Unit 1

Question 1

The cyclin D-cdk4 complex phosphorylates C-terminal residues of pRB upon growth factor stimulation. What events does this lead to?

Answer 1

The cyclin E gene is expressed upon release of HDAC from pRB.

This first step of pRB phosphorylation results in a negative charge that causes intramolecular interactions with lycine residues near the LXCXE domain. The resultant conformation change releases HDAC but not E2F. The release of HDAC from pRB allows expression of the cyclin E gene.

Question 2

What happens if the G1 checkpoint fails?

Answer 2

Arrest of the cell cycle in response to DNA damage to prevent its replication

Question 3

What happens if the G2 checkpoint fails?

Answer 3

Arrest of the cell cycle in response to damaged and unreplicated DNA

Question 4

What happens if the M checkpoint fails?

Answer 4

Arrest of chromosomal segregation in response to misalignment of the mitotic spindle

Question 5

Which one of the following statements concerning the retinoblastoma protein (pRB) is false?

A. pRB phosphorylation is carried out in a single step reaction.

B. pRB regulates the cell cycle by inhibiting the transition from G1 to S phase.

C. pRB can be bound to HDAC and E2F transcription factors at the same time.

D. Conformational changes in pRB result after phosphorylation and cause the release of HDAC and E2F.

Answer 5

A

pRB is phosphorylated in two steps, first by cyclin D-cdk4, and then by cyclin E-cdk2

Question 6

Which one of the following statements is false?

A. Cyclins and their associated cdks coordinate and regulate the passage of cells through the cell cycle.

B. The pairing of cyclins to cdks is non-specific.

C. Cyclin D is the first cyclin to be synthesized.

D. Cyclin D plays a role in the regulation and expression of the cyclin E gene.

Answer 6

B

The pairing of cyclins to cdks is highly specific.

Question 7

Which statement about the mechanisms of pRB action is true?

A. E2F release from pRB causes transcription of cyclin E target genes.

B. HDAC binds to the B-chain of pRB by an LXCXE motif.

C. Phosphorylation of Ser567 by cyclin D-cdk4 causes E2F release.

D. pRB acts as a transcription factor to promote S phase progression

Answer 7

B

A - HDAC release from pRB allows cyclin E gene expression

C - Phosphorylation of Ser567 by cyclin E-cdk2 causes E2F release

D - pRB does not act as a transcription factor but rather inhibits the transcription factor E2F through protein-protein interaction

Question 8

What was the first cdk inhibitor to be tested in clinical trials?

Answer 8

Flavopiridol

a semi-synthetic flavonoid that is a competitive inhibitor of all cdks tested, and acts by targeting their ATP-binding site

Question 9

Which one of the following statements is false?

A. Over-expression of cyclin D by gene amplification is observed in about 15% of breast cancers.

B.Cyclin D enhances estrogen receptor- mediated transcription by binding to the hormone-binding domain.

C. EGFR exerts its mitogenic effect by the induction of cyclin D expression.

D. Experimental evidence suggests Cyclin D is a tumor suppressor gene.

Answer 9

D

Experimental evidence suggests Cyclin D is a proto-oncogene

Question 10

Which one of the following statements about aneuploidy is false?

A. It is the condition of having an abnormal chromosome number and content.

B. It may be caused by defects in centrosomes.

C. It is a common characteristic of human solid tumors.

D. It may be caused by defects in apoptosis.

Answer 10

D

Aneuploidy may lead to cell death.

Question 11

Which statement regarding Aurora kinases is true?

A. They are used to treat breast cancer.

B. Aurora kinases are frequently deficient in human tumors.

C. Aurora kinases are involved in many aspects of mitosis and chromosomal segregation, including regulation of the spindle.

D. Tyrosine kinase inhibitors that target aurora kinases have been tested in clinical trials.

Answer 11

C

A - Inhibitors of Aurora kinases are being developed as cancer therapies

B - Aurora kinases are frequently overexpressed in human tumors and act as proto-oncogenes

D - Aurora kinases are NOT tyrosine kinases. They are serine/threonine kinases. Inhibitors of aurora kinases are in clinical trials.

Question 12

All of the following drugs interfere with microtubule and spindle formation except:

a. Tamoxifen
b. Vincristine
c. Vinblastine
d. Paclitaxel/taxol

Answer 12

Tamoxifen is a competitive inhibitor of estrogen

(Vincristine & Vinblastine inhibit microtuble assembly; Paclitaxel/taxol stabilize microtubules)

Question 13

What are kinases?

Answer 13

enzymes that phosporlate

Question 14

What is an enzyme?

Answer 14

protein that acts as a biological catalyst [to accelerate chemical reactions]

Question 15

What are phosphatases?

Answer 15

enzymes that remove phosphate groups (“undo kinases”; many but not all phosphatases are tumor suppressors)

Question 16

Draw cell cycle stages, including restriction and check points

Answer 16

Question 17

Is cell cycle reversible?

Answer 17

No

Question 18

Which of the following statements about cyclin B is correct?

A. Its protein concentration remains constant throughout the cell cycle.

B. It abruptly disappears in late M-phase due to its degradation in proteosomes.

C. The amount of cyclin B is irrelevant to cell cycle progression and CDK alone can phosphorylates its substrates just fine.

Answer 18

B

Question 19

p15, p16, p21 and p27 [inhibit or activate] cyclin-CDK complexes.

Answer 19

inhibit

Question 20

Is Rb gene an oncogene or tumor suppressor gene?

Answer 20

tumor suppressor gene

Question 21

The Rb protein …

a. is a key substrate of the cyclin / cdk complexes
b. binds and neutralizes epidermal growth factor

Answer 21

b. binds and neutralizes epidermal growth factor

Question 22

When Rb is in the phosphorylated state it releases _____ to be active in regulating gene expression.

