L7 Flashcards
Another name for TS genes
Anti-growth gene
What are TSGs
Genes that suppress cell proliferation
Phenotype of TSGs?
Usually RECESSIVE at cellular lvl i.e. TSG loss usually affects cells phenotype when both copies of gene are lost
Dominant vs. recessive: these terms refer to ______ of a gene, or to phenotype
Dominant vs. recessive: these terms refer to ALLELES of a gene, or to phenotype
e.g. an allele that expresses its phenotypic effect even when heterozygous with a recessive allele is _____
dominant
Oncogene mutations are _______: phenotype is evident even when heterozygous – they typically act as ______ (gain-of-function) or _______ (new function)
Oncogene mutations are DOMINANT: phenotype is evident even when heterozygous – they typically act as HYPERMORPHS (gain-of-function) or NEOMORPHS (new function)
Does Knudson’s 2-hit hypothesis apply to oncogenes, TSGs, or both?
Only TSGs because they are recessive. TSG loss usually affects cell phenotype when both copies of the gene are lost.
TSG mutations are typically ______ (reduced function) or ______ (complete loss-of-function or null)
TSG mutations are typically HYPOMORPHS (reduced function) or AMORPHS (complete loss-of-function or null)
Whare are the 2 forms of retinoblastoma (Rb)
Sporadic and familial/inherited forms of the disease
How does inherited/familial retinoblastoma differ from sporadic?
Inherited
- Occurs at younger age
- Develop tumor in BOTH eyes (bilateral), suggesting underlying predisposition
- Those with bilateral disease (often seen in inherited retinoblastoma) have greatly inc risk of developing bone cancer in adolescence. Contrast to, after treatment, children w/unilateral sporadic retinoblastoma had no further risk of retinoblastoma and no elevated risk of tumors elsewhere
What did Knudson conclude after his kinetic analysis on retinoblastoma
- Rate of occurrence of sporadic retinoblastoma consistent with 2 RANDOM EVENTS
- Rate of occurrence of inherited retinoblastoma consistent with SINGLE RANDOM EVENT
- Knudson suggested that multiple “hits” to DNA were necessary to cause cancer. In the children with inherited retinoblastoma, the first insult was inherited in the DNA, and any second insult would rapidly lead to cancer. In non-inherited retinoblastoma, two “hits” had to take place before a tumor could develop, explaining the age difference.
Draw the genes and mutations and disease of Rb, comparing inherited vs. non-inherited
Lecture 7 Slide 8
What are 5 mechanisms of LOH?
- Loss of the chromosomal region harboring the gene
- Mitotic recombination (a rare event)
- Inappropriate chromosomal segregation
- Gene conversion
- Epigenetic gene silencing by methylation of the promoter
Using a diagram, depict how mitotic recombination can lead to LOH
Slide 10
Using a diagram, depict how chromosomal non-disjunction can lead to LOH
Slide 11
Mis-segregation of chromosomes during mitosis
Using a diagram, depict how gene conversion can lead to LOH
Slide 12
- DNA pol begins replication replication on template strand of red chromosome
- DNA pol jumps to template strand of homologous, green chromosome
- After copying segment of green template strand, DNA pol jumps back to template strand of red chromosome and continues copying
What is a CpG island
- A cluster of CpG dinucleotide sequences, often located in the vicinity of a gene PROMOTER
- Higher G+C content than the genome average
- Typically are unmethylated in normal cells
Using a diagram, depict how epigenetic silencing by methylation of promotor can lead to LOH
Treatment of DNA with BISULFITE converts the CYTOSINE residues to URACIL but leaves the 5methylcytosines (most common methylation mark) residues unaffected. Methylation of CpGs can REPRESS TRANSCRIPTION of the nearby gene (ie. mechanism of LOH)
How to find tumor suppressor genes?
