Lecture 6: Tumor Suppressors

Question 1

Tumor Suppressor Gene

Answer 1

Gene that encodes a protein that regulates cell division, keeping it in check. Can be inactivated by mutation, methylation, or post-translational modification.

Question 2

Cancer susceptibility gene

Answer 2

A gene that when changed/mutated gives an individual an increased risk of developing cancer.

Question 3

2 main functions of tumor suppressors

Answer 3

1. Gatekeepers: Check progression through cell cycle and cell division
2. Caretakers: Maintenance of cellular genome

Question 4

5 functional types of tumor suppressor GENES

Answer 4

1. Cell cycle progression
2. Receptors or signal transducers
3. Checkpoint-control proteins
4. Induction of apoptosis
5. Repair of DNA

Question 5

7 biological functions of tumor suppressor PROTEINS

Answer 5

1. Inhibition of mitogenic signaling pathways
2. Inhibition of cell cycle progression
3. Inhibition of “Pro-growth” programs of metabolism and angiogenesis
4. Inhibition of invasion and metastasis
5. Maintain chromosomal stability
6. DNA repair factors
7. Induction of apoptosis

Question 6

Hereditary cancer syndrome

Answer 6

Genetic predisposition to certain types of cancer, often with onset at an early age.

Question 7

Predisposition

Answer 7

A type of inherited disorder in which there is a higher than normal risk of certain types of cancer.

Question 8

Gene who causes Cowden syndrome

Answer 8

PTEN

Question 9

Cowden syndrome

Answer 9

Rare inherited disorder marked by presence of many benign, non-cancerous growths called hamartomas and increased risk for developing cancerous tumors.

Question 10

Familial Adenomatous Polyposis

Answer 10

Lining of the colon with numerous small polyps

Question 11

Li-Fraumeni Syndrome

Answer 11

Hereditary disorder that increases the risk you and your family will develop cancer

Question 12

Neurofibromatosis Type 1

Answer 12

Genetic condition that causes tumors to grow along the nerves. Tumors are usually non-cancerous but can become cancerous.

Question 13

Gene associated with Familial adenomatous polyposis

Answer 13

APC

Question 14

Cowden Syndrome

Answer 14

PTEN

Question 15

Li-Fraumeni Syndrome

Answer 15

P53

Question 16

Indicators for potential hereditary risk

Answer 16

-Cancer occurring at young age
-Individuals from families with known mutation associated with cancer risk
-Family history that indicates risk
-1st or 2nd degree relative with any cancer diagnosis under 45 of sarcoma at any age
-Any pattern of cancer association
-Presence of premalignant conditions

Question 17

Retinoblastoma

Answer 17

Condition that causes variety of mechanisms like loss of function mutations and inhibition of RB by binding of viral oncoprotein to inhibit RB anti-proliferative effects in cancer.

Question 18

RBgene

Answer 18

Encodes RB protein that inhibits E2F transcription factors. Transcription factors regulate genes essential for cells to pass from G1 to the S phase of cell cycle.

Question 19

Origin of pediatric retinoblastomas

Answer 19

Arises from precursor of cone cells

Question 20

Leukocoria

Answer 20

Abnormal reflection of a “White Pupil” from greek word leukos for white and kore for pupil. Refers to reflection of white light in pupil

Question 21

Two hit hypothesis

Answer 21

Since most loss-of-function mutations are recessive, both of the tumor suppressor gene cells must be mutated

Question 21

Survival rate of retinoblastomas

Answer 21

95%

Question 22

Two-hit hypothesis in sporadic retinoblastoma

Answer 22

Both normal RB alleles undergo somatic mutation in the same cell. Probability is low.

Question 23

Two-Hit hypothesis in inherited retinobladtomas

Answer 23

Children inherit one RB allele and retinoblastoma develops when the normal RB undergoes a spontaneous somatic mutation known as “The second hit”

Question 24

Two-hit theory in BRCA1 and BRCA2

Answer 24

When one of the 2 active copies of these genes becomes inactive a persons remaining copy will become inactivated causing uncontrolled cell growth

Question 25

Why are mutant proto-oncogenes usually not transmitted to germ line

Answer 25

These mutant cells likely disturb normal cell behavior and disrupt normal tissue development, therefore, embryos rarely develop to term. This causes mutant alleles to disappear from germ-line

Question 26

Why are mutant tumor suppressor genes transmitted through germ-line

Answer 26

Since these alleles often are recessive their presence is usually absent and therefore compatible in embryo development. Cancerous phenotypes become apparent in small number of cells after large delay

Question 27

9 Hallmarks of aging

Answer 27

-Genomic instability -Telomere attrition -Epigenetic alterations -Loss of proteostasis -Disregulated nutrient-sensing -mitochondrial dysfunction -Cellular senescence -Stem cell exhaustion -Altered intercellular communication

Question 27

Cellular senescence

Answer 27

Prevents the proliferation of damaged cells to prevent cancer and promote tissue homeostasis.

Question 28

P53 function in aging process

Answer 28

Decline of function shows possible mechanism for increased tumor incidence

Question 29

P53 Loss

Answer 29

Critical factor in promoting genomic

Question 30

BRCA1 Loss of function

Answer 30

Results from reduced protein expression or incorrect subcellular localization. and works in DNA repair, gene modulation, and cell cycle arrest

Question 31

5 mechanisms of PTEN malignancy

Answer 31

-Mutations -Methylation -RNA/Transcriptional -miRNA -Post-translational modifications

Question 32

Therapeutic approach to compensate for PTEN loss of function

Answer 32

Rapamycin activating mTOR inhibitors in combination treatment to overcome cancer resistance to treatment

Question 33

Promoter methylation

Answer 33

Important mechanism for inactivating tumor suppressor genes

Question 34

Loss of heterozygosity

Answer 34

Loss of one parents contribution to cell known to be involved in somatic loss of wild-type alleles in many inherited cancer syndromes