A. Ras

B. Akt

C. E2F

Answer 22

C

Question 23

All of the following can be adopted as therapeutic strategies for cancer treatment or intervention except__.

a. inhibitors for cdks
b. overexpression of cyclin D
c. inhibitors of the mitotic spindle
d. inhibitors against Chk1 and Chk2

Answer 23

B

Question 24

What are the upstream activators of p53?

Answer 24

• DNA damage
• Oncogene activation
• Cell stress

Question 25

What are the downstream effects of p53?

Answer 25

* Cell cycle arrest or senescence * DNA repair * Apoptosis * Inhibition of angiogenesis

Question 26

What is the strict definition of a tumor suppressor gene as stated by Knudson’s Hypothesis?

Answer 26

A gene in which a germline mutation predisposes individuals to cancer.

Question 27

Which viral products interact with p53 and pRB? Do they activate or inactivate them?

Answer 27

* Adenovirus E1A, papilloma virus E7 and SV40 LgT **inactivate** RB * Adenovirus E1B, papilloma virus E6 and SV40 LgT **inactivate** p53

Question 28

Which one of the following statements about p53 is false? ## Footnote A. It was the first oncogene to be identified. B. In the absence of cellular stress, low levels of p53 induce antioxidant activity C. It is a transcription factor that contains four distinct domains, including a DNA binding domain. D. The mechanism by which p53 becomes activated is dependent on the nature of the stress signal.

Answer 28

**A** p53 was the first tumor suppressor gene to be identified

Question 29

Which of the following statements about Retinoblastoma is false? ## Footnote A. Familial retinoblastoma involves inheriting one germline mutation in the Rb gene and acquiring a second mutation later in life. B. In the familial form of the disease, one mutated gene increases the probability that a second mutation will occur. C. In sporadic retinoblastoma, mutations occur in both alleles of the Rb gene in the same retinoblast after birth. D. The mechanism of action of the Rb gene in cancer does not follow the concept of a tumor suppressor gene described by Knudson’s two-hit hypothesis.

Answer 29

**D** The Rb gene does fit the concept of a tumor suppressor gene as described by Knudson’s hypothesis: one germline mutation predisposes an individual to cancer.

Question 30

Which of the following does NOT describe p53 mutations in tumor cells: ## Footnote A. Most mutations involve single amino acid substitutions B. Many mutant p53 mutants are more stable than wildtype protein. C. Most occur in the DNA-binding domain. D. Most involve nonsense or frameshift mutations that lead to inactivated truncated protein.

Answer 30

**D** This statement is not true for p53 but describes mutations found in many other tumor suppressor genes.

Question 31

What is the role of PTEN (phosphate and tensin homolog) on chromosome 10? ## Footnote A. Dephosphorylation of PIP2 to form PIP3. B. Dephosphorylation of the membrane lipid PIP3 to form PIP2. C. To cause Cowden syndrome. D. To remove inhibitory signals and hence induce kinase activity.

Answer 31

**B**

Question 32

Which of the following therapeutic drugs targets the p53 regulator, MDM2? ## Footnote A. Pifithrin-alpha B. Herceptin C. Nutlins D. Vinblastine

Answer 32

**C** Nutlins mimic the amino acids of p53 and target MDM2. This aims to activate endogenous p53 in cells that over-express MDM2.

Question 33

Which one of the following correctly describes the downstream cell effects of p53 paired with a p53 target gene? ## Footnote A. Cell stress, apoptosis, DNA damage, cell cycle arrest. B. Cell cycle arrest, apoptosis, DNA repair, inhibition of angiogenesis. C. Aberrant growth signals, oncogene activation. D. Apoptosis, DNA repair, and cell cycle induction.

Answer 33

**B**

Question 34

Which of the following statements regarding Li-Fraumeni syndrome is true? ## Footnote A. It follows Knudson’s two-hit hypothesis. B. Patients develop cancer at an old age. C. Patients develop multiple primary tumors. D. Patients develop retinoblastoma.

Answer 34

**C**

Question 35

Recessive cancer-driver loss-of-function (LOF) mutations are most frequently associated with what genes?

Answer 35

Tumor suppressor genes. Dominant cancer-driver LOF mutations are typically associated with oncogenes.

Question 36

Would you expect the cancer-driver genes carried by oncogenic (cancer causing) retroviruses to be dominant or recessive?

Answer 36

Dominant - otherwise they wouldn't be expected to cause cancer in cells expressing wild-type versions of the genes (i.e., proto-oncogenes).

Question 37

Would you expect the frequency of LOF tumor suppressor mutant alleles or LOF oncogene alleles to be more frequent in human populations?

Answer 37

Because the cancer-causing properties of LOF tumor suppressor alleles are recessive, they would not be expected to be negatively selected against as effectively as would dominant LOF oncogene mutations. Thus, LOF tumor suppressor alleles would be expected to be in relatively higher frequency than LOF oncogene alleles in human populations.

Question 38

Why is a woman who has inherited a copy of a LOF BRCA allele prone to developing breast and/or ovarian cancers?

Answer 38

BRCA is involved in DNA repair (predominantly repair of double-strand breaks) and is a classic example of a tumor suppressor gene. Women who inherit a single LOF BRCA gene will be heterozygous at the BRCA locus with one functional and one non-functional allele. They are more prone to developing cancer because they only need to acquire a single additional LOF in their functional allele as depicted in Knudson's "two hit hypothesis".

Question 39

Why are Ashkenazi Jewish women especially prone to develop breast/ovarian cancer?

Answer 39

Because due to a historic "founder effect" in this ethnic group, the frequency of the LOF mutant BRCA allele is in significantly higher frequency in this group than in other women.

Question 40

What is the difference between kinases and phosphatases?

Answer 40

Kinases phosphorylate proteins in various signaling cascades that often involved in inducing hallmarks of cancer (e.g., unregulated cellular replication,loss of apoptotic function, etc.). Phosphatases antagonize kinase activity by removing phosphate groups

Question 41

Give an example of a tumor suppressor gene that encodes a phosphatase and described the biological significance of a LOF mutation in this gene.

