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Oncology > 3 - Genetics > Flashcards

3 - Genetics Flashcards

1
Q

At what level does the malignant phenotype occur?

A

Genetic!

At the DNA level

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2
Q

Type of origin - Most tumors

A

Clonal! You can trace the lineage back to the original heritable mutation in one cell.

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3
Q

Polyclonal tumors

A

They exist, but they’re rare!! It means independently, separate cells have mutated to their malignant form.

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4
Q

How many steps are in the process of cancer development?

A

Multi

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5
Q

Phenotypic properties of cancer cells

A 
Loss of control over cell growth
Failure of cellular differentiation
Inappropriate resistance to cell death
Acquisition of angiogenic capacity
Acquisition of metastatic potential
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6
Q

Steps of Metastasis

A 
Destruction of basal lamina
Infiltration of local connective tissue
Intravasation
Extravasation
Distal colonization
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7
Q

Each step of cancer development is due to

A

A specific genetic or epigenetic alteration
These accumulate and work together
They are subject to clonal selection
Some of these are rate-limiting!!

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8
Q

Multiple genetic alterations leading to cancer development

A

Some are inherited.

MOST are acquired somatically.

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9
Q

Alterations that increase the rate of cell division

A

C-Myc activation

Rb inactivation

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10
Q

Alterations that decrease genomic stability

A

Inactivation of mismatch repair genes

p53 mutations

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11
Q

Mismatch repair genes

A

hMSH2

hMLH1

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12
Q

What typically induces the genetic alterations associated with malignancy?

A

Viruses
Chemicals
Radiation
Random Errors

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13
Q

What genes, when altered, promote cancer?

A

Proto-oncogenes

Tumor suppressor genes

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14
Q

What is an example of a gene altered in a restricted set of tumor types?

A

APC tumor suppressor in colorectal carcinoma

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15
Q

What is an example of a gene altered in a broad spectrum of tumor types

A

p53 tumor suppressor

Ras proto-concogene

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16
Q

Proto-oncogenes

A

Promote cancer when malignantly ACTIVATED
Gain-of-function (eg Ras)

“Dominant” at the cellular level. Can elicit a tumor even in the presence of the wild type allele.

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17
Q

Tumor suppressor genes

A

Promote cancer when malignantly INACTIVATED
Loss-of-function

“Recessive” at the cellular level. Typically will not promote a tumor in heterozygotes unless the other allele (the wild type) is also lost.

Exception: Dominant negative mutations (eg p53)

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18
Q

Mechanisms for oncogene activation

A 
Coding mutations (leading to altered protein function)
eg Ras
Chromosomal rearrangements (eg translocations, leading to gene dysregulation or overexpression)
eg c-Myc gene translocation (Burkitt's Lymphoma)
Gene amplification (leading to overexpression)
eg MDM2 gene amplification (Sarcomas)
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19
Q

How many human cancers are heritable?

A

Fewer than 10%!!

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20
Q

How are hereditary syndromes of cancer susceptibility usually caused?

A

Germline mutations of tumor suppressor genes

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21
Q

Hereditary syndromes of cancer susceptibility

A

Familial retinoblastoma (Rb)
Li-Fraumeni syndrome (p53)
Familial adenomatous polyposis coli (APC)
Hereditary non-adenomatous cc (MLH1, MSH2)
Familial breast & ovarian cancer (BRCA1, BRCA2)

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22
Q

Fully penetrant mutations

A

Segregate as dominant traits in mendelian fashion

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23
Q

2 forms of Retinoblastoma

A

Sporadic

Heritable

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24
Q

Sporadic Retinoblastoma

A

60% of cases
~6 years
Single tumor (only one eye)
Their kids have the same rate of retinoblastoma as the general population
Both Rb alleles normal in the germline
Both Rb alleles inactivated or lost in tumors

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25
Q

Heritable Retioblastoma

A

40% of cases
~2 years
Multiple tumors (both eyes)
Their kids have a 50% chance of having a retinoblastoma
Transmit an “Rb susceptibility gene” in a dominant mendelian fashion
One Rb gene lesion in the germline
Second Rb allele inactivated or lost in tumors