- RE-based genetic markers (i.e. DNA probes)
- DNA sequence analyses
- mRNA analyses
- Protein levels
_____ arm of chromosome ____ contains p53; very commonly mutated TSG
SHORT arm of chromosome 17 contains p53; very commonly mutated TSG
Describe and draw a diagram showing pRB and cell cycle control
Slide 23
Retinoblastoma protein: transcriptional repressor;; binds E2F transcription factor - Phosphorylated Rb is inactive, lifts repression on E2F, and allows cell cycle progression
TSGs act to constrain cell proliferation or survival ( “gatekeepers”; i.e. suppress increases in cell # by suppressing ______ or triggering ________
Other: those that act to maintain the genome and suppress ______ (“caretakers”)
TSGs act to constrain cell proliferation or survival ( “gatekeepers”; i.e. suppress increases in cell # by suppressing PROLIFERATION or triggering APOPTOSIS
Other: those that act to maintain the genome and suppress MUTATIONS (“caretakers”)
In most cases, ____ copies of a TSG must be inactivated to cause a proliferation/survival advantage
In most cases, BOTH copies of a TSG must be inactivated to cause a proliferation/survival advantage
However, some TSGs are ______
i.e. loss of _____ allele leads to increased tumor susceptibility
However, some TSGs are HAPLOINSUFFICIENT
i.e. loss of ONE allele leads to increased tumor susceptibility
The loss of TSGs may occur far more frequently during the development of a tumor than the activation of proto- oncogenes into oncogenes. Why?
There are more to inactivate a gene than to specifically “activate” it e.g. many diff DNA mutations could result in loss-of-fxn e.g. premature stop codon
*Note either event may be necessary but not sufficient for tumorigenesis
Why don’t individuals who carry a mutant TSG get thousands of tumors? (e.g. a mutant TSG undergoes LOH in approx 1 in 105 cells, and adult has more than 1013 cells)
Because cancer is a “multi-step” process
- A mutant gene may be necessary for tumor formation But not, on its own, be sufficient for tumor formation
- Mutations in additional oncogenes or TSGs are required
Why don’t all individuals who carry a mutant oncogene get cancer?
Because cancer is a “multi-step” process
- A mutant gene may be necessary for tumor formation But not, on its own, be sufficient for tumor formation
- Mutations in additional oncogenes or TSGs are required
Example how colon tumor progression and LOH in various chromosomal arms are needed for tumour formation
Slide 27
Draw the paradigms of tumor supression
Slide 30
Define quasi sufficiency
tumor suppression is impaired after subtle downregulation of expression level even without complete loss of one allele (even subtle downregulation has an effect)
Define obligate haploinsuffiency
occurs when haploinsufficiency is more tumorgenic than complete loss of TSG (aka both alleles). this is usually due to activation of fail-safe mechanisms following complete loss of TSG expression ie.e. cell compensates for complete loss but not partial loss.
Slide 32
N/A
What are examples of distinct molecular mechanisms that might be responsible for converting a proto-oncogene into a potent oncogene?
- Gene amplification
- Chromosome rearrangement
- Mutation
- insertional mutagenesis
- AA substitution - Post-transcriptional modification by miRNAs leading to an oncogenic phenotype
- Epigenetic changes leading to INC ACTIVITY
- Cause increase or deregulation of expression
- Cause alteration of oncogene structure
Why is the inheritance of mutant, activated oncogenes responsible for only a small proportion of familial cancer syndromes, while the inheritance of defective tumor suppressor genes (TSGs) is responsible for the majority of these diseases?
“Inheritance of a defective allele of a TSG is often compatible with normal embryonic development. The phenotypic effects of this genetic defect may only become apparent with great delay, sometimes in midlife, when its presence is revealed by the loss of the surviving wild-type allele (e.g. LOH) and the outgrowth of a particular type of tumor. “ (adapted from Weinberg, p. 247).
Inheritance of mutant activated oncogenes are often incompatible with normal embryonic development and thus would not be transmitted to the next generation. A single mutant (oncogene) allele is often sufficient to generate a phenotype (ie. is dominant)
How might the loss of TSG function yield an outcome that is, at the cell biological level, indistinguishable from the acquisition of an active oncogene?
A TSG and an active oncogene could act on the same signaling pathway in a cell.
E.g: Neurofibromin (NF1) is a TSG;; it normally functions as a Ras-GAP that strongly stimulates GTP hydrolysis and Ras inactivation. If NF1 function is lost, then Ras will not be inactivated. In this example, the TSG would have a phenotype similar to an oncogenic Ras mutation that inactivates the intrinsic GTPase activity of Ras, thereby leading to constitutively activated Ras signaling.
I.e. loss-of-function of NF1 (a tumor suppressor) leads to the same result as gain-of-function of Ras (an oncogene);; the end result in both cases is constitutively activated Ras signaling
What criteria need to be satisfied before a gene can be categorized as a TSG?