Answer 41

The PTEN gene ("phosphatase and tensin homologue deleted on chromosome 10") was originally cloned as a tumor suppressor for brain tumors. ... PTEN is important because its loss misregulates multiple Akt-dependent and -independent pathways critical for the development of cancer. For example, PTEN de-phosphorylates the membrane lipid PIP3 to form PIP2. This antagonizes the PIP3 kinase pathway favoring oncogenesis.

Question 42

What makes the RB gene an especially important tumor suppressor?

Answer 42

The RB gene encodes is a multifunctional protein (RB) that has over 100 protein-binding partners. It is a transcriptional co-factor that can bind to transcription factors and either induce or inhibit transcription factor activity

Question 43

What are reactive oxygen species (ROS)?

Answer 43

**Reactive oxygen species (ROS)** are chemically reactive chemical species containing oxygen. Examples include peroxides, **superoxide**, hydroxyl radical, singlet oxygen, and alpha-oxygen. Despite their beneficial activities, **reactive oxygen species** clearly can be toxic to cells. ROS often possess an unpaired electron, which makes them highly **reactive** and thereby able to damage all macromolecules, including lipids, proteins and nucleic acids (i.e., DNA/RNA).

Question 44

What is the relationship between p53 and reactive oxygen species (ROS)?

Answer 44

In the absence of cellular stress, low levels of p53 induces antioxidant activity which decreases levels of ROC and subsequent DNA damage. ROS can act as both an up-stream signal that triggers p53 activation and as a downstream factor that mediates apoptosis

Question 45

What are the two potential responses of p53 to cellular stress/DNA damage?

Answer 45

Activation of functional (i.e., non-mutated) p53 by low to moderate levels of cellular stress / DNA damage will initiate cellular responses that suppress tumor formation (cell cycle arrest/DNA repair). More severe DNA damage induces p53 mediated irreversible cell cycle arrest (senescence) and/or apoptosis (programed cell death).

Question 46

What type of regulatory control is mediated by p53 and what is the significance of its regulatory control over the p21 gene?

Answer 46

The protein product of the p53 gene binds as a tetramer to a P53 response element. P53 is believed to bind to app 300 different gene promoters including that of the p21 gene. P21 is a potent cyclin-dependent kinase inhibitor. The P21 protein binds to and inhibits the activity of cyclin-CDK2, -CDK1, and -CDK4/6 complexes, and thus functions as a regulator of cell cycle progression at G1and S phase.

Question 47

What is Ubiquitination?

Answer 47

Ubiquitination (also known as ubiquitylation or ubiquitinylation) is an enzymatic post-translational modification in which a ubiquitin protein is attached to a substrate protein. Ubiquitin is best known for its function in targeting proteins for degradation by the proteasome.

Question 48

What is the "p53-MDM2 feedback loop"?

Answer 48

P53 induces the transcription of the Mdm2 gene, whose protein product, in turn, negatively regulates p53. MDM2 is a ubiquitin ligase that adds ubiquitin to p53 targeting it for degradation.

Question 49

How does p53 regulate apoptosis?

Answer 49

P53 induces genes that promote apoptosis (e.g., NOXA, PUMA, P53 AIP1-all release cytochrome c the activator of apoptosis) and Bax 1while genes that antagonize/block apoptosis (e.g., Bcl2) are repressed.

Question 50

How does activation of the Myc protooncogene affect p53 function?

Answer 50

Without competition from Myc, p53 and cofactor Miz-1 bind to the promoter of p21 and induce transcription resulting in cell cycle inhibition. Upon activation, Myc competes with p53 for the cofactor Miz-1. The Myc-Miz-1 complex binds to the p21 promoter and inhibits transcription thereby blocking cell cycle inhibition (i.e., increased replication) and driving the system towards apoptosis (sometimes facilitated by the binding of other pro-apoptotic cofactors to p53 (e.g., ASPP-apoptosis Stimulating protein) - UNLESS ADDITIONAL MUTATIONS ARISE WHICH INHIBIT APOPTOSIS.

Question 51

How does the human papilloma virus (HPV) interact with p53 to cause cervical cancer?

Answer 51

The p53 gene is rarely mutated in cervical cancers. Rather the the causative agent , HPV, is causally equivalent to a p53 LOF mutation because HPV’s E6 protein leads to the degradation of p53.

Question 52

Which of the following is **not** a mechanism for termination of tyrosine kinase activity of EGFR? ## Footnote A. Additional phosphorylation. B. Dephosphorylation of regulatory phosphorylated tyrosine residues. C. Inhibition of receptor endocytosis and degradation. D. Binding of negative regulators to the kinase domain

Answer 52

**C** Degradation and endocytosis of the EGFR leads to inactivation of this receptor.

Question 53

Which one of the following is the molecular target of the therapeutic drug, Herceptin? ## Footnote A. The tyrosine kinase domain of ErbB2 B. The extracellular domain of ErbB2 C. The transmembrane domain of ErbB2 D. EGF

Answer 53

**B** Herceptin is a monoclonal antibody which binds the extracellular domain of the ErbB2 receptor with high affinity. It induces antibody-dependent cellular cytotoxicity and enhances receptor degradation.

Question 54

Which one of the following statements is **false**? ## Footnote A. MAPKK (MEK) is phosphorylated by activated Raf B. MAPKs function only in the cytoplasm C. The MAP kinase family contain proteins that are serine/threonine kinases. D. MAPKs affect the activity of transcription factors via phosphorylation.

Answer 54

**B** This statement is false. MAPKs enter the nucleus to regulate gene expression.

Question 55

Which of the following therapeutic drugs target Raf tyrosine kinase activity? ## Footnote A. Gleevec B. Herceptin and Erbitux C. Tykerb (lapatinib) and Tarceva (erlotinib) D. Nexavar and Zelboraf

Answer 55

**D** Nexavar is a multi-kinase inhibitor and Raf is one target. Nexavar was approved in 2005. Zelboraf is also a Raf inhibitor.