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26
Q

Sporadic Retinoblastoma - Two required rate-limiting lesions

A

Both alterations acquired somatically
Incidence: 1 in 10^5 (random probability)
Very rare, involves only one eye

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27
Q

Heritable Retinoblastoma - Two required rate-limiting lesions

A

One alteration inherited in the germline (eg “Rb susceptibility gene”)
Second alteration acquired somatically.
Incidence: 10 tumors per person (lifetime). With 10^7 cell divisions, there are just too many opportunities for mutation!
Fully penetrant (transmitted via mendelian dominance)
Tumor suppressor gene (thus this is an exception to mendelian trends for tumor suppressor genes
Affects both eyes

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28
Q

Rb gene - Two rate-limiting genetic alterations

A

Cytogenetic abnormalities of Chromosome 13

A second hit on the other allele

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29
Q

Cytogenetic abnormalities of Chromosome 13

A 
Interstitial deletions (variable length)
ALL involve material from 13q14

Sporadic patients - Deletions in tumor cells only
Heritable patients - Deletions in both normal & tumor cells (that means this is the inherited first hit!)

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30
Q

Both alleles of a gene on 13q14 are knocked out

A

Retinoblastoma!

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31
Q

How do we inactivate the second Rb allele?

A

De novo mutation
Chromosome loss
Chromosome loss & replication
Gene conversion

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32
Q

Some carriers of hereditary retinoblastoma will also develop

A

Osteosarcoma (low/incomplete penetrance)

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33
Q

When is Rb normally hypophosphorylated?

A 
G0 (resting cells)
Early G1 (cycling cells)
34
Q

When is Rb normally hyperphosphorylated?

A

S phase

G2

35
Q

When does Rb get phosphorylated?

A

Before the G1/S transition

At the restriction point of the cell cycle

36
Q

What phosphorylates Rb?

A

Enzymatic complex

CDK4 / Cyclin D

37
Q

The Restriction Point

A

Late G1
Major control point of cell cycle progression
Mediated by E2F family of transcription factors
E2F binds the promoters of genes required for the progression of the cell cycle

38
Q

S phase genes regulated by E2F

A 
Thymidine Kinase
Dihydrofolate Reductase (DHFR)
DNA Polymerase α
ORC1
Histone H2A
Cyclin E
Cyclin A
39
Q

Thymidine Kinase - Function

A

Nucleotide Synthesis

40
Q

Dihydrofolate Reductase (DHFR) - Function

A

Nucleotide Synthesis

41
Q

DNA Polymerase α - Function

A

DNA Synthesis

42
Q

ORC1 - Function

A

DNA Synthesis

43
Q

Histone H2A - Function

A

Chromosome Assembly

44
Q

Cyclin E - Function

A

Cell Cycle Progression

45
Q

Cyclin A - Function

A

Cell Cycle Progression

46
Q

Hypophosphorylated Rb

A

Restrains cell proliferation

How:
Binds to promoter-bound E2F in early G1
Inactivates E2F-controlled transcription
S phase genes are repressed
G1/S transition is blocked
47
Q

CDK4/Cyclin D

A

Phosphorylates Rb in its “pocket” causing it to dissociate from E2F
E2F-controlled transcription remains active
S phase begins

This process is a common focal point of major signal transduction pathways controlling normal cell growth

48
Q

E2F controls

A

Transcription of proteins needed for S phase

49
Q

Hyperphosphorylated Rb

A

Allows cells to proliferate

How:
CDK4/Cyclin D phosphorylates Rb in its “pocket” causing it to dissociate from E2F
E2F-controlled transcription remains active
S phase begins

50
Q

Loss of Rb Function

A

Uncontrolled growth

How:
Deregulation of E2F (and G1/S transition)

51
Q

Mutations leading to Inactive Rb Function - Direct

A

Rb gene deletion (retinoblastoma)
Point mutations in the Rb pocket (retinoblastoma)
Occupancy of the Rb pocket by early proteins of DNA tumor viruses (HPV)

