10 Molecular Basis of Cancer I Flashcards

1
Q

Approximately how many mutations are needed to produce a cancer?

A

Multiple (5-7?)

No single mutation is sufficient to yield a malignant phenotype

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2
Q

If tissue cells have a maintained structure and organized growth, what are the characteristics of tumor cells?

A

Loss of tissue structure
invasion into adjacent tissue
continued growth

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3
Q

What is the size of the minimum detectable tumor?

What is the maximum tumor load compatible with life?

A

Min: ~1gm = 10^9 cells
Max: ~1kg = 10^12 cells (10 additional cell mass doublings)

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4
Q

What is the elapsed time to 10^9 cells (min. detectable tumor) for a single transformed cell in culture?
For tumor initiation in vivo?

A

90 days in culture

10-30 years in vivo

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5
Q

Tumors only grow if the loss is less than the increase. What are the 4 routes of tumor cell loss?

A

host defenses
terminal differentiation
shedding
necrosis

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6
Q

What is the basic flow diagram for cancer?

A

Normal cell -> Acquired DNA damage (chemical, radiation, virus) -> Either growth arrest/cell death OR failure of DNA repair -> Mutations in genome -> Expression of altered gene products and loss of regulatory gene products -> Clonal expansion, additional mutations, heterogeneity -> Malignant neoplasm

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7
Q

How are oncogenes neoplasia-associated genes?
Dominant/recessive inheritance?
Basis for familial cancer syndromes?

A

Provides cell with positive function
Dominant inheritance - only one copy needed
No basis for familial cancer syndromes

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8
Q

How are tumor suppressor genes neoplasia-associated genes?
Dominant/recessive inheritance?
Basis for familial cancer syndromes?

A

Loss leads to acquired cancer phenotype
Recessive - both copies mutated or deleted
Yes, basis for familial cancer syndromes

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9
Q

How are genome maintenance genes neoplasia-associated?

Basis for familial cancer syndromes?

A

Loss leads to more rapid acquisition of mutations
Does not contribute to cancer phenotype directly
Yes, basis for familial cancer syndromes

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10
Q

T/F

Reconstitution of genome maintenance reverses the neoplastic phenotype

A

False. It does not. Inhibition of oncogene action or reconstitution of tumor suppressor activity eliminates the neoplastic phenotype

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11
Q

Proto-oncogenes are:

A

Normal cellular gene that turns into an oncogene thru mutation

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12
Q

Mechanisms for proto-oncogenes becoming oncogenes are:

A

-altered regulatory domain
-fusion with another peptide coding sequence to result in new unregulated function
-increased expression
duplication (amplification)
loss of promoter methylation

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13
Q

What are the 5 inherited cancer syndromes? What gene is affected?
Are they autosomal dominant or recessive genetically?

A
Autosomal recessive
Retinoblastoma - RB
Li-Fraumeni syndrome - p53
Familial adenomatosis/colon cancer - APC
Breast cancer - BRCA1
Multiple endocrine neoplasia 1 & 2 - MEN1, RET
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14
Q

What is Knudson’s 2 hit hypothesis? How does it involve loss of heterozygosity?

A

Tumor suppressor gene mutations are recessive. Both alleles must be inactivated to exhibit the phenotype. If one allele is already lost the likelihood of development of cancer is much higher. In many cases, the mutant allele is duplicated or the wild type allele is deleted resulting in loss of heterozygosity.

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15
Q

T/F

Morphologically similar tumors can have distinct genetic markers that specify different treatments and prognoses

A

True

Genetic analysis is increasingly used in cancer diagnosis

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16
Q

T/F

There is tissue specificity of certain genes for certain cancers.

A

True

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17
Q

What is the flow diagram example for colorectal cancer with the gene mutation for each step?

A

Normal epithelium -> (loss or mutation of APC) -> hyperproliferative epithelium -> (loss of DNA methylation) -> early adenoma -> (mutation of Ras gene) -> intermediate adenoma -> (loss of tumor suppressor on chromosome 18q) -> late adenoma -> (loss of p53) -> carcinoma

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18
Q

What are the 3 malignant characteristics that are acquired by neoplasms over time?

A

accelerated growth
invasiveness
metastatic potential

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19
Q

What is the cause of continued gene alterations in a tumor?

A

Competing subclones, some with different mutations, divide. When a more advantageous mutation comes along, it predominates. The more aggressive subclones will outgrow others, but there is still heterogeneity within the tumor.

20
Q

What do subpopulations of a tumor differ in?