Question 56

Which of the following statements is **false**, regarding the chronological sequence of events of the EGF signal transduction pathway? ## Footnote A. ...- SOS → RAS-GTP →RAS-GDP→ RAF → MEK ... B. EGF→ binding to EGFR → receptor dimerization → autophosphorylation ... C. Grb2 recognises the phosphate on EGFR with its SH2 domain and recruits the protein SOS via its SH3 domain. D. The EGFR signal transduction pathway illustrates how growth factor signals from outside the cell are passed through the cell and get carried to the nucleus to affect gene expression.

Answer 56

**A** This is false because RAS-GDP is an inactive form of the protein; SOS catalyzes the activation of RAS to its RAS-GTP form

Question 57

Which one of the following statements is false? ## Footnote A. Patients with specific mutations in the EGFR gene respond to Iressa. B. Patients with KRAS mutations respond to Erbitux, a monoclonal antibody that targets EGFR. C. The FDA now recommends screening for KRAS mutations before using Erbitux. D. Herceptin is the first genomics-based therapy administered selectively based on the molecular profile of the tumour.

Answer 57

**B** This statement is false. Patients with KRAS mutations do not respond to Erbitux because KRAS is downstream of EGFR- the target of Erbitux.

Question 58

Which one of the following statements is false? ## Footnote A. Many growth factor receptors are tyrosine kinases. B. SH2 is an example of a protein domain that has high affinity binding for phosphorylated EGFR. C. Raf initiates a serine/threonine kinase cascade. D. Raf is activated by the kinsae activity of RAS.

Answer 58

**D** This statement is a false statement. Although RAS activates Raf, it does not do this via phosphorylation and RAS is not a kinase.

Question 59

Which one of the following statements is true? ## Footnote A. Retroviruses are a major cause of human cancers. B. Proto-oncogenes are altered forms of normal genes. C. Oncogenic activation of receptor tyrosine kinases may occur through specific mutations that lead to constitutive tyrosine activation. D. Oncogenic activation may not occur via epigenetic mechanisms.

Answer 59

**C** This statement is true. Several point mutations in EGFR that lead to constitutive activity have been identified in human tumors.

Question 60

Which one of the following statements about pharmacogenomics is true? ## Footnote A. It is the study of the influence of epigenetic modifications to drug metabolism. B. It is the study of the influence of the genome on an individual’s response to a drug. C. It is the study of drugs that modify the genome. D. It did not influence the patient response to Iressa.

Answer 60

**B**

Question 61

Which of the following cancer drugs is **not** classified as a small molecule tyrosine kinase inhibitor? ## Footnote A. Gilotrif (afatinib) B. Gleevec (imatinib) C. Erbitux (cetuximab) D. Tarceva (erlotinib)

Answer 61

**C** Erbitux is not a small molecule tyrosine kinase inhibitor. It is a monoclonal antibody that binds to the extracellular domain of EGFRs.

Question 62

In relation to interacting transcription factors, which one of the following statements is **false**? ## Footnote A. Both Myc and MAX contain a basic helix-loop-helix leucine zipper. B. Upon interaction with Myc, MAX down regulates tumor growth and suppresses oncogene regulation. C. Upon interaction with MAD or Mxi-1, MAX antagonizes the function of myc. D. The action of MAX is dependent on the identities of its partners.

Answer 62

**B** This statement is false. Interaction between Myc and MAX results in cell proliferation.

Question 63

What are receptor tyrosine kinases?

Answer 63

Receptor tyrosine kinases are proteins located in the membrane of cells . Upon binding of their ligand, they dimerize releasing their kinase domains and the proteins start phosphorylating themselves (auto-phosphorylation).

Question 64

What are the sequential steps that characterize the EGFR signaling pathway?

Answer 64

* growth factor binding * receptor dimerization * autophosphorylation * activation of intracellular transducers * a serine/threonine kinase cascade * activation of transcription factors and subsequent regulation of gene expression

Question 65

How does phosphorylated EGFR lead to activation of RAS?

Answer 65

The phosphorylated receptor recruits GRB and SOS proteins to the cell membrane. SOS activates RAS by the exchange of GDP with GTP.

Question 66

What are the consequences of RAS activation on downstream signaling?

Answer 66

* Activated RAS activates RAF. * RAF phosphorylates/activates MEK. * MEK phosphorylates/activates MAPK. * MAPK (aka, ERK) enters the nucleus and phosphorylates/activates transcription factors turning on genes that control cell growth.

Question 67

What are the three MAP kinase pathways? Which of the MAP kinase pathways is activated by growth factors?

Answer 67

There are at least 3 distinct MAP kinase pathways: MAPK, JNK and p38. While MAPK is activated by growth factors (EGF) , JNK and p38 are activated by environmental signals (e.g., UV and ionizing radiation) and they typically induce apoptosis.

Question 68

Name one important transcription factor that is a target of the MAPK cascade and give an example of a function it regulates?

Answer 68

The transcription factor AP-1 is an important target of the MAPK cascade. For example, AP1 induces cell cycle progression by binding to and activating the cyclin Dprotein- a critical regulator of the cell cycle.

Question 69

In addition to RAF, are there other effector proteins activated by RAS? Give and example and describe it's downstream effect on cell function.

Answer 69

In addition to RAF, there are several other effector proteins activated by Ras- e.g., PI3K. A second messenger, PIP3 recruits PDK-1 and Akt. Activated Akt is involved in anti-apoptotic and other functions by phosphorylating various target proteins. Activated Akt can also get into nucleus and phosphorylate transcription actors (e.g., FOXO) involved in lipid and nucleotide synthesis.

Question 70

Are all tyrosine kinases growth factor receptors?

Answer 70

No, for example SRC is a non-receptor tyrosine kinase protein that in humans is encoded by the Srcgene- it phosphorylates specific tyrosine residues in other non-receptor tyrosine kinases . It plays a role in the regulation of embryonic development and cell growth. An elevated level of activity of c-Src is believed to be linked to cancer progression by promoting other signals relevant to cancer development (e.g., angiogenesis, cell survival).