52
Q

HPV

A

Encodes 2 proteins required for tumorigenesis
E7 (one of those 2) binds the pocket of hypophosphorylated Rb
E2F is deregulated
G1/S transition is deregulated

53
Q

p16

A

Inhibits CDK4/Cyclin

54
Q

Tumor Suppressor

A

Rb

55
Q

Oncoproteins

A

E2F
CDK4
Cyclin D
p16

56
Q

Mutations leading to Inactive Rb Function - Indirect

A

Overexpression of Cyclin D1 (Breast cancer, B Cell Lymphoma)
Loss of p16, a CDK4 inhibitor (Many human cancers)
Inherited point mutation in CDK4, rendering it insensitive to p16’s inhibition (Familial melanoma)

57
Q

Inactivation of Rb Function

A

Occurs in most, if not all human tumors

58
Q

p53 encodes

A

Transcription factor

The most broadly-altered gene in human cancer

59
Q

How is the p53 gene usually altered in human tumors?

A

Missense mutations

60
Q

Example of a dominant-positive mutation

A

Ras proto-oncogenes

61
Q

Example of a recessive-negative mutation

A

Rb loss

62
Q

Example of a dominant-negative mutation

A

p53 missense mutation
Only one allele needs to mutate for a malignant phenotype
The mutation leads to loss-of-function of that tumor suppressor

63
Q

Dominant-Negative Mutations

A

One allele mutates

The protein products of BOTH alleles are functionally inactivated.

64
Q

How does p53 normally function in the cell?

A

Homo-tetramer which serves as a transcription factor

65
Q

How does a p53 mutation become dominant?

A

Mutant p53 is much more stable than wild-type p53

With one mutant allele, levels of mutant p53 much higher than that of wild-type

66
Q

Li-Fraumeni Syndrome (LFS)

A

Rare hereditary condition
Germline mutations of p53
Carriers develop many forms of cancer

67
Q

p53 sporadic cancers

A

Often have somatic mutations of p53 (dominant-negative)
Very common in human cancer
Found in many different forms of cancer

68
Q

What is the half life of normal p53 polypeptides?

A

~30 minutes

69
Q

What genotoxic stresses can damage the p53 gene?

A

UV light
Ionizing radiation
Chemical carcinogens
Errors in replication

70
Q

What does a damaged p53 gene lead to?

A

Post-translational modifications of p53 polypeptides
ESPECIALLY Phosphorylation & Acetylation
This leads to a half life of ~150 min (stabilized peptide!)
Higher steady state levels
Increased transcriptional activity of p53

71
Q

Increased transcriptional activity of p53 - Normal Fibroblasts

A

G1 arrest

DNA repair

72
Q

Increased transcriptional activity of p53 - Certain epithelial cells

A

G1 arrest

DNA repair

73
Q

Increased transcriptional activity of p53 - Thymocytes

A

Apoptosis

74
Q

p53’s ultimate job

A

Ceasing the replication of damaged DNA
Preventing oncogenic mutation accumulation
Maintaining genetic integrity in cells under genotoxic stress

75
Q

Transcriptional targets of p53

A 
p21 CDK Inhibitor
14-3-3σ
PUMA
p53R2 Nuclear Ribonucleotide Reductase
p48 Subunit of the XPA Complex
and more!!
76
Q

p21 CDK Inhibitor

A

Activated p53 binds its promoter

Leads to G1 & G2 arrest (fibroblasts)

77
Q

14-3-3σ

A

Induced by p53

Leads to G2 arrest (epithelial cells)

78
Q

PUMA

A 
Induced by p53
Promotes apoptosis (thymocytes, fibroblasts, neurons)
79
Q

p53R2 Nuclear Ribonucleotide Reductase

A

Induced by p53

Required for DNA repair

80
Q

p48 Subunit of the XPA Complex

A

Induced by p53

Required for nucleotide excision repair

81
Q

ATM

A

One of the tumor suppressor kinases that detects DNA damage and activates p53 via phosphorylation

82
Q

Mdm2

A

One of the oncoproteins that ubiquitinates & targets p53 for destruction

Oncology (23 decks)

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