Module Three: Cancer Genetics Flashcards

1
Q

What is the multi-step model of cancer development?

A

The accumulation of genetic and epigenetic alterations resulting from the:
Activation of oncogenes resulting in excessive growth signals
Inactivation of tumour suppressor genes resulting in the removal of normal control

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2
Q

What is knudson’s two hit hypothesis?

A

Tumour suppressor genes act recessively i.e. Both copies of genes must be inactivated for growth control to be lost

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3
Q

What are the genes that are responsible for many familial cancers?

A

Rb, tp53, p16, BRAC1/2, APC, hMLH1

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4
Q

What are the limitations of gene therapy for cancer treatment?

A

Targeted delivery, expression, multiple TSG defects

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5
Q

What does the Rb code for?

A

Codes for a nuclear protein that is a major inhibitor of the cell cycle

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6
Q

Sporadic Rb1 gene mutations are found in what cancers?

A

Bone, lung and breast (and retinoblastoma)

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7
Q

What does the adenomatous polyposis coli gene have critical roles in?

A

Cell division and adhesion, regulates beta-catenin activity and the Wnt pathway

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8
Q

Germline mutations in APC are responsible for what syndrome?

A

Familial polyposis syndrome affecting the large bowl

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9
Q

95% of APC mutations cause what?

A

Frame shifts that lead to production of a truncated, inactive protein

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10
Q

What do the BRCA1 and 2 genes code for?

A

Codes for the proteins involved in the repair of damaged DNA

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11
Q

What inactivates BRCA1 in sporadic breast cancers?

A

Methylation

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12
Q

What genes encode for proteins that repair DNA mismatches arising during cell replication?

A

MLH1, MSH2, MSH6, PMS2

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13
Q

Inactivation of mismatch repair genes results in what?

A

Micro satellite instability

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14
Q

Germline mutations are responsible for?

A

Lynch syndrome

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15
Q

TP53 functions in:

A

Cell cycle arrest, DNA repair and apoptosis

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16
Q

What syndrome is a result of TP53 germ line mutations?

A

Li-Fraumeni Syndrome

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17
Q

Apart from mutation and chromosomal loss, TP53 can occur by what?

A

Binding to viral proteins

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18
Q

What viruses bind to TP53?

A

SV40, papilloma, Adenovirus

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19
Q

What can inhibit the activity of TP53 through feedback mechanism?

A

MDM2

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20
Q

How many regions does the central part of TP53 contain?

A

5

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21
Q

TP53 is a what?

A

Nuclear phosphoprotein

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22
Q

What are examples of low risk genetic factors?

A

Genes involved in carcinogen breakdown, DNA Repair

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23
Q

What cancers are associated with Lynch syndrome?dw

A

Colorectal, endometrial, rarer: gastric, renal

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24
Q

What are the five steps to genetic testing?

A

Step one: is a familial cancer syndrome likely based on the analysis of pedigree?
Step two: is there a family member who has had cancer and is willing to have genetic testing to find the specific mutation?
Step three: genetic testing => is a mutation detected in a known familial cancer syndrome gene?
Step 4: predictive testing is offered to other family members (with appropriate counselling)
Step 5: negative result: close surveillance not necessary
Positive: screening, prevention, surgery

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25
Role of familial cancer clinics?
Risk assessment Genetic testing Counselling Surveillance advice
26
Define: epigenetics
The study of DNA and chromatin modifications that persist from one cell division to the next, despite a lack of change in the underlying DNA sequence Or The study of heritable changes in gene expression that occur independent of changes in the primary DNA sequence
27
Examples of epigenetic factors
DNA methylation of cytokines in CpG dinucleotides His tone modification (acetylation and methylation of specific lysine residues on histones H3 and H4 Small non-coding RNA (microRNA)
28
What are the two molecular pathways involved in bowel cancer
Chromosomal instability | CpG island methylator phenotype
29
Where does methylation occur?
Cytosine residue of cytosine-p-guanine dinucleotides
30
How does DNA methylation lead to silencing?
Directly inhibits the binding of transcription factors
31
DNA methylation patterns are determined by an interplay between:
The environment (dietary folate, vitamins) Age DNA methyl transferase (DNMT1, DNMT 3A, DNMT3B)
32
What are the challenges of demethylating agents?
Specificity and toxicity
33
Genes that control cell cycle control ?
P73, p16, p15, p14
34
Genes that control Regulation of apoptosis
DAP-kinase, p73
35
Genes that control Invasion / tumour architecture
E-cadherin, VHL, APC, APC, TIMP3
36
Growth factor receptors
ER, RARb
37
Genes that control Drug uptake and sensitivity?
MDR1, MRP
38
Genes that control DNA damage and repair?
MLH1, O6-MGMT, BRCA1
39
What are micro satellites ?
Repetitive DNA sequences scattered throughout the genome
40
What is microsatellite instability?
Shortening or lengthening of repeats in tumour DNA due to defective DNA mismatch repair mechanisms
41
Where do the large majority of MSJ tumours occur?
Proximal colon
42
What are the 6 hallmarks of cancer?
``` Resisting cell death Inducing angiogenesis Enabling replicative immortality Sustaining proliferative signals Activating invasion and metastasis Evading growth suppressors ```
43
What transcription factors orchestrate EMT and are involved in most steps of invasion and metastasis?
Snail, slug, twist, zeb1/2
44
What is the EMT
Epithelial Mesenchymal transition
45
What are the emerging hallmarks of cancer development?
Deregulating cellular energetics | Avoiding immune destruction
46
What are the enabling characteristics of the emerging hallmarks?
Genome instability and mutation | Tumour promoting infiltration
47
Inflammatory cells that contribute to hallmark capabilities by releasing:
Growth factors that sustain proliferative signalling Survival factors that limit cell death Pro-angiogeneic factors
48
What does a virion consist of?
Genome Capsid Membrane Ligands
49
What are the three viral shapes?
Helical Polyhedral Binal
50
6 WHO recognised on oncoviruses?
``` HBV HCV HPV EBV HIV-1 HTLV-1 ```
51
What is the mechanism of viral oncogenesis?
Virus Cell Integration Transformation
52
Viral genes interfere with control of cell cycle replication causing:
Loss of growth control Reduced adhesion Motility Invasion
53
Oncogene definition
A gene that has the potential to transform a normal cell into a malignant cell
54
P53 is bound to what
Mdm2
55
HPV causes what cancers?
Cervical, vulval, uterine, penile, anal, oral-pharyngeal
56
HBV, HCV causes what cancer?
Hepatocellular
57
EBV is associated with what cancers?
Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal, Duncan's syndrome, B cell lymphoma
58
KSHV/ HHV-8
Kaposi's sarcoma
59
MCV is associated with what cancer?
Merkel cell carcinoma
60
HTLV-1 is associated with was cancer?
Adult T cell leukaemia
61
What HPV strains are associated with cancer?
16 and 18
62
What are the HPV vaccines?
Cervirax (bivalvent) | Gardasil (quadvalent)
63
What cells does EBV infect?
B cells and epithelial cells
64
EBV induces what chromosomal translocation?
8:14 translocation Break in chromosome 14 at q32