Question 71

What are potential advantage of targeting cancer therapies to mRNAs rather than proteins?

Answer 71

Only a small fraction of proteins can be inhibited. Protein inhibitors have low specificity and proteins can rapidly acquire resistance to protein inhibitors. Small regulatory RNA drugs can target any gene and they have high specificity. The probability of genes acquiring resistance to RNA drugs is low.

Question 72

What are the 4 types of proteins involved in the transduction of a growth factor signal?

Answer 72

1. growth factors 2. growth factor receptors (many are tyrosine kinases) 3. intracellular signal transducers 4. nuclear transcription factors (which elicit the mitogenic effect thru the regulation of gene expression)

Question 73

Which experimental method is not used to study transcription factor binding? ## Footnote A. Gel/band shift assays B. DNAse footprinting C. Sodium bisulphate treatment and methylation specific PCR D. Promoter mutagenesis and in vitro transcription assays

Answer 73

**C** This method is not useful to study transcription factor binding but rather is used to examine methylation patterns in individual genes.

Question 74

Which one of the following is false? ## Footnote A. Hypermethylation of promoter regions activates gene expression. B. Epigenetic alterations do not cause mutation. C. Epigenetic alterations regulate gene expression. D. Histone acetyltransferases (HATs) acetylate specific histone-tail lysine amino acids and this correlates with increased gene expression.

Answer 74

**A** This statement is false, as hypermethylation causes gene silencing.

Question 75

Which of the following therapeutic strategies is **incorrectly** matched to a drug for cancer treatment? ## Footnote A. DNA methylation inhibitor: 5-aza-2’-deoxycytidine B. Telomerase inhibitor: Imetelstat C. HAT (histoine acetyltransferase) inhibitors: SAHA (vorinostat) D. HDAC (histone deacetylase) inhibitors: Romidepsin

Answer 75

**C** These are wrongly matched. SAHA is an approved drug that acts as an HDAC (histone deacetylase) inhibitor.

Question 76

Which one of the following statements is false? ## Footnote A. AP-1 is a transcription factor which is important for cellular growth, differentiation and death. B. AP-1 binds to the TPA response element in the promoter region of their target genes. C. AP-1 is made of one component from either the Jun family or the Fos family. D. AP-1 is activated in response to specific signals such as growth factors, ROS and radiation.

Answer 76

**C** This statement is false. AP-1 is a dimer of proteins from the Jun and Fos family.

Question 77

Which one of the following enzymes is not associated with epigenetic carcinogenesis? ## Footnote a. DNA methyltransferase b. Telomerase C. DNA polymerase delta/epsilon D. Histone acetyltransferase

Answer 77

**C** This enzyme is involved in DNA repair, such as in nucleotide excision repair, and not in epigenetic carcinogenesis.

Question 78

Which statement below about is false? ## Footnote A. Telomeres can be transcribed into long noncoding RNA that contains telomeric repeat-containing RNA which can inhibit telomerase. B. Telomeres protect the ends of chromosomes from digestion by nucleases. C. Telomere length is maintained in some cells by an enzyme that contains reverse transcriptase activity and an RNA template. D. Telomeres induce mechanisms that repair DNA double-strand breaks.

Answer 78

**D** This statement is false. Telomeres prevent the induction of mechanisms that repair DNA double-strand breaks.

Question 79

Which one of the following statements is false? ## Footnote A. Telomeres shorten with each round of replication. B. Telomeres are composed of thousands of TTAGGG repeats and their associated shelterin complex. C. Telomeres play a role in the replicative potential of a cell. D. Telomerase activity is decreased in 90% of tumors.

Answer 79

**D** This statement is false. Telomerase activity is increased in approximately 90% of tumors.

Question 80

The majority of cancer-related single nucleotide polymorphisms are located in: ## Footnote A. Coding regions of the genome B. Introns and exons C. Untranslated regions and coding regions D. Intergenic (between genes) and introns of the genome

Answer 80

**D**

Question 81

What is the role of histone acetyltransferases (HATs) in epigenetic regulation of transcription? ## Footnote A. They remove acetyl groups from histones. B. They increase chromatin folding by adding acetyl groups. C. They add acetyl groups to histones and relax chromatin folding. D. They restore a positive charge to lysine residues of the histone tails and increase chromatin compaction.

Answer 81

**C** HATs acetylate specific histone-tail lysine amino acids and other non-histone proteins.

Question 82

Which statement about microRNAs (miRNAs) is false? ## Footnote A. They are small non-protein–coding RNAs that are processed into a mature single-stranded molecule that joins with an RNA-induced silencing complex (RISC). B. They hybridize to the 5’ end of a specific mRNA and block the initiation of translation. C. It has been demonstrated that overexpression of a single miRNA, called mir-155, can lead to cancer in mice. D. miRNA expression profiles of tumors are able to discriminate between different types of cancer

Answer 82

**B** This statement is false. miRNAs hybridize to the 3’ untranslated end of a specific mRNA (perfectly) or set of mRNAs (imperfectly) to regulate translation into protein.

Question 83

What is a gene?

Answer 83

A region of DNA sequence that codes for a functional product - could be a protein, rRNA, tRNA, etc

Question 84

Compared with other possible di-nucleotide sequences in mammalian genome, CpG sites are\_\_\_ in genome: A. under-represented B. the same in terms of their frequency C. over-represented

Answer 84

**A** The C in CpG sites is prone to methlyation by DNMTs, and spontaneous deamination of methylcytosine leads to C to T transition.

Question 85

DNA hypermethylation at the CpG island in the promoter region of a tumor suppressor gene _______ the expression of the tumor suppressor gene in cancer cells. A. turns off B. turns on

Answer 85

**A**

Question 86

What does DNMT stand for?

Answer 86

DNA methyltransferase enzymes that mediate the covalent addition of a methyl group

Question 87

What does HAT stand for?

Answer 87

histone acetyltransferase * add acetyl groups * relaxes chromatin folding and leads to increased gene expression

Question 88

What does HDAC stand for?

