Module Three: Cancer Genetics

Question 1

What is the multi-step model of cancer development?

Answer 1

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

Question 2

What is knudson’s two hit hypothesis?

Answer 2

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

Question 3

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

Answer 3

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

Question 4

What are the limitations of gene therapy for cancer treatment?

Answer 4

Targeted delivery, expression, multiple TSG defects

Question 5

What does the Rb code for?

Answer 5

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

Question 6

Sporadic Rb1 gene mutations are found in what cancers?

Answer 6

Bone, lung and breast (and retinoblastoma)

Question 7

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

Answer 7

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

Question 8

Germline mutations in APC are responsible for what syndrome?

Answer 8

Familial polyposis syndrome affecting the large bowl

Question 9

95% of APC mutations cause what?

Answer 9

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

Question 10

What do the BRCA1 and 2 genes code for?

Answer 10

Codes for the proteins involved in the repair of damaged DNA

Question 11

What inactivates BRCA1 in sporadic breast cancers?

Answer 11

Methylation

Question 12

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

Answer 12

MLH1, MSH2, MSH6, PMS2

Question 13

Inactivation of mismatch repair genes results in what?

Answer 13

Micro satellite instability

Question 14

Germline mutations are responsible for?

Answer 14

Lynch syndrome

Question 15

TP53 functions in:

Answer 15

Cell cycle arrest, DNA repair and apoptosis

Question 16

What syndrome is a result of TP53 germ line mutations?

Answer 16

Li-Fraumeni Syndrome

Question 17

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

Answer 17

Binding to viral proteins

Question 18

What viruses bind to TP53?

Answer 18

SV40, papilloma, Adenovirus

Question 19

What can inhibit the activity of TP53 through feedback mechanism?

Answer 19

MDM2

Question 20

How many regions does the central part of TP53 contain?

Answer 20

5

Question 21

TP53 is a what?

Answer 21

Nuclear phosphoprotein

Question 22

What are examples of low risk genetic factors?

Answer 22

Genes involved in carcinogen breakdown, DNA Repair

Question 23

What cancers are associated with Lynch syndrome?dw

Answer 23

Colorectal, endometrial, rarer: gastric, renal

Question 24

What are the five steps to genetic testing?

Answer 24

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

Question 25

Role of familial cancer clinics?

Answer 25

Risk assessment Genetic testing Counselling Surveillance advice

Question 26

Define: epigenetics

Answer 26

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

Question 27

Examples of epigenetic factors

Answer 27

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)

Question 28

What are the two molecular pathways involved in bowel cancer

Answer 28

Chromosomal instability | CpG island methylator phenotype

Question 29

Where does methylation occur?

Answer 29

Cytosine residue of cytosine-p-guanine dinucleotides

Question 30

How does DNA methylation lead to silencing?

Answer 30

Directly inhibits the binding of transcription factors

Question 31

DNA methylation patterns are determined by an interplay between:

Answer 31

The environment (dietary folate, vitamins) Age DNA methyl transferase (DNMT1, DNMT 3A, DNMT3B)

Question 32

What are the challenges of demethylating agents?

Answer 32

Specificity and toxicity

Question 33

Genes that control cell cycle control ?

Answer 33

P73, p16, p15, p14

Question 34

Genes that control Regulation of apoptosis

Answer 34

DAP-kinase, p73

Question 35

Genes that control Invasion / tumour architecture

Answer 35

E-cadherin, VHL, APC, APC, TIMP3

Question 36

Growth factor receptors

Answer 36

ER, RARb

Question 37

Genes that control Drug uptake and sensitivity?

Answer 37

MDR1, MRP

Question 38

Genes that control DNA damage and repair?

Answer 38

MLH1, O6-MGMT, BRCA1

Question 39

What are micro satellites ?

Answer 39

Repetitive DNA sequences scattered throughout the genome

Question 40

What is microsatellite instability?

Answer 40

Shortening or lengthening of repeats in tumour DNA due to defective DNA mismatch repair mechanisms

Question 41

Where do the large majority of MSJ tumours occur?

Answer 41

Proximal colon

Question 42

What are the 6 hallmarks of cancer?

Answer 42

``` Resisting cell death Inducing angiogenesis Enabling replicative immortality Sustaining proliferative signals Activating invasion and metastasis Evading growth suppressors ```

Question 43

What transcription factors orchestrate EMT and are involved in most steps of invasion and metastasis?

Answer 43

Snail, slug, twist, zeb1/2

Question 44

What is the EMT

Answer 44

Epithelial Mesenchymal transition

Question 45

What are the emerging hallmarks of cancer development?

Answer 45

Deregulating cellular energetics | Avoiding immune destruction

Question 46

What are the enabling characteristics of the emerging hallmarks?

Answer 46

Genome instability and mutation | Tumour promoting infiltration

Question 47

Inflammatory cells that contribute to hallmark capabilities by releasing:

Answer 47

Growth factors that sustain proliferative signalling Survival factors that limit cell death Pro-angiogeneic factors

Question 48

What does a virion consist of?

Answer 48

Genome Capsid Membrane Ligands

Question 49

What are the three viral shapes?

Answer 49

Helical Polyhedral Binal

Question 50

6 WHO recognised on oncoviruses?

Answer 50

``` HBV HCV HPV EBV HIV-1 HTLV-1 ```

Question 51

What is the mechanism of viral oncogenesis?

Answer 51

Virus Cell Integration Transformation

Question 52

Viral genes interfere with control of cell cycle replication causing:

Answer 52

Loss of growth control Reduced adhesion Motility Invasion

Question 53

Oncogene definition

Answer 53

A gene that has the potential to transform a normal cell into a malignant cell

Question 54

P53 is bound to what

Answer 54

Mdm2

Question 55

HPV causes what cancers?

Answer 55

Cervical, vulval, uterine, penile, anal, oral-pharyngeal

Question 56

HBV, HCV causes what cancer?

Answer 56

Hepatocellular

Question 57

EBV is associated with what cancers?

Answer 57

Burkitt's lymphoma, Hodgkin's lymphoma, nasopharyngeal, Duncan's syndrome, B cell lymphoma

Question 58

KSHV/ HHV-8

Answer 58

Kaposi's sarcoma

Question 59

MCV is associated with what cancer?

Answer 59

Merkel cell carcinoma

Question 60

HTLV-1 is associated with was cancer?

Answer 60

Adult T cell leukaemia

Question 61

What HPV strains are associated with cancer?

Answer 61

16 and 18

Question 62

What are the HPV vaccines?

Answer 62

Cervirax (bivalvent) | Gardasil (quadvalent)

Question 63

What cells does EBV infect?

Answer 63

B cells and epithelial cells

Question 64

EBV induces what chromosomal translocation?

Answer 64

8:14 translocation Break in chromosome 14 at q32