Numerous genes identified as “candidate” TSGs because their expression was depressed or absent in cancer cells, but detectable in corresponding normal cells BUT this observation is not sufficient;; may be a reflection of normal differentiation pattern;; may be a consequence and not a cause of the transformation process
So must run
1) Fxnal tests
- Rescue or revert to the normal phenotype (or induce apoptosis) by introducing a wild-type copy of the gene into cancer cells
- May be complicated since ectopic expression of many genes can have negative effects (can lead to inhibition of growth or cell death)
- Test made more rigorous by determining whether candidate TSG can halt the growth of a cancer cell (but leave normal cells unaffected) when expressed at normal physiological levels
2) Genetic criteria
- If a gene repeatedly undergoes LOH (but could still just be closely linked to a bona fide TSG) “
- a gene can be called a tumor suppressor gene only if it undergoes LOH in many tumor cell genomes and if the resulting homozygous alleles bear clear and obvious inactivating mutations”
- What is remaining flaw with this criterion? it excludes TSGs that are silenced by epigenetic phenomena such as promoter methylation
3) Other tests
- Knock-out mouse models:
Do resulting heterozygotes exhibit increased susceptibility to cancer? Particularly in a genetic background containing mutations in other TSGs
(i.e. multistep tumorigenesis)
Ex vivo studies of tumor tissue
- Lastly, can the tumor suppressor ability of a candidate TSG be rationalized in terms of the biochemical activity of its protein product?
Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer
1) general concepts
2) main findings/points related to lecture topics
- Fusobacterium nucleatum = prevalent bacterial species in colorectal cancer tissues.
- Colonization of human colorectal cancers with Fusobacterium and associated microbiome maintained in distal metastases, demonstrating microbiome stability btwn paired primary and metastatic tumors.
- In situ hybridization analysis revealed that FB predominantly associated with cancer cells in metastatic lesions
- Mouse xenografts of human primary colorectal adenocarcinomas found to retain viable FB and its associated microbiome thru successive passages.
- Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced FB load, cancer cell proliferation, n overall tumor growth.
- Further investigation of antimicrobial interventions as a potential treatment for patients with FB-associated colorectal cancer.
The search for infectious causes of human cancers: Where and why
1) general concepts
2) main findings/points related to lecture topics
- a larger # of infectious agents identified either cause or contribute to specific human cancers (2 members of herpes virus family: Epstein–Barr virus and human herpes virus type 8; high risk and low risk human papillomaviruses (HPV), Hep B and C viruses, human polyomavirus, Merkel cell polyomavirus, the human T-lymphotropic retrovirus type
- bacterium Helicobacter pylori, contributor to gastric cancer
- gender diff for human papilloma virus (HPV) cause females have cervix
- Certain infectious agents may be necessary but not sufficient?
- Cancer is a multi-step process
1. No human cancer arises as the acute consequence of infection.
2. Latency periods between primary infection and cancer development are frequently 15-40 yrs
3. Besides some rare exceptions, no synthesis of the infectious agents occurs in cancer cells
4. Most of the infections are common in human populations; only a small proportion of infected individuals develop cancer
5. Mutations in host cell genes or within the viral genome are mandatory for malignant conversion.
6. Chemical n physical carcinogens act usually as mutagens
6. Some infectious agents act as indirect carcinogen, w/out genes in cancer cells - ubiquity of most of these infections and the long time periods required for malignant transformation were the main reasons for the remarkable difficulties in identifying their carcinogenic functions.
The Hallmarks of Cancer
1) general concepts
2) main findings/points related to lecture topics
- Rules that govern the transformation of normal human cells into malignant cancers
- Enabling replicative immortality
- turn on TELOMERASE
- therapeutic: telomerase inhibitors - Inducing angiogenesis
- produce VEGF inducer
- therapeutic: inhibitors of VEGR signaling - Resisting cell death
- produce IGF survival factors
- therapeutic: proapoptotic BH3 mimetics - Sustaining proliferative signaling
- activate H-Ras oncogene
- therapeutic: EGRF inhibitors - Activating invasion and metastasis
- inactivate E-cadherin
- inhibitors of HGF/c-Met - Evading growth suppressors
- lose RB suppressor
- therapeutic: Cyclin-dependent kinase inhibitors - Genome instability
- therapeutic: PARP inhibitor - Tumor-promoting inflammation
- therapeutic selective anti-inflammatory drugs - Avoiding immune destruction
- therapeutic: immune activating anti-CTLA4 mAb - Deregulating cell energetics
- therapeutic: aerobic glycolysis inhibitors
Hallmarks of Cancer: The Next Generation
1) general concepts
2) main findings/points related to lecture topics
a
Some TSGs undergo LOH in fewer than 20% of tumors of a given type. Why and how do such low rates of LOH complicate the identification and molecular isolation of such genes?
