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Oncology > 3 - Genetics > Flashcards

3 - Genetics Flashcards

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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
Heritable Retioblastoma
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
26
Sporadic Retinoblastoma - Two required rate-limiting lesions
Both alterations acquired somatically Incidence: 1 in 10^5 (random probability) Very rare, involves only one eye
27
Heritable Retinoblastoma - Two required rate-limiting lesions
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
28
Rb gene - Two rate-limiting genetic alterations
Cytogenetic abnormalities of Chromosome 13 | A second hit on the other allele
29
Cytogenetic abnormalities of Chromosome 13
``` 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!)
30
Both alleles of a gene on 13q14 are knocked out
Retinoblastoma!
31
How do we inactivate the second Rb allele?
De novo mutation Chromosome loss Chromosome loss & replication Gene conversion
32
Some carriers of hereditary retinoblastoma will also develop
Osteosarcoma (low/incomplete penetrance)
33
When is Rb normally hypophosphorylated?
``` G0 (resting cells) Early G1 (cycling cells) ```
34
When is Rb normally hyperphosphorylated?
S phase | G2
35
When does Rb get phosphorylated?
Before the G1/S transition | At the restriction point of the cell cycle
36
What phosphorylates Rb?
Enzymatic complex | CDK4 / Cyclin D
37
The Restriction Point
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
S phase genes regulated by E2F
``` Thymidine Kinase Dihydrofolate Reductase (DHFR) DNA Polymerase α ORC1 Histone H2A Cyclin E Cyclin A ```
39
Thymidine Kinase - Function
Nucleotide Synthesis
40
Dihydrofolate Reductase (DHFR) - Function
Nucleotide Synthesis
41
DNA Polymerase α - Function
DNA Synthesis
42
ORC1 - Function
DNA Synthesis
43
Histone H2A - Function
Chromosome Assembly
44
Cyclin E - Function
Cell Cycle Progression
45
Cyclin A - Function
Cell Cycle Progression
46
Hypophosphorylated Rb
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
CDK4/Cyclin D
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
E2F controls
Transcription of proteins needed for S phase
49
Hyperphosphorylated Rb
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
Loss of Rb Function
Uncontrolled growth How: Deregulation of E2F (and G1/S transition)
51
Mutations leading to Inactive Rb Function - Direct
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
HPV
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
p16
Inhibits CDK4/Cyclin
54
Tumor Suppressor
Rb
55
Oncoproteins
E2F CDK4 Cyclin D p16
56
Mutations leading to Inactive Rb Function - Indirect
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
Inactivation of Rb Function
Occurs in most, if not all human tumors
58
p53 encodes
Transcription factor | The most broadly-altered gene in human cancer
59
How is the p53 gene usually altered in human tumors?
Missense mutations
60
Example of a dominant-positive mutation
Ras proto-oncogenes
61
Example of a recessive-negative mutation
Rb loss
62
Example of a dominant-negative mutation
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
Dominant-Negative Mutations
One allele mutates | The protein products of BOTH alleles are functionally inactivated.
64
How does p53 normally function in the cell?
Homo-tetramer which serves as a transcription factor
65
How does a p53 mutation become dominant?
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
Li-Fraumeni Syndrome (LFS)
Rare hereditary condition Germline mutations of p53 Carriers develop many forms of cancer
67
p53 sporadic cancers
Often have somatic mutations of p53 (dominant-negative) Very common in human cancer Found in many different forms of cancer
68
What is the half life of normal p53 polypeptides?
~30 minutes
69
What genotoxic stresses can damage the p53 gene?
UV light Ionizing radiation Chemical carcinogens Errors in replication
70
What does a damaged p53 gene lead to?
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
Increased transcriptional activity of p53 - Normal Fibroblasts
G1 arrest | DNA repair
72
Increased transcriptional activity of p53 - Certain epithelial cells
G1 arrest | DNA repair
73
Increased transcriptional activity of p53 - Thymocytes
Apoptosis
74
p53's ultimate job
Ceasing the replication of damaged DNA Preventing oncogenic mutation accumulation Maintaining genetic integrity in cells under genotoxic stress
75
Transcriptional targets of p53
``` p21 CDK Inhibitor 14-3-3σ PUMA p53R2 Nuclear Ribonucleotide Reductase p48 Subunit of the XPA Complex and more!! ```
76
p21 CDK Inhibitor
Activated p53 binds its promoter | Leads to G1 & G2 arrest (fibroblasts)
77
14-3-3σ
Induced by p53 | Leads to G2 arrest (epithelial cells)
78
PUMA
``` Induced by p53 Promotes apoptosis (thymocytes, fibroblasts, neurons) ```
79
p53R2 Nuclear Ribonucleotide Reductase
Induced by p53 | Required for DNA repair
80
p48 Subunit of the XPA Complex
Induced by p53 | Required for nucleotide excision repair
81
ATM
One of the tumor suppressor kinases that detects DNA damage and activates p53 via phosphorylation
82
Mdm2
One of the oncoproteins that ubiquitinates & targets p53 for destruction

Oncology (23 decks)

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