Module Three: Cancer Genetics Flashcards
What is the multi-step model of cancer development?
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
What is knudson’s two hit hypothesis?
Tumour suppressor genes act recessively i.e. Both copies of genes must be inactivated for growth control to be lost
What are the genes that are responsible for many familial cancers?
Rb, tp53, p16, BRAC1/2, APC, hMLH1
What are the limitations of gene therapy for cancer treatment?
Targeted delivery, expression, multiple TSG defects
What does the Rb code for?
Codes for a nuclear protein that is a major inhibitor of the cell cycle
Sporadic Rb1 gene mutations are found in what cancers?
Bone, lung and breast (and retinoblastoma)
What does the adenomatous polyposis coli gene have critical roles in?
Cell division and adhesion, regulates beta-catenin activity and the Wnt pathway
Germline mutations in APC are responsible for what syndrome?
Familial polyposis syndrome affecting the large bowl
95% of APC mutations cause what?
Frame shifts that lead to production of a truncated, inactive protein
What do the BRCA1 and 2 genes code for?
Codes for the proteins involved in the repair of damaged DNA
What inactivates BRCA1 in sporadic breast cancers?
Methylation
What genes encode for proteins that repair DNA mismatches arising during cell replication?
MLH1, MSH2, MSH6, PMS2
Inactivation of mismatch repair genes results in what?
Micro satellite instability
Germline mutations are responsible for?
Lynch syndrome
TP53 functions in:
Cell cycle arrest, DNA repair and apoptosis
What syndrome is a result of TP53 germ line mutations?
Li-Fraumeni Syndrome
Apart from mutation and chromosomal loss, TP53 can occur by what?
Binding to viral proteins
What viruses bind to TP53?
SV40, papilloma, Adenovirus
What can inhibit the activity of TP53 through feedback mechanism?
MDM2
How many regions does the central part of TP53 contain?
5
TP53 is a what?
Nuclear phosphoprotein
What are examples of low risk genetic factors?
Genes involved in carcinogen breakdown, DNA Repair
What cancers are associated with Lynch syndrome?dw
Colorectal, endometrial, rarer: gastric, renal
What are the five steps to genetic testing?
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
Role of familial cancer clinics?
Risk assessment
Genetic testing
Counselling
Surveillance advice
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
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)
What are the two molecular pathways involved in bowel cancer
Chromosomal instability
CpG island methylator phenotype
Where does methylation occur?
Cytosine residue of cytosine-p-guanine dinucleotides
How does DNA methylation lead to silencing?
Directly inhibits the binding of transcription factors
DNA methylation patterns are determined by an interplay between:
The environment (dietary folate, vitamins)
Age
DNA methyl transferase (DNMT1, DNMT 3A, DNMT3B)
What are the challenges of demethylating agents?
Specificity and toxicity
Genes that control cell cycle control ?
P73, p16, p15, p14
Genes that control Regulation of apoptosis
DAP-kinase, p73
Genes that control Invasion / tumour architecture
E-cadherin, VHL, APC, APC, TIMP3
Growth factor receptors
ER, RARb
Genes that control Drug uptake and sensitivity?
MDR1, MRP
Genes that control DNA damage and repair?
MLH1, O6-MGMT, BRCA1
What are micro satellites ?
Repetitive DNA sequences scattered throughout the genome
What is microsatellite instability?
Shortening or lengthening of repeats in tumour DNA due to defective DNA mismatch repair mechanisms
Where do the large majority of MSJ tumours occur?
Proximal colon
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
What transcription factors orchestrate EMT and are involved in most steps of invasion and metastasis?
Snail, slug, twist, zeb1/2
What is the EMT
Epithelial Mesenchymal transition
What are the emerging hallmarks of cancer development?
Deregulating cellular energetics
Avoiding immune destruction
What are the enabling characteristics of the emerging hallmarks?
Genome instability and mutation
Tumour promoting infiltration
Inflammatory cells that contribute to hallmark capabilities by releasing:
Growth factors that sustain proliferative signalling
Survival factors that limit cell death
Pro-angiogeneic factors
What does a virion consist of?
Genome
Capsid
Membrane
Ligands
What are the three viral shapes?
Helical
Polyhedral
Binal
6 WHO recognised on oncoviruses?
HBV HCV HPV EBV HIV-1 HTLV-1
What is the mechanism of viral oncogenesis?
Virus
Cell
Integration
Transformation
Viral genes interfere with control of cell cycle replication causing:
Loss of growth control
Reduced adhesion
Motility
Invasion
Oncogene definition
A gene that has the potential to transform a normal cell into a malignant cell
P53 is bound to what
Mdm2
HPV causes what cancers?
Cervical, vulval, uterine, penile, anal, oral-pharyngeal
HBV, HCV causes what cancer?
Hepatocellular
EBV is associated with what cancers?
Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal, Duncan’s syndrome, B cell lymphoma
KSHV/ HHV-8
Kaposi’s sarcoma
MCV is associated with what cancer?
Merkel cell carcinoma
HTLV-1 is associated with was cancer?
Adult T cell leukaemia
What HPV strains are associated with cancer?
16 and 18
What are the HPV vaccines?
Cervirax (bivalvent)
Gardasil (quadvalent)
What cells does EBV infect?
B cells and epithelial cells
EBV induces what chromosomal translocation?
8:14 translocation
Break in chromosome 14 at q32