Answer 88

histone deacetylases * removes acetyl groups * stabilizes chromatin compaction, limits chromatin accessibility and represses gene expression

Question 89

What does HMT stand for?

Answer 89

histone methyltransferase enzyme that catalyzes the transfer of methyl groups to lysine and arginine residues of histone proteins

Question 90

What does lncRNA stand for?

Answer 90

long noncoding RNA

Question 91

Have any epigenetics modifiers been approved for use in the clinic, or are these only hypothetical targets for drug development? A. Some have been approved B. None have been approved. This is only a hypothetical concept

Answer 91

**A**

Question 92

Which of the following is correct regarding the mechanisms of action for miRNAs? A. miRNA completely disrupts target gene function by creating ds DNA breaks in its target DNA sequences. B. miRNA silences the target gene expression by blocking the translation and degradation of its target RNA transcripts.

Answer 92

**B**

Question 93

Telomerase is \_\_\_\_. A. a reverse-transcriptase B. a DNA polymerase C. also called RNA polymerase II

Answer 93

**A**

Question 94

Which of the following are characteristics of epigenetic abnormalities versus genetic abnormalities? A. an epigenetic abnormaly is caused by deletion of chromosomes whereas a genetic abnormality is only caused by changes in single nucleotide B. an epigenetic abnormality cannot be passed from one generation to the other whereas genetic abnormalities are always transmitted from mother to child C. an epigenetic abnormality affects the way genes are expressed but not the DNA sequences of the genes per se whereas genetic abnormalities involve differences in DNA sequences for the normal vs abnormal (cancer) condition

Answer 94

**C**

Question 95

Cancer cells have up-regulated _________ (name the enzyme) activity, which assist in lengthening their telomeres.

Answer 95

telomerase

Question 96

Are microRNAs junk RNAs that have been carried in the genome as pieces of prehistoric genes and have no function now? A. yes B. no

Answer 96

**B**

Question 97

If non-coding RNAs are involved in regulating gene expression, their presence or absence can be used as a tool for diagnosing cancers. A. true B. false

Answer 97

**A**

Question 98

Although most cancers result from the accumulation of mutations over time, evidence suggests that a single catastrophic event may account for a small number of cancers. Which statement below is false? ## Footnote A. Such an event is called chromothripsis. B. Evidence for this event includes the identification of a characteristic translocation betweentwo particular chromosomes in a cancer cell. C. This event is fairly common for bone cancer. D. Three possible mechanisms for this event include ionizing radiation, telomere dysfunction, and/or aborted apoptosis.

Answer 98

**B** This statement is false. Evidence includes many localized rearrangements withina specific chromosome, the pattern of which is unlikely to have occurred by a gradual process.

Question 99

Which of the following intermediates is not formed during radiolysis? ## Footnote A. Hydrogen peroxide B. Superoxide radical C. Hydroxyl radical D. Water

Answer 99

**D** Radiolysis is the interaction of ionizing radiation with water that generates reactive oxygen species.

Question 100

Which one of the following statements is true? ## Footnote A. Alkylating agents are commonly created during the cooking of meat. B. The hydroxyl radical is a very unreactive molecule. C. A short electromagnetic wavelength correlates with low energy radiation. D. The depth of transmission of UV light is dependent on the wavelength.

Answer 100

**D** UVA penetrates the acellular dermis level; UVB penetrates the basal level of the epidermis and UVC is almost completely absorbed by the ozone layer of the atmosphere and rarely reaches the skin. Sunscreens work by use of a variety of UV-absorbent chemicals, both organic and inorganic.

Question 101

What unit is used to indicate the amount of biological damage by radiation? ## Footnote A. Sieverts B. Grays C. Ionizing potential D. Wavelength

Answer 101

**A**

Question 102

Which one of the following pairs of a class of chemical carcinogen and a correspondingexample is not correct? ## Footnote A. Nitrosamines: created by the reaction of preservatives during the smoking of food. B. Polyphenol: epigallocatechin-3-gallate(EGCG). C. Alkylating agents: mustard gas. D. Aromatic amines: benzo[a]pyrene.

Answer 102

**B** This is not a known carcinogen; rather it is a food constituent that is linked to reducing cancer risk and EGCG is a polyphenol found in green tea.

Question 103

Which one of the following cancer drugs mimics an endogenous metabolite and interferes with nucleic acid synthesis? ## Footnote A. Methotrexate B. Cyclophosphamide C. Doxorubicin D. Vincristine

Answer 103

**A** This is an anti-metabolite drug that mimics dihydrofolate. It competitively inhibits the enzyme, dihydrofolate reductase, required for the regeneration of the tetrahydrofolate and results in the disruption of DNA synthesis.

Question 104

Which of the following DNA repair mechanisms are **incorrectly** matched to the type of damage they repair? ## Footnote A. One step repair: damage caused by alkylating agents. B. Base excision repair: bases chemically altered by endogenous mechanisms. C. Nucleotide excision repair: replication errors that have escaped editing by polymerases. D. Mismatch repair: replication errors that have escaped editing by polymerases.

Answer 104

**C** Nucleotide excision repair is specific for helix-distorting lesions caused by environmental agents.

Question 105

UV from the sun is carcinogenic and is the principal cause of skin cancer. Which type ofUV light is the most effective carcinogen and what is the most common UV photoproduct? ## Footnote A. UVA (W.L. 320–380nm) and pyrimidine-pyrimidone photoproducts. B. UVB and pyrimidine-pyrimidone photoproducts. C. UVC and cyclobutane pyrimidine dimers. D. UVB and cyclobutane pyrimidine dimers.

Answer 105

**D** UVB is the most effective carcinogen of the three types of UV light andcyclobutane pyrimidine dimers are the most common UV photoproduct.

Question 106

Which of the following statements about kataegis is false? ## Footnote A. It may be caused by the shattering of a chromosome or chromosomes due to radiation. B. The observation of kataegis shakes the conventional view that cancer is caused by the accumulation of mutations over time. C. It is small localized regions of hypermutation. D. It may be caused by deamination of cytosines to form uracil by a family of cytidine deaminases, called APOBECs.

