How do you classify the type of cancer?
By the tissue affected
What does the grade of a tumour mean?
Differentiation, nuclear and cytoplasmic abnormalities, number of mitoses, extension of necrosis...
How do you define the stage of a cancer?
TNM classification and number
What is TNM classification
T: size of the tumor
N: putative regional lymph node invasion
M: distant metastases
What are the main steps towards formation of a cancer?
Initiation→Promotion→ Progression-→ Metastasis
What genes are often associated with hereditary cancers?
BRCA1, BRCA2
What are the first 6 hallmarks of cancer?
1.Sustained proliferation signals
2.Evasion of growth supressors
3.Invasion and metastasis
4.Replicative immortality
5.Sustained angiogensis
6.Resisting cell death
What are the 4 next generation hallmarks of cancer?
1.Evasion of the immune system
2.Tumour promoting inflammation
3.Genome instability and mutation
4.Deregulating cellular energetics
What is the effect of a mutation of BRCA1?
Affects the ability to repair dsDNA breaks and affects checkpoint controls during the cell cycle
What class of drugs targets the hallmark “ Sustained proliferation signals”
EGFR inhibitors
What class of drugs targets the hallmark “Evasion of growth supressors”
CDK inhibitors
What class of drugs targets the hallmark “Invasion and metastasis”
Inhibitors of HGF/cMet
What class of drugs targets the hallmark “Replicative immortality”
Telomerase inhibitors
What class of drugs targets the hallmark ”Sustained angiogensis”
Inhbitors of VEGF signalling
What class of drugs targets the hallmark “Resisting cell death”
Proapoptotic drugs
What class of drugs targets the hallmark “Evasion of the immune system”
PDL-1 and PD-1 inhibitors
What class of drugs targets the hallmark “Tumour promoting inflammation”
selective anti-inflammatory drugs
What class of drugs targets the hallmark “Genome instability and mutation”
PARP inhibitors
What class of drugs targets the hallmark”Deregulating cellular energetics”
Aerobic glycolysis inhibitors
What is Ras and what does a mutation in Ras lead to?
Ras is a proto-oncogene. A mutation in RAS makes it stay in the LOCKED conformation or GTP conformation, which means that it is continuously activated and does not require any signal for it to stimulate cell division.
Describe “READERS” in epigenetics
specialized domain containing proteins that identify and interpret the modifications from Writers
Describe “WRITERS” in epigenetics
introduce various chemical modifications on DNA and histones
Describe “ERASERS” in epigenetics
proteins that are capable of removing modifications to DNA or histones that were produced by epigenetic writers to regulate gene expression
Epigenetic transcriptional control can occur through:
1.DNA methylation
2.Histone modification and chromatin remodelling
3.Non-coding RNA's
Name 3 epigenetic writers
DNMTs
HMTs
HATs
Name one epigenetic reader
UHRF1
Name 3 epigenetic erasers
1.DNA-demethylating enzymes
2.KDMs
3.HDACs
What do DNMTs catalyze
The addition of a methyl group to the 5th carbon position of cytosines, especially at a C followed by a guanine
What is the reaction of DNMT
cytosine→5-methylcytosine
What does DNA hypermethylation lead to?
Promoter silencing of tumorsuppressor genes
What does DNA Hypomethylation lead to?
Genome instability and Oncogene activation
What does high expression of UHRF1 lead to?
Hypermethylation→Inhibition of TSG
What kind of biomarker can UHRF1 be?
prognosis and diagnostic biomarker
What does UHRF1 bind to?
HDAC1 and DNMT1 through the SRA domain
What are the Ten-Eleven Translocation (TET) enzymes?
DNA-demethylating enzymes (Erasers)
What type of reactions do the TET enzymes do?
Oxidation reactions
What are the reaction steps catalyzed by the TET enzymes?
5-methylcytosine→5hydroxymethylcytosine →5-formylcytosine→5-carboxylcytosine
Are levels of 5-hydroxy-methylcytosine HIGH or LOW in cancer?
LOW
On which 2 amino acids does histone modification often occur?
Lysine and arginine
which domain of the histone is often methylated?
H3 tail
Is MLL a histone methylation reader, writer or eraser?
writer
What does MLL methylate?
H3K4
Low levels of histone modification is associated with good or bad survival prognosis in patients?
Bad prognosis
Name 2 histone methylation Readers:
HP1 and Chd1
Name a class of histone methylation erasers and two examples from this class:
HDMs (LSD and JMJC)
True or false “ Histone methylation can either promote or inhibit gene expression”
True
Name the class of histone acetylation writers:
KATs or HATs
Name the class of histone acetylation readers:
The BETs
What does BET stand for?
Bromodomain and extraterminal domain proteins
What is BET?
A histone acetylation reader
Name the 4 members of the BET family:
BRD2, BRD3, BRD4, BRDt
What is the name of the histone acetylation erasers?
HDACs
What happens when HