Carcinogenesis I

Question 1

Malignant cancer cell properties

Answer 1

1. unresponsive to normal signals for proliferation control
2. de differentiated- lack many of the specialized structures and functions of the tissues
3. invasive- capable of outgrowth into neighboring normal tissues to extend the boundaries of the tumor
4. metastatic- capable of shedding cells and let them drift through circulatory system and proliferate in other sites of the body
5. clonal in origin- derived from single cell

Question 2

multi-step process for carcinogenesis

Answer 2

accumulation of many somatic, genetic alterations, or mutations

Question 3

multi step processes: 4 steps

Answer 3

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

Question 4

heredity vs envrionment

Answer 4

cancer- not inherited disease as single mendelian gene

accumulation of somatic mutations produced by environmental factors

Age- big factor, need time for accumulations

Question 5

Mutation in a DNA repair gene

Answer 5

• increases the rate of mutations
  ex) p53, BRCA1, BRCA2
• earlier the mutation is, more severe the cancer is

Question 6

2 typical mutated genes in tumor initiation

Answer 6

1. oncogenes

2. anti oncogenes or tumor suppressors

Question 7

oncogene

Answer 7

• normally stimulate cellular proliferation

- mutation-> activate

Question 8

tumor suppressor or anti-oncogene

Answer 8

• normally inhabit cellular proliferation

- mutation-> inactivation

Question 9

cytogenetic abnormalities for malignancy

Answer 9

1. translocation and gene deletion
2. Loss of heterozygosity
3. aneuploidy

Question 10

Translocation and gene deletions

Answer 10

activate oncogenes, inactivate the tumor suppressor

Question 11

Loss of heterozygosity (LOH)

Answer 11

loss of tumor suppressor due to one loss from birth (already inactivated and loss of the one allele with function

Knudson theory– two hits or events needed for retinobalstoma, either by sporadic cases or inherited cases

Ex) retinobalstoma, APC gene in FAP (familial adenomatous polyposis)

Question 12

Aneuploidy

Answer 12

poor prognosis of cancers

Question 13

two events for LOH

Answer 13

LOH- loss of normal function of one. Another allele is already inactivated

1st hit: point mutation that inactivates one tumor suppressor gene(TSG), (hereditary cancer syndrome), no cancer

2nd hit: large deletion resulting in the loss of function of TSG allele,
develop cancer

Question 14

how is Knudson’s theory supported?

Answer 14

Loss of heterozygosity causes cancer and it needs the two steps events

Question 15

dominant syndromes cancer

Answer 15

autosomal dominant-
1. familial andenomatous polyposis (FAP-APC gene)

2. familial retinobalstoma (RB gene)- susceptibility inherited, (LOH
3. familal breast and ovarian cancer (BRCA1, BRCA2 gene mutations)
4. Wilms tumor syndromes

Question 16

recessive syndromes cancer

Answer 16

1. xeroderma pigmentosa (XP genes)
2. ataxia telangiectasia (AT gene)
3. Bloom syndrome (FA gene)
4. Fanconi congenital aplastic anemia (FA gene)

Question 17

Rb(retinoblastoma) gene discovery

Answer 17

RB gene–> cancer susceptibility gene

The first anti-oncogene or tumor suppressor gene

Question 18

cytogenetic analysis of retinoblastoma

Answer 18

abnormal chromosome 13q14 structure

Question 19

molecular eveidence for retinoblastoma cells from patients

Answer 19

• lack RB completely
• both RB genes deleted ( PCR or southern blot) in tumor cells
• some patients with partial RB deletions or rearrangements of RB
• RB heterozygous gene in normal nonmalignant retinal cells

Question 20

RB gene protein properties

Answer 20

1. hyper-phosphorylated rapidly in proliferating cell at S or G2
   * ** no inhabition-> cell division
2. hypo-phosphorylated in non-proliferating cell in G0 and G1
   * * repress cell from entering S phase
3. no RB protein–> no down-regulation of cell division
   * ** tumor suppressor
4. Phosphorylation by CDK
   * ** phosphorylation inactivates RB protein (cell G1 to S)
5. target for animal tumor viruses

Question 21

example of animal tumor virus target

Answer 21

1. SV40
2. HPV

-drive quiescent cell into S phase of the cell cycle

• proliferate by producing viral proteins
  -SV40 T antigen
  -HPV E70
  inactivating RB protein

Question 22

HeLa cell

Answer 22

E7 blocks Rb
E6 blocks p53

If E6,7 blocked–> cell returns normal

Question 23

Rb protein function and cancer

Answer 23

• Rb protein inhabits cell to enter S phase ( no proliferation

Question 24

RB protein mechanism

Answer 24

• RB binds E2F family of transcription factor to inhabit the replication

Question 25

cell proliferation requirement

Answer 25

1. EGFR and growth factor interact with CDK4/6 and CyclinD1-3
2. CDK4/6 and CyclinD1-3 phosphorlyate CDK2 and Cyclin E
3. phosphorylated CDK2 and CyclinE phosphorylate Rb
   * * Rb phosphorylation= Rb inactivation
4. Without Rb, cell proliferation

Question 26

mutation of Rb

Answer 26

• Rb cannot bind to E2F transcription factor.

- un-inhabited E2F drives cell to S phase all the time

Question 27

hall mark of tumor suppressor for Rb gene

Answer 27

normal tissue of patient–> one defective retionbalstoma gene, one normal copy
(non-malignant cell–> heterozygous)

tumor cell–> acquired homozygous for retinobalstoma susceptibility gene
- clones from a single cell with acquired homozygous