Answer 106

**A** This statement is false. A shattering of a chromosome or chromosomes isreferred to as chromothripsis.

Question 107

Which statement about “synthetic lethal” combinations is false? ## Footnote A. Poly (ADP-ribose) polymerase (PARP) inhibitors and tumors with BRCA1/2 mutations is asynthetic lethal combination being tested in clinical trials. B. Poly (ADP-ribose) polymerase (PARP) inhibitors block a pathway involved in breast cell proliferation and can be used to treat breast cancer. C. Each of the components in a “synthetic lethal” combination alone does not cause a cytotoxic effect. Healthy cells treated with PARP inhibitors are viable because these cells contain a functioning homologous recombination DNA repair pathway. D. Olaparib is a poly-(ADP-ribose) polymerase (PARP) inhibitor that has been approved for the treatment of ovarian cancer patients with BRCA1 or BRCA2 mutations.

Answer 107

B This statement is false. PARP inhibitors block a DNA repair pathway and not cell proliferation.

Question 108

What are the 3 general steps information flow in cells?

Answer 108

Replication (DNA to DNA) Transcription (DNA to RNA) Translation (RNA to Protein)

Question 109

What are the two types of point mutations?

Answer 109

**Transition:** purine (A & G) replaced by purine; or pyrimidine (C & T) replaced by pyrimidineb) **Transversion:** pyrimidine replaced by purine; or purine replaced by pyrimidine

Question 110

What are three possible consequences of point mutations?

Answer 110

**Synonymous mutations:** DNA change does not change amino acid (due to redundancy of code) **Missense mutations:** DNA change results in amino acid change in protein. **Nonsense mutation:** DNA change results in change from amino acid encoding codon to a STOP codon

Question 111

Burkitt's lymphoma is almost always associated with what type of mutation?

Answer 111

BL is almost always associated with a translocation placing the myc gene under IgH promoter Control

Question 112

What is one of the most significant differences between germline and somatic mutations?

Answer 112

**Germline mutations** are inherited from one generation to the next. **Somatic mutations** are not inherited from one generation to the next.

Question 113

What is the difference between spontaneous and induced mutations?

Answer 113

**Spontaneous mutations** are usually due to random errors in the replication process while **induced mutations** are causally linked to some external (e.g., environmental) factor.

Question 114

What is the consequence of DNA damage in a cell?

Answer 114

DNA damage usually results in a pause in the cell replicative process (cell cycle). If DNA damage is not too severe, the cell attempts to repair the damage. If the DNA damage is severe and cannot be repaired, the cell is usually induced to self-destruct (e.g., apoptosis).

Question 115

How are most point mutations generally repaired?

Answer 115

The most important repair mechanism is theproofreading function of DNA polymerase –ability to excisedmismatched bases and insert correct bases. The DNA replication error rate is around 10^-5; the proofreading function of DNA polymerase reduces this to less than 10^-7

Question 116

Why is excessive exposure to the sun often associated with skin cancer?

Answer 116

Because uv-light can generate thymine dimers which often lead to frame shift mutations. If this occurs in genes associated with the regulation of key cellular processes (e.g., cell cycle control) it can lead to cancer.

Question 117

Why are mutations in the BRCA gene often associated with an increased probability of developing cancer?

Answer 117

The BRCA genes help repair double stranded DNA breaks through homologous recombination. If BRCA genes acquire loss-of-function mutations, the homologous recombination repair system is defective. The alternative non-homologous recombination double stranded break repair system generates deletions at the site of repair that can lead to an increased probability of that functionally significant mutations will arise in genes leading to cancer.

Question 118

Why are PARP inhibitors often used in the treatment of patients with BRCA loss-of-function mutations?

Answer 118

PARP (Poly ADP-ribose polymerase) is involved in the repair of single strand DNA breaks in DNA. If single strand breaks are not repaired, they can lead to an increased frequency of double strand breaks. Double strand breaks will normally be repaired by BRCA-mediated homologous double-strand break repair. It is believed that by chemically inhibiting PARP, the frequency of double strand breaks will occur and that these will be effectively repaired in "normal" cells with functional BRCA genes. However, in cancer cells lacking BRCA function, double strand breaks will not be repaired hopefully leading to targeted death (apoptosis) of cells homozygous for the BRCA mutations.

Question 119

What are the four major categories of cancer therapy?

Answer 119

1. Chemotherapy (DNA-damaging agents, DNA replication inhibitors) 2. Radiation 3. Targeted gene therapy 4. Immunotherapy

Question 120

What are the 10 hallmarks of cancer?

Answer 120

Originally identified: 1. growth signal autonomy 2. evasion of growth inhibitory signals 3. unlimited replicative potential 4. invasion and matastasis 5. angiogenesis 6. evasion of cell death Additions: 1. avoiding immune destruction 2. tumor-promoting inflamation 3. genomic instability and mutation 4. reprogramming energy metabolism

Question 121

What are the hallmarks of normal cell function?

Answer 121

* cell metabolism * cell differentiation * gene / protein regulation * mutation / DNA repair * cell death

Question 122

phenotype of transformed (cancer) cells in culture

Answer 122

* adopt a round morphology (rather than flat and extended) * exhibit anchorage independence (can grow without attaching to the substrate) * can grow in conditions of low serum * fail to exhibit conatact inhibition (grow as piles of cells or "foci" against a monolayer of normal cells)

Question 123

Which one of the following statements correctly describes why there has been an increase in the number of cases of cancer in recent years? ## Footnote A. People are making fewer visits to their doctors. B. People are living longer. C. The genes for cancer confer an advantage of survival and are being selected for during the evolution of the species. D. The growth in the population and migration has enabled cancer to spread.

Answer 123

B Cancer is, most often, a multi-step process. Living longer means that we are exposed to more carcinogens and there is increased time for mutations to accumulate.