- LOH occurs at a higher frequency per cell generation than any other form of identifying and isolating TSGs. Because the other forms of identification such as mitotic recombination and promoter methylation occur more infrequently per cell generation, we rely heavily on the events of LOH to identify a TSG. Therefore, low rates of LOH in a given tumor type, make identification of the TSG more difficult.
●Most chromosomes have some LOH, so it can’t always be associated with cancer. ●The tools for identifying LOH yield results pretty quickly, whereas tools to identify hyper-methylation aren’t as robust.
●To sum it up, LOH occurs more frequently than mutations or methylation
What factors might influence the identities of the tissues affected by an inherited, defective allele of a TSG?
Whether the defective allele was present in the embryonic stage or later: If the mutation occurred during germ cell development or embryonic development the defective gene would be more likely to show throughout the body in genes which are expressed in multiple tissue types.
●Some TSGs like the Rb gene may be tissue specific. (I.e. Rb only affects retina)
●Presence of environmental factors such as the fact that people exposed to high radiation are more at risk for skin cancer.
What factors may determine whether the inactivation of a TSG occurs at a frequency per cell generation higher than the activation of an oncogene?
Tumor suppressor genes (TSG) transform into oncogenes under certain physiological conditions. The frequency of a tumor suppressor gene inactivation increases with the increased frequency of exposure to mutagens such as UV light, chemical agents, etc
Name 3 distinct molecular mechanisms that allow chromosomal translocations to activate proto-oncogenes into oncogenes with an example of each
- Can change protein structure-HMGA2
- Place a gene under control of foreign transcriptional promotor and lead to overexpression-myc oncogens in Burkitts Lymphoma
- Can fuse 2 protein coding sequences together and get a hybrid protein–Bcr-Abl protein in CML
Name 2 distinct molecular mechanisms responsible for converting a single proto-oncogene into a potent oncogene with examples of each.
- Ones that change the structure of the protein–point mutations, chromosomal translocations that result in hybrids
- Ones that increase deregulated expression of proteins–gene amplification, chromosomal translocation
Since proto-oncogenes represent distinct liabilities for an organism, in that they can incite cancer,
why have these genes not been eliminated from the genomes of chrodates?
Proto-oncogenes are required for the normal control of cell growth. These oncogenes regulate the cell cycle by commanding the cell to undergo divisons.
If these proto oncogenes are eliminated from the genomes of the chordates , they will disrupt the normal functioning of the body. So these can only be eliminated by the evolution process
What mechanisms might cause a certain region of chromosomal DNA to accidentally undergo amplification?
Promoter insertion, enhancer insertion, or chromosomal translocation such that a certain region of chromosomal DNA was placed just downstream of a highly-expressed sequence thereby amplifying it’s expression, or if the promoter of a highly transcribed gene was placed right before a gene that normally is not highly expressed.
what evidence suggests that a proto-onocogene like src is actually a normal cellular gene rather than a gene that has been inserted into the germ line by an infecting retrovirus?
When a DNA probe specific for recognizing src was used by scientists, they discovered presence of src sequences in DNA of uninfected chicken cells. It was also found that src gene was highly conserved normal gene of all vertebrate species. The discovery of c-src suggested that mutational mechanisms can activate proto-oncogenes which reside in normal sites in chromosomes. This means that c-src as well as other proto-oncogenes are actually normal cellular genes and not genes inserted by infecting retrovirus in germ line.
When a normal cell and a cancer cell are experimentally fused, the resulting hybrids lose the ability to form tumors in mice. This suggests that:
A. The cancer cell alleles are dominant over the normal cell alleles.
B. The cancer cell alleles are recessive to the normal cell alleles.
C. The normal and cancer cell alleles are co-dominant.
D. The original tumor cells likely did not come from a mouse.
B. The cancer cell alleles are recessive to the normal cell alleles.
Sporadic (non-familial) cases of retinoblastoma require:
A. An inactivating somatic mutation in one copy of Rb.
B. Two somatic inactivating mutations, one in each of the two copies of Rb.
C. One somatic mutation in Rb, leading to increased Rb activity.
D. Somatic mutations in both copies of Rb, leading to increased Rb activity.
B. Two somatic inactivating mutations, one in each of the two copies of Rb.
Which of the following is TRUE of CpG methylation changes seen in cancer cells?
