

How are malignant cancer cells metastatic?

Answer 6

they are capable of shedding cells. These cells can drift thru circ. system and proliferate at different sites in body.

Question 7

What does it mean for a malignant cancer cell to be clonal in origin?

Answer 7

derived from a single cell

Question 8

Describe conversion of normal cells to metastatic cells

Answer 8

normal cell -> early neoplasia -> progressive neoplasia -> carcinoma -> metastasis

Question 9

For normal cells to change into neoplastic cells, what must take place?

Answer 9

Change in cellular hereditary must take place

Question 10

Mutagenic events in gametic/somatic cells will produce tumors years later.

Answer 10

somatic cells (ie. UV)

-somatic mut produced by environmental factors.

Question 11

What is the multistep process for carcinogenesis?

Answer 11

1. tumor initiation
2. promotion
3. conversion
4. progression

Question 12

proto-oncogenes are critical for what?

Answer 12

growth
repair
and homeostasis

Question 13

what do tumor suppressor genes code for?

Answer 13

anti-proliferation signals,

proteins that suppress mitosis and growth

Question 14

3 different types of cytogenic abnormalities associated with malignancy?

Answer 14

1. translocations and gene deletions
2. LOH
3. Aneuploidy

Question 15

HPV
what is it?
What does it make?

Answer 15

virus that wants to push cells into S phase.

Makes E6 and E7 oncoproteins

Question 16

What does E6 and E7 do?

Answer 16

E6: inactivates p53
E7: inactivates Rb

Both E6+7 are made by HPV

Question 17

What does the 1st and 2nd hit usually consist of?

Answer 17

1st: a pt mut
- inactivates 1 copy of TSG
2nd: a large del
- that results in loss of functional TSG allele (the last one)

Question 18

retinoblastoma (Rb) tumors show what in ch?

Answer 18

partial or complete deletion of Rb gene in ch14q14

Question 19

How does Rb inhibit txn initiation?

Answer 19

Rb can bind to E2F TF

Question 20

How does Rb get inactivated? (process)

Answer 20

1. GF+EGFR binds CDK 4,6 and CYCD1-3
2. CDK 4,6 and CYCD1-3 bcomes protein kinase
3. protein kinase activates 2nd protein kinase (CDK2 and CYC E)
4. Both protein kinases together inactivate Rb protein (phosphorylates it)
5. Rb cannot bind E2F

Question 21

Hallmark of TSG

Answer 21

tumor cells have descended as clone from single cell that acquired homozygosity for susceptibility to malignancy gene.

Non malignant cells:
-heterozygous loss of TSG
Malignant cells
-homozygosity loss of TSG

Question 22

Familial adenomatous polyposis (FAP) is caused by what??

Answer 22

Autosomal dominant fashion

-LOH of WT APC gene on ch5q
in cells of adenomatous polyps of colon

Question 23

Indiv. who inherit 1 defective APC gene have ___% higher risk of developing colon cancer by 50

Answer 23

90%

Question 24

APC function

Answer 24

1. encodes cytoplasmic protein that regulates phosphorylation which controls localization of beta-catenin
2. cause degredation of unbound cytoplasmic beta-cathenin

Question 25

Breast and Ovarian Cancer mut in what genes?

Answer 25

BRCA1 + BRCA2

Question 26

Functions of BRCA1+2?

Answer 26

1. Scaffold 2. DNA Repair 3. checkpoint

Question 27

Heterozygous mut of BRCA1 + BRCA2?

Answer 27

Breast/Ovarian cancer - | 5% of women with breast cancer are hetero

Question 28

Homozygous BRCA2?

Answer 28

Fanconi's Anemia: -bc BRCA2 is allelic with FAND1

Question 29

75% of p53 mutations - what type?

Answer 29

Missense

Question 30

50% of APC mutations - what type?

Answer 30

Frameshift

Question 31

56 % of ATM mutations - what type?

Answer 31

Frameshift

Question 32

Fanconi's anemia will result in what?

Answer 32

``` pts get bone marrow failure ~5yrs recessive disease (both copies of BRCA2 mut) ```

Question 33

54 % of BRCA1 mutations - what type?

Answer 33

Frameshift

Question 34

Majority of mutations in cancer due to what type of mut?

Answer 34

Frameshift - (inactivates protein)

Question 35

P53 protein is what? Why is mutation in p53 so damaging?

Answer 35

A txn factor (4 subunits) - Dominant negative mutation: prevents WT prot from acting as TXN factor - --->"spoiler" effect: 1 mutated p53 subunit = bad txn factor

Question 36

mut 175 in p53 gene results in what type of cancer?

Answer 36

lung cancer

Question 37

What is the function of beta catenin?

Answer 37

if not P by APC gene --> nucleus and activates txn of oncogenes (C-MYC)

Question 38

If APC is lost, what happens to c-myc?

Answer 38

overexpression of cmyc = cancer

Question 39

What is the function of APC complex (and also E-Cadherin)?

Answer 39

phosphorylates beta catenin, preventing it from entering nucleus

Question 40

HPV: E6 has what type of activity?

Answer 40

Ubiquitin ligase activity -> ubiq p53 -> degredation of p53 if E6 present ---> inhibits apoptosis --->(normally want p53 for apop)

Question 41

HPV: E7 has what type of activity?

Answer 41

Competes with RB (TSG) and pushes cell cycle foward to S phase

Question 42

Retroviruses are single/double strand viruses

Answer 42

single

Question 43

How were oncogenes discovered?

Answer 43

ALV virus: normal (doesnt cause tumor devel) RSV virus: oncogenic 1. found chicken with Src gene next to other genes (gag, pol, env) 2. Saw that the chicken had tumors 3. took out Src and put in healthy chicken 4. Other chicken also devel tumors. -cellular component must be present: Src was incorporated into host genome

Question 44

List 4 viral oncogenes and its oncoproteins

Answer 44

1. Rous sarcoma virus (RSV) : v-src 2. avian erythroblastosis virus (aev) : v-erb 3. abelson leukemia virus (alv) : v-able 4. random fused oncogene w/ gag : v-myc

Question 45

v-src function

Answer 45

causes fibrosarcomas in birds

Question 46

v-erb function

Answer 46

causes erythroblastomas in chickens

Question 47

v-abl function

Answer 47

causes abelson leukemia in mice

Question 48

v-myc function

Answer 48

elicits neoplastic transformation of cells

Question 49

List useful oncogenes that can be used as molecular markers for prognosis in cancer

Answer 49

1. c-ras 2. N-Myc 3. HER2/erbB2 -detection = poor prognosis

Question 50

c-ras gene mutation causes? Model type?

Answer 50

mutation in hu bladder cells ---> production of unregulated ras protein - qualitative

Question 51

N-myc gene mutation causes? Model type?

Answer 51

mutation in neuroblastoma quantitative

Question 52

HER2/erbB2 oncogenic activity? Model type?

Answer 52

gene is amplified in breast cancer ----> causes increased numbers in tyrosine kinase rcptrs quantitative

Question 53

What antibody is used against erbB2/HER2?

Answer 53

herceptin

Question 54

Function of herceptin?

Answer 54

its an antibody that binds to erbB2/HER2 receptor and blocks activity of rcptr. ---->extends life of breast cancer pts

Question 55

What drug is used against chronic myelogenic leukemia?

Answer 55

GLEEVAC!!!!!

Question 56

Function of gleevac?

Answer 56

beesh: its an ATP analog (mimics ATP) - binds to active site of ABL tyrosine kinase in pts w/ BCR-ABL translocation - ---> prevents phosphorylation ---> treats CML