A
Subpopulations differ in:
growth rate
karyotype
invasion and metastatic ability
hormonal responsiveness
antineoplastic drug susceptibility
21
Q

Are the following cancers examples of aggressive or not aggressive tumors?

  • chronic lymphocytic leukemia
  • prostate cancer
  • basal cell carcinoma
A

These rarely become aggressive

22
Q

What are the 7 characteristics of cancer?

A
genome instability
self-sufficiency growth signals
insensitivity to growth inhibition
evasion of programmed cell death
limitless replication potential
sustained angiogenesis
tissue invasion and metastasis
23
Q

What are the causes of genome instability? What functions are lost?

A

Decreased DNA repair
Loss of response to DNA damage
damage sensors - DNA breaks and mismatch detection
damage response mechanism - cell cycle arrest, apoptosis, DNA repair

24
Q

What does p53 induce?

A

DNA repair
cell cycle arrest in cells with DNA damage
cell death in cells with DNA damage

25
Q

How is p53 activated?

A

By DNA damage:

  • double strand breaks
  • genotoxic cancer therapy (chemotherapy & radiation)
26
Q

What is the function of BRCA1?

How is it activated?

A

DNA repair protein
Functions with other proteins to repair ds-DNA breaks
Activated by DNA damage

27
Q

How do tumor cells’ respond to:
growth factors?
inhibitory factors
contact inhibition

A

Decreased requirement for growth factors
insensitivity to inhibitory factors
no contact inhibition

28
Q

Rb blocks what cell cycle transition?

A

G1-S transition

29
Q

How is Rb inhibited?

A

Phosphorylation by cyclinD/CDK4

30
Q

What state is Rb active in? How does Rb function?

A

When active (hypophosphorylated) it binds the E2F site on DNA, blocking transcription of S phase genes

31
Q

What tumor suppressor gene can be inhibited by viral oncogenes? What is the example of a virus given?

A

Rb can be inhibited by viral oncogenes - E7 protein from human papillomavirus

32
Q

What disease is associated with Rb germline mutation?

A

Retinoblastoma

33
Q

Which group has the following functions? proto-oncogenes/tumor suppressor genes/genome maintenance genes?

  • growth factors
  • cell surface receptors
  • intracellular transducers
  • transcription factors
  • cell cycle control proteins
  • anti-apoptosis factors
A

proto-oncogenes

34
Q

What is the translocation that causes the bcr-abl formation?

What disease does this cause?

A
reciprocal t(9;22) translocation
CML (chronic myelogenous leukemia)
35
Q

What is the change in function from the bcr-abl translocation?

A

results in an unregulated tyrosine kinase that induces multiple signal transduction pathways

36
Q

What is the use of Gleevec?

A

It inhibits the bcr-abl kinase

37
Q

What is the function of HER2 (c-erb/c-neu)?

A

Epidermal growth factor (EGF) receptor

38
Q

HER2 (c-erb/c-neu) is overexpressed in what types of cancers?

A

breast and ovarian cancers and some others

39
Q

What is the use of Herceptin?

A

It is a monoclonal antibody against HER2 (c-erb/c-neu)

It may reduce surface EGF activation of tumor cells and kill tumor cells thru the immune system (unclear mechanism)

40
Q

What is the most common childhood lymphoma?

A

Burkitt’s lymphoma

41
Q

What mutated gene is associated with Burkitt’s lymphoma? What is the change in activity and the outcome from that change?

A

c-myc

Increased myc activity is associated with B-lymphocyte proliferation

42
Q

What kind of DNA mutations cause increased myc activity?

A

Point mutation or deletion of myc regulatory domain

t(8;14) translocation

43
Q

What mutated gene is associated with neuroblastomas?

What is the change in activity and the outcome from that change?

A

N-myc
Increased activity
Amplification and insertion outside chromosome 2p; formation of double minute extra chromosomal fragments

44
Q

What kind of function does p53 have? Proto-oncogene/tumor suppressor/genome maintenance?
How is it mutated to contribute to cancer?

A

tumor suppressor

inactive or dominant negative thru missense, nonsense, or small deletions

45
Q

What kind of function does Ras have? Proto-oncogene/tumor suppressor/genome maintenance?
How is it mutated to contribute to cancer?

A

oncogene

loss of inhibition or unregulated activation thru missense, nonsense, or small deletions

46
Q

What kind of function does JAK2 have? Proto-oncogene/tumor suppressor/genome maintenance?
How is it mutated to contribute to cancer?

A

oncogene

loss of inhibition or unregulated activation thru missense, nonsense, or small deletions