A. Global levels of methylation throughout the cell genome often increase.
B. There is decrease in DNA methyltransferase enzyme activity compared to normal cells.
C. Hypomethylation of CpG islands occurs in promoters of TSGs.
D. Hypermethylation of CpG islands occurs in promoters of TSGs.
D. Hypermethylation of CpG islands occurs in promoters of TSGs.
The APC protein acts as a TSG by:
A. Encouraging degradation of beta-catenin.
B. Activating beta-catenin
C. Discouraging beta-catenin relocation from cytoplasm to nuclei
D. Both A and C.
Which of the following statements about NF1 is FALSE?
A. It regulates Ras signaling through stabilizing the Ras-GTP state.
B. Cells lacking NF1 have higher levels of GTP-bound Ras.
C. NF1 is an example of a Ras-GAP.
D. Both B and C are both false.
A. It regulates Ras signaling through stabilizing the Ras-GTP state.
You are studying a cell line in which the loss of just one copy of a TSG leads to increased proliferation of the cells. This would be an example of genetic
A. Homozygosity
B. Co-dominance
C. Haploinsufficiency.
D. Instability
C. Haploinsufficiency.
During regulation of cellular response to oxygen levels, HIF-1a protein levels may increase in response to:
A. Oxygen conditions stabilizing at normal physiologic levels.
B. Cells experiencing hypoxic conditions.
C. Over-saturating oxygen levels
D. HIF-1a binding to pVHL.
B. Cells experiencing hypoxic conditions.
Which of the following genes is NOT classified as a tumor suppressor?
A. VEGF
B. p16
C. PTEN
D. VHL
A. VEGF
Cellular inactivation of TSGs can occur as the result of:
A. Somatic mutation.
B. Promoter demethylation.
C. Loss of heterozygosity.
D. Both A and C.
D. Both A and C.
You are studying cancer cells, and hypothesize that you have found a previously unidentified TSG. Which of the following results would support your hypothesis?
A. You have found loss of heterozygosity in the chromosome locus containing your gene in a number of human lung cancer samples.
B. You have identified a gain-of-function mutation in this gene that results in the transformation of normal cells.
C. Functional analysis has revealed that the wild-type form of the gene that you have identified serves to drive proliferation.
D. Both B and C.
A. You have found loss of heterozygosity in the chromosome locus containing your gene in a number of human lung cancer samples.
The term “adenocarcinoma” refers to cancer cells of what origin?
A. Muscle
B. Blood
C. Glands
D. Bone
C. Glands
“Hyperplasia” refers to tissues in which cells exhibit
A. Loss of control over proliferation
B. Change in individual cellular morphology
C. Ability to invade surrounding tissue
D. Loss of anchorage-dependent growth
A. Loss of control over proliferation
Which of the following is true of carcinomas?
A. They constitute <1% of tumors seen in Western clinics
B. They typically involve epithelial cells of origin
C. They arise mainly from the mesoderm
D. All of the above
B. They typically involve epithelial cells of origin
Which of the following would NOT normally be considered a mutation?
A. Methylation of a particular CpG site in DNA that normally isn’t methylated
B. A change in a single DNA base from what was coded in the germline
C. An arm of chromosome 8 being swapped with the arm of chromosome 14
D. Shortening of a DNA microsatellite repeat region in a gene occurring during mitosis
A. Methylation of a particular CpG site in DNA that normally isn’t methylated
Cancer cells exhibit changes in morphology consistent with
A. Terminal differentiation
B. Trans-differentiation
C. Onco-differentiation
D. De-differentiation
D. De-differentiation
What feature of tumor-causing Rous Sarcoma Virus (RSV) distinguishes it from ancestral Avian Leukosis Virus (ALV)?