Question 124

What are the phases of clinical trials and the purpose of each?

Answer 124

* Phase I: Safety (20-100 healthy patients) * Phase II: Efficacy (100-300) * Phase III: Efficacy & comparison to conventional treatment (1,000-3,000)

Question 125

Which one of the following statements describes the effect of most cytotoxic chemotherapies upon cancer cells? ## Footnote A. Cessation of DNA replication. B. Inhibition of translation and tumor suppressor production. C. Induction of apoptosis by DNA damage. D. Poisoning of the mitochondria to reduce cell metabolism.

Answer 125

C

Question 126

Which of the following statements regarding the “therapeutic index” is false? ## Footnote A. It is the value of the difference between the minimum effective dose and the maximum tolerated dose. B. The larger the value, the safer the drug. C. The therapeutic index for most chemotherapies is small compared to aspirin. D. It is the value of the difference between the maximum effective dose and the minimum tolerated dose.

Answer 126

D The correct definition is: It is the value of the difference between the minimum effective dose and the maximum tolerated dose.

Question 127

Which one of the following characteristics of cancer cells causes cancers to be lethal? ## Footnote A. The ability of cancer cells to change shape. B. The ability to grow in low serum. C. The ability to inhibit angiogenesis. D. The ability to metastasize from a primary site to secondary sites and to invade other organs.

Answer 127

D Metastasis poses a difficult clinical problem: cancer cells compete with normal cells for oxygen and nutrients and can physically obstruct the function of organs.

Question 128

Which one of the following concepts correctly describes what Knudson’s two-hit hypothesis explains? ## Footnote A. Proto-oncogenes can be mutated to become oncogenes. B. The development of cancer is clonal. C. The mechanism behind hereditary conditions that predispose individuals to an increased risk of cancer. D. Haploinsufficiency

Answer 128

C The “two- hit” hypothesis states that both alleles of a tumor suppressor gene need to be mutated to trigger carcinogenesis and that a germline mutation in one allele of a tumor suppressor results in a condition of an increased risk of cancer.

Question 129

Which one of the following statements is false? ## Footnote A. Cancer is considered as a group of diseases. B. There are approximately ten types of cancer. C. Cancer is diagnosed by the presence of a malignant tumor. D. A cancer is described according to its cell of origin.

Answer 129

B This is false. Over 100 types of cancer have been classified and subsets are still being defined.

Question 130

Which one of the following statements correctly describes an oncogene? ## Footnote A. A gene that codes for a protein that helps inhibit tumor growth and formation. B. A mutated gene whose protein product is produced in increased quantities or has increased activity and contributes to carcinogenesis. C. A type of cancer therapy. D. A mutated gene whose protein product is produced in deficient quantities and contributes to carcinogenesis.

Answer 130

B It acts in a dominant manner to initiate tumor formation.

Question 131

What is the relevance of the Human Genome Project to cancer biology? ## Footnote A. We now understand that the genomic profile of an individual’s tumor is not unique to that patient but shared among all those with that type of cancer. B. It has used technologies that are so efficient it will be a long time before improvements are made. C. It provided the basis for whole-genomic sequencing of individual tumors and genome-wide association studies. D. The completion of the Human Genome Project has allowed us to know who will get cancer later in life.

Answer 131

C Work by Puente et al. (2011) and Wolpin et al. (2014) are examples. The International Cancer Genome Consortium has been organized to characterize and sequence several hundreds of tumors for 50 types of cancer.

Question 132

What is cancer?

Answer 132

Cancer is a disease caused when cells divide uncontrollably and spread into surrounding tissues.

Question 133

What are possible reasons why the frequency of different types of cancer varies among ethnic groups/geographic locations?

Answer 133

Genetics Environment (diet, pollution, bacteria/viruses)

Question 134

What is evidence that cancer is a genetic-based disease?

Answer 134

Mutagens are carcinogens; oncogenic viruses carry cancer causing genes, propensity for cancers is an inherited trait

Question 135

What might explain why the frequency of cancer onset increases with age?

Answer 135

Somatic mutations accumulate over time immune system functions are reduced with age

Question 136

What are Cancer Driver Genes?

Answer 136

Cancer driver genes (CDGs) are the genes whose mutations cause tumor growth.

Question 137

What is the difference between oncogenes and tumor suppressor genes?

Answer 137

Both are cancer driver genes. Cancer causing mutations in oncogenes are usually dominant while cancer causing mutations in tumor suppressor genes are usually recessive.

Question 138

What is the difference between cell death due to necrosis and apoptosis?

Answer 138

**Necrosis** has been classically defined as an unprogrammed form of cell death that occurs in response to overwhelming chemical or physical insult. Typical endpoints of necrosis include the swelling and rupture of necrotic cells **Apoptosis** (from Ancient Greek ἀπόπτωσις, apóptōsis, "falling off") is a form of programmed cell death that occurs in multicellular organisms

Question 139

What is meant by the terms "gene regulation"?

Answer 139

Gene regulation is the process of turning genes on and off. During early development, cells begin to take on specific functions. Gene regulation ensures that the appropriate genes are expressed at the proper times.

Question 140

At what levels can gene regulation occur?

Answer 140

Transcriptional (DNA to RNA) Post-transcriptional (RNA modification) Translational (RNA to Protein) Post-translational (protein modification)

Question 141

What is a "cellular signaling pathway"?

Answer 141

Cell Signaling Pathways. Cell signaling governs basic cellular activities and coordinates cell actions through a complex coordination of responses to cellular microenvironment. A cell receives signals from its environment when a molecule, such as a hormone or growth factor, binds to a specific protein receptor on or in the cell. After the first molecule in the pathway receives a signal, it activates another molecule. The disruption or errors found within this communication chain gives rise to various diseases and cancers.

Question 142

Cell function is dependent upon a highly integrated network of gene/protein interactions. How does this present a challenge to our understanding and treatment of cancer?

Answer 142

It suggests that cancer should be considered as a system-wise diseaseand not a problem in one or a few genes.