03/02d Neoplasia III

Question 1

What is clonal expansion?

Answer 1

The idea that all the cells in a tumor or cancer are derived from a single cell
This is confirmed by the fact that all cells maintain the earliest genetic alteration that lead to cancer

Question 2

Why do tumor cells have so many mutations?

Answer 2

They must change to evade the immune system, develop metastasis, and initiate angiogenesis

Question 3

What is the progression of genetic mutations in HNPCC?

Answer 3

1) Mutations in tumor suppressors - APC/beta-catenin, FAP
2) Mutations in oncogenes - FAS/BRAF, 18q
3) Mutations in chromosomal or microsatellite genes (caretaker genes) - p53, PIK3CA

Question 4

What gene functions can be altered in cancer? Name seven

Answer 4

1) Oncogene activation - self-sufficient from growth factor
2) Inactivation of tumor suppressor genes - ignore inhibitory signals
3) Evasion of apoptosis
4) Defects in DNA
5) Expression to telomerase - limitless replicative potential
6) Sustained angiogenesis
7) Ability to invade and metastasize

Question 5

What genetic mechanisms can occur to activate oncogenes or inactivate tumor suppressors?

Answer 5

1) Mutations, and disruptions by viruses
2) Genetic amplifications, usually of areas containing oncogenes
3) Deletion of tumor suppressor genes
4) Translocations, often of chromosome segments

Question 6

What are protooncogenes? What is their relationship with oncogenes?

Answer 6

Protooncogenes are normal cellular genes which are involved in growth regulation (growth factors, growth factor receptors, growth signal pathways, etc.)
When protooncogenes are activated in specific ways, they become oncogenes and lead to unrestricted growth

Question 7

What is SRC?

Answer 7

A gene that is acquired from host cells by Rous sarcoma virus when it integrates into the host genome
Functions to stimulate host cells to divide, and thus spread more virus

Question 8

What is c-SRC? What is v-SRC?

Answer 8

c-SRC is a proto-oncogene, which functions in controlling cell division and has an inhibitory site at its C-terminal
v-SRC is an oncogene, which lacks the inhibitory site found on c-SRC and is thus constitutively active, which leads to inappropriate cell division

Question 9

What is the most common oncogene found in human cancers?

Answer 9

Ras

Question 10

What does Ras code for?

Answer 10

A protein that binds GTP and degrades it to GDP

When mutated, Ras encodes a constitutively active protein which continually transduces signals for cell growth

Question 11

What are five oncogenes which are commonly amplified in human cancers?

Answer 11

Ras
Myc
Cyclin D1 (CCND1)
EGFR (ERBB1) 
ERBB2 (Her2/neu)

Question 12

What is a tumor suppressor gene?

Answer 12

A gene that slows cell growth, causes cell differentiation, activates apoptosis, or repairs DNA

Question 13

What is the significance of amplified ERBB2?

Answer 13

Correlates with poor prognosis in breast cancer

Question 14

Chromosomal translocation between Ch. 8 and Ch. 14 corresponds with what type of cancer?

Answer 14

Burkitt’s lymphoma

Question 15

Chromosomal translocation between Ch. 9 and Ch. 22 correspond with what type of cancer?

Answer 15

Chronic myelogenous leukemia

Question 16

How many alleles do you need to activate an oncogene

Answer 16

1

Question 17

How many alleles do you need to activate a tumor suppressor?

Answer 17

2

Question 18

What is the function of Rb?

Answer 18

Controls the cell’s transition from the G1 phase to the S phase of the cell cycle

Question 19

How does Rb work?

Answer 19

Hypophosphorylated Rb binds to E2F (transcription factor) –> cell cycle does NOT progress
Hyperphosphorylated Rb does not bind to E2F –> cell cycle moves forward

Question 20

What is TP53?

Answer 20

“The guardian of the genome”
Prevents replication of DNA which has been damaged
Mutated in more than half of human tumors

Question 21

What happens if p53 is mutated?

Answer 21

The cell cycle isn’t halted when DNA is damaged

Damaged DNA is passed on to new cells, which leads to accumulation of mutations

Question 22

What are “gate-keeper genes”?

Answer 22

Tissue-specific cancer genes

Mutated at a very early stage of cancer initiation

Question 23

What genes are often mutated in familial adenomatous polyposis?

Answer 23

APC/beta-catenin pathway proteins

Question 24

What is the function of APC/beta-catenin pathway? What happens when it is mutated?

Answer 24

APC binds beta-catenin, which prevents the transcription of growth-promoting genes
Mutations in APC or catenin allow unregulated transcription of growth-promoters, which can lead to colorectal tumors

Question 25

What are caretaker genes?

Answer 25

Genes which maintain genomic or stability by DNA repair or maintenance of chromosomal stability
Loss of function increases the risk of mutations in other genes, such as oncogenes and tumor suppressors

Question 26

What is HNPCC?

Answer 26

Hereditary non-polyposis colon cancer
Occurs at a young age, and does not arise in polyps
Found in multiple direct family relatives
Due to mutations in DNA mistmatch repair genes

Question 27

What is Warburg’s hypothesis?

Answer 27

The idea that the primary cause of cancer is the replacement of the respiration of oxygen in normal body cells by aerobic glycolysis