A. RSV genome has lost the viral replication genes that ALV has
B. RSV has an oncogene that ALV does not
C. RSV infection is limited to mammals whereas ALV infects birds
D. RSV causes cancer whereas ALV only induces benign tumors
B. RSV has an oncogene that ALV does not
The evolutionary origin of the v-src gene is most likely
A. A viral replication gene that mutated and gained cancer-causing properties
B. A stretch of non-coding DNA in bird genome where ancient viruses integrated
C. A bacterial gene that turned into a viral gene
D. A normal bird gene that became part of a viral genome and mutated
D. A normal bird gene that became part of a viral genome and mutated
We consider the rare event of viral-induced in vivo transformation of host cells as a “failure” of the virus’ replication cycle because
A. Viral genomes normally don’t integrate into the host genome
B. Successful viral replication usually results in host cell death
C. Viruses need to keep the cell in G1 phase in order to make more viral particles
D. Viral replication in a cell effectively shuts down expression of all host genes
B. Successful viral replication usually results in host cell death
Which statement is true about the relationship between viral infection and cancer?
A. Any virus type can cause cancer if it infects the “right” cell type
B. Only people with compromised immune systems get cancer from viral infection
C. About one fifth of all cancer types can be linked to viral infection
D. Tumors that arise from viral infection never become malignant
B. Successful viral replication usually results in host cell death
Why do cancer cells induced by DNA viruses preferentially carry copies of viral “early” gene fragments more than “late” genes?
A. Early genes encourage cell cycle arrest
B. Early genes integrate into the host genome whereas late genes do not
C. Early genes stay silent whereas late genes are actively expressed
D. Early genes are responsible for encouraging cell cycle progression into S phase
D. Early genes are responsible for encouraging cell cycle progression into S phase
What is the distinction between the terms “proto-oncogene” and “oncogene”?
A. Proto-oncogenes are the normal wild-type condition of oncogenes
B. Products of proto-oncogenes are what control expression of oncogenes
C. Proto-oncogenes are a family of evolutionarily ancient oncogenes
D. Proto-oncogenes favor tumorigenesis whereas oncogenes block it
A. Proto-oncogenes are the normal wild-type condition of oncogenes
Use of a Kaplan Meier plot would be most appropriate for displaying
A. The number of cancer cells required before a tumor is clinically detectible
B. The rates of certain cancers compared across different geographical areas
C. The time elapsed between experimental drug treatment and patient death
D. The time it takes for a transformed cell to undergo mitosis
C. The time elapsed between experimental drug treatment and patient death
N-Ras, K-Ras, and H-Ras are best described as
A. Three unrelated oncogenes that each cause sarcomas
B. Three different cancer-causing mutations found in the same ras gene
C. Different activation states of the Ras protein
D. Three closely related genes that likely evolved from a single ras gene
D. Three closely related genes that likely evolved from a single ras gene
Ras mutations involving amino acid 12 may be oncogenic if they
A. Destabilize the protein causing it to fall apart
B. Increase the cleavage rate of bound GTP back to GDP
C. Stabilize the binding of GTP to Ras
D. Block the ability of Ras to interact with its normal downstream targets
C. Stabilize the binding of GTP to Ras
The t(8;14) event is best described as resulting in
A. Amplification of gene expression leading to oncogenic properties
B. Truncation of important protein domains leading to constitutive activation
C. Point mutations that alter the intracellular location of proteins
D. A novel chimeric protein fusing the peptides of two unrelated proteins
A. Amplification of gene expression leading to oncogenic properties
Tumors that arise from mesenchymal cell types are called
A. Carcinomas
B. Lymphomas
C. Sarcomas
D. Adenocarcinomas
C. Sarcomas
Which of the following types of cellular changes would be considered to be malignant?
A. Dysplasia
B. Squamous cell carcinoma
C. Papilloma
D. Adenoma
B. Squamous cell carcinoma
Which of the following schematics MOST likely describes the correct order of cellular changes that occur in the progression of malignancy?
A. Normal → hyperplastic → dysplastic → neoplastic → metastatic
B. Normal → dysplastic → hyperplastic → neoplastic → metastatic
C. Normal → hyperplastic → dysplastic → metastatic → neoplastic
D. Normal → neoplastic → dysplastic → hyperplastic → metastatic
A. Normal → hyperplastic → dysplastic → neoplastic → metastatic
Analysis of a patient’s lung tumor reveals that all of the malignant cells in this tumor have a specific chromosomal abnormality involving a fusion event between two sets of chromosomes. This MOST likely suggests that
A. This mutation was inherited.
B. The tumor is polyclonal.
C. The tumor is monoclonal in origin.
D. A large number of normal cells simultaneously underwent this mutation.
C. The tumor is monoclonal in origin.
During which phase of the cell cycle would you expect most of the RB protein in a cell to be HYPO-phosphorylated?
