Cancer

Question 1

What causes cancer?

Answer 1

somatic mutations that deregulate the signaling pathways that control these processes

Question 2

oncogenes

Answer 2

dominantly acting gene that can contribute to cancer; dominant, drive cell growth or survival, accelerator stuck to the floor

Question 3

tumor suppressor genes

Answer 3

genes that must lose their function to become tumorgenic: recessive, normally inhibit cell growth or survival, brake fails

Question 4

gate keepers (tumor suppressors)

Answer 4

recessive, preserve genomic integrity

Question 5

differences between normal and tumor cells (5)

Answer 5

1. contact inhibition 2. serum requirements 3. anchorage independent growth 4.tumorigenesis in mice 5. morphology

Question 6

proto-oncogenes

Answer 6

a normal gene that can become an oncogene through mutation

Question 7

Mutations that convert proto-oncogenes to oncogenes

Answer 7

1. create over-expression of a normal protein 2. create abnormal, constitutively active protein

Question 8

acutely transforming retroviruses

Answer 8

defective viruses that have picked up an oncogene and express it in a cell

Question 9

slow transforming retroviruses

Answer 9

replication competent viruses that activate a cellular proto-oncogene through inserting adjacent to it and changing its expression

Question 10

Ex. Growth factor oncogene: v-sis oncogene

Answer 10

overexpresses PDGF B (growth factor) - generates its own growth factor so that it can be turned on all the time(autocrine or paracrine)

Question 11

Ex. Growth factor receptor oncogenes: EGF receptor and Her2 (v-erbB)

Answer 11

mutation truncates the protein that dimerizes (v-erbB) and will activate tyrosine kinase (no growth factor needed)

Question 12

Ex. Intracellular signal transducer oncogenes: 1. Ras 2. v-RAF

Answer 12

1. if GAP affected so that it cannot convert RasGTP to RasGDP, Ras will stay on 2. v-RAF constitutively activates pathway

Question 13

Ex. Of nuclear transcription factor oncogenes: MAP Kinase

Answer 13

may over phosphorylate and over-activate ets family transcription factors and subsequently fos

Question 14

Ex. Of cyclin oncogene: vin1 (cyclinD)

Answer 14

vin1 will push cells through the G1/S transistion of the cell cycle by phosphorylating Rb and inactivating it so that the cell cycle can procede

Question 15

Ex. Anti-apoptosis pathway oncogene: Bcl-2

Answer 15

when overexpressed, the cell cannot release cytochrome C from the mitochondria, so it can’t undergo the apoptotic process

Question 16

inherited retinoblastoma

Answer 16

early onset, multiple tumors, bilateral

Question 17

sporadic retinoblastoma

Answer 17

late onset, one tumor, unilateral

Question 18

inheritance pattern of retinoblastoma

Answer 18

need two “hits” to have the tumor (inherited already has one hit in all cells, more likely to get the second hit somatically)

Question 19

retinoblastoma

Answer 19

1. caused by mutations that inactivate both Rb alleles (recessise at the cell level) 2. genetically it is inherited in a dominant way (bc it is so likely that they will acquire a second somatic mutation (90% likelihood))

Question 20

loss of heterozygosity (LOH)

Answer 20

when in tumor suppressor genes, the cell is heterozygous for the allele in normal cells - but in tumor cells there is a missegregation, gene conversion, or independent mutation event that makes the cell homozygous for that allele (only have mutant allele)

Question 21

Types of Tumor Supressors: cell cycle inhibitor proteins - p16

Answer 21

p16 regulated G1/S, without it, the cell will go through the cell cycle without this regulating step

Question 22

Types of Tumor Supressors: signaling pathway proteins - TGFB Pathway

Answer 22

pathway that activate genes that regulate the cell cycle, if you can’t activate the pathway there will be unregulated proliferation bc none of the genes have been expressed

Question 23

Types of Tumor Supressors: inhibitors of cell proliferation pathways, Wnt (also GAP-NF1)

Answer 23

Wnt regulates balance of cell death vs cell growth (esp in intestine). Need Wnt to activate transcription of cell cyclin (cyclin D) to promote cell growth

Question 24

Wnt pathway tumor suppressors

Answer 24

APC, Axin

Question 25

Wnt pathway proto-oncogenes

Answer 25

Wnt, B-catenin, c-myc, cyclin D

Question 26

Types of Tumor Supressors: checkpoint control proteins - p53

Answer 26

usually p53 is degraded in the cell, when DNA damage is present, it is phosphorylated and activates p21 to block cell cycle progession - w/o p53 you can’t stop the cell cycle when there is damage and it will accumulate (unique dominant negative mutations of p53 - as long as one of the tetramers is a mutant, it will be inactive AND the mutant copy is much more stable/prevalent)

Question 27

Types of Tumor Supressors: proteins that promote apoptosis - apaf1

Answer 27

need Apaf1 to activate caspases and apoptose, but w/o apaf1 you can not execute apoptosis

Question 28

Types of Tumor Supressors: Dna repair proteins - mismatch, NER, homologous recombo)

Answer 28

if you lose the function of proteins that repair DNA, you have lots of mutations building up!

Question 29

4 mechanisms to activate oncogenes or inactivate tumor suppressor genes

Answer 29

1. missense, nonsense, and frameshift mutations (p53, Ras) 2. Chromosomal rearrangements (inversion, deletion, reciprocal translocation) 3. amplification (extra chromosomes/regions) 4. deletion (tumor suppressor genes, occasionally activates oncogenes)

Question 30

2 possible results of chromosomal translocations

Answer 30

1. cause inappropriate expression of a normal protein (Bcl2) 2. fuse two gene together to create a chimeric, novel protein with altered activity (BCR/ABL)

Question 31

2 mecahnisms of amplification

Answer 31

1. low level - extra chromosomes 2. high level - hundreds of gene copies (homogenously staining regions and double minute chromosomes creates extra chormosomal fragements)

Question 32

how do cancers develope?

Answer 32

usually, it is a multi-step process. Many mutations building up contribute to the final carcinoma

Question 33

examples of using biochem in clinical practice

Answer 33

1. RT-PCR to test for BCR/ABL translocation 2. make tx decisions based on the mutations present in certain cancers 3. targeted therapies (examples. retinoic acid and Imatinib)