A. G0
B. G1
C. S
D. M
B. G1
If you see high levels of cyclin D and rising levels of cyclin E and CDK2, what event is the cell likely approaching?
A. Entry into mitosis
B. Exiting mitosis
C. Crossing the R point
D. Completing the S phase
C. Crossing the R point
Which statement is most true about RB protein?
A. Hyperphosphorylated RB binds tightly to E2F proteins
B. Cellular RB protein levels are eliminated as the cell approaches mitosis
C. Hypophosphorylated RB is the state in which it inhibits E2F1,2,3 proteins
D. RB protein must release E2F proteins in order for them to repress gene expression
C. Hypophosphorylated RB is the state in which it inhibits E2F1,2,3 proteins
What would the best description be of how cyclins control CDKs?
A. Cyclins label CDK for degradation
B. Cyclins directly bind CDK genes and activate their expression
C. Cyclins get stabilized by CDK binding and de-phosphorylate RB
D. Cyclins bind CDKs as a way to direct CDK activity to proper protein targets
D. Cyclins bind CDKs as a way to direct CDK activity to proper protein targets
An increase in cellular cyclin D protein levels may result from:
A. The cell entering S phase
B. Various mitogenic signals from outside the cell during G1 phase
C. Dominant-negative RB mutants improperly blocking cyclin-E1A oncoprotein interactions
D. The cell staying in G0 phase longer than normal
B. Various mitogenic signals from outside the cell during G1 phase
How do waves of cyclin A, D, B and E levels prevent the cell cycle from “backing up”?
A. Cyclins set a rigid timer that each phase of the cell must adhere to on time.
B. Cyclins are constantly inhibiting CDKs from stimulating gene expression found in the prior phase of the cycle
C. Cyclins work together with CDKs to emphasize expression of those genes that are needed for the cell to move into the next phase
D. Cyclins can only work with 1 specific CDK type and that alone determines the cell cycle phase
C. Cyclins work together with CDKs to emphasize expression of those genes that are needed for the cell to move into the next phase
All of the following are true of the R point EXCEPT
A. It occurs at the G2/M transition.
B. The cell’s fate beyond this point is largely independent of growth factors in the cell’s surroundings.
C. Deregulation of signaling controlling the R point is common in cancer cells.
D. It coincides with increased activation of cyclin E/CDK2 complexes.
A. It occurs at the G2/M transition.
Histone deacetylase (HDAC) enzymes
A. Promote initiation of transcription.
B. Complex with hyperphosphorylated pRb.
C. Repress E2F family activity.
D. Add acetyl groups to E2F promoters.
C. Repress E2F family activity.
Activation of Myc may result in all of the following EXCEPT
A. Hyperphosphorylation of pRb.
B. Increased expression of CDK4.
C. Degradation of p27Kip1.
D. Decreased activation of cyclin E/CDK2 complexes.
D. Decreased activation of cyclin E/CDK2 complexes.
Which of the following may result from activation of TGF-β receptor?
A. Increased activation of cyclin D/CDK4/6 complexes
B. Reduced expression of p21Cip1
C. Reduced expression of p15INK4B
D. Decreased activation of cyclin E/CDK2 complexes
D. Decreased activation of cyclin E/CDK2 complexes
A transforming cell that lacks telomerase activity may
A. Be in crisis.
B. Have shortening telomeric repeat sequences.
C. Exhibit chromosome breakage and improper chromosome fusions.
D. All of the above
D. All of the above
Why does it take years for a cancerous tumor to form if theoretically 40 cell divisions (such as over 40 days) would generate 10e12 cells?
A. Cancer cells spend a long time between rounds of mitosis
B. Several tumor cells must work together to gain immortality
C. The vast majority of daughter cells in each round undergo apoptosis
D. Re-expression of hTERT only happens once a sizable tumor mass starts forming
C. The vast majority of daughter cells in each round undergo apoptosis
Which of the following mechanisms may contribute to tumorigenesis driven by the myconcogene? A. Increased myccopy number B. Constitutive activation of mycunder the transcriptional control of viral promoters C. Chromosomal translocations D. A, B, and C E. None of the above
D. A, B, and C E
DNA from human lung tumor cells was used to transfect NIH 3T3 (mouse embryo fibroblast) cells. After several weeks, some of these cells formed foci, or clusters of cells, on the plate. Cells isolated from these foci were able to grow in soft agar and formed tumors when injected subcutaneously into immunocompromised mice. These results suggest that…
A. The oncogene present in the human lung tumor cells is also able to transform NIH 3T3 mouse cells.
B. The NIH 3T3 cells were most likely transformed by multiple oncogenes present in the donor cells.
C. The NIH 3T3 cells were most likely transformed by a single oncogene present in the donor cells.
D. A and C
E. A, B, and C.
D. A and C
Fusion of the reading frames of the bcrand ablgenes, as is often observed in cases of chronic myelogenous leukemia (CML), is an example of what type of genetic alteration? (Level 1)A.A reciprocal chromosomal translocationB.A nonreciprocal chromosomal translocationC.A frameshift mutationD.A chromosomal deletionE.None of the above
A
The transforming abilities of the Bcr-Abl fusion protein are due primarily to the deregulated firing of its tyrosine kinase, which is equivalent to what domain of thenormal Abl protein? (Level 2)A.The SH1 domainB.The SH2 domain
C.The SH3 domainD.The DNA binding domainE.None of the above
A
Approximately what percentage of human tumors are associated with infectious agents? (Level 1)A. 5%B. 10%C.20%D. 40%E. 60%
C
Which of the following is true of carcinomas? (Level 2)A.They are responsible for >80% of Western world cancer deaths.B.They involve cell types arising from all three embryonic germ layers.C.They often involve epithelial cells.D.Examples of tissue sites where they are found include the lung and pancreas.E.All of the above.
- 1 E
- 2 C
- 3 B
- 4 A
- 5 C
- 6 D
- 7 A
- 8 C
- 9 E
- 10 E
- 11 B
- 12 D
Dulbecco and Rubin discovered that they could infect chicken embryo fibroblasts with RSV in culture. Which of the following was NOT a characteristic exhibited bythese cells after they were infected? (Level 2)A.Virus particles were produced by these cells for many weeks.B.Cells formed clusters, or foci, after infection.C.The cells seemed to demonstrate uninhibited proliferation.D.The cells exhibited flattened morphology.E.The cells exhibited metabolic properties similar to those observed in tumor cells
C
Experiments using temperature-sensitive mutants of RSV to infect chicken embryo fibroblasts demonstrated that: - infection with RSV is necessary to initiate transformation of these cells, but the RSV genome is not needed to maintain the transformed state- the RSV transforming gene is necessary for both the initiation and maintenance of transformation in these cells - infection with RSV alone is unable to transform these cells- cells infected with RSV continue to exhibit normal cellular morphology- none of the abov
the RSV transforming gene is necessary for both the initiation and maintenance of transformation in these cells
Which of the following is considered to be a tumor virus? (Level 1)A.Hepatitis Bvirus (HBV)B.Human papillomavirus (HPV)C.Shope fibroma virusD.Human adenovirus 5E.All of the above
E
Which of the following is a property of transformed cells? (Level 2)A.Rounded shapeB.Reduced requirement for mitogenic growth factorsC.Loss of contact inhibitionD.Increased transport of glucoseE.All of the above
E
The ability of cells suspended in soft (semi-solid) agarmedium to form colonies isa good predictor that (Level 3)A.These cells will form tumors if injected subcutaneously into immunocompromised mice.
B.These cells have stopped proliferating and will die.C.These cells would fail to grow in normal medium.D.These cells have an increased requirement for growth factors.
A
Which of the following statements is FALSE regarding Ras mutations in cancer patients?
*A. Oncogenic mutations usually result in higher levels of GDP-bound Ras
B. Oncogenic mutations usually result in higher levels of GTP-bound Ras
C. Cells often have compromised activity of GTPase-activation proteins (GAPs)
D. B and C
E. None of the above
A
Over expression of growth receptors helps to promote cancer growth by…
A. Stimulating the dimerization and transphosphorylation of the receptors
B. Turning off downstream signaling
C. Promoting mitogenic signaling
*D. A and C
E. None of the above
D
Which of the following statements regarding EMT is/are TRUE in regards to cancer cells?
*A. Promotes tumor cell migration
B. Promotes immune-mediated cytotoxic lysis
C. Long term treatment of cancer cells with TKI’s completely impede EMT
D. A and C
E. None of the above
A
Which of the following is FALSE regarding Tyrosine kinase inhibitors?
A. Small molecules that are either reversible or irreversible
*B. Only effective on extracellular targets
C. Bind with ATP binding pockets on the intracellular catalytic kinase domain
D. B and C
E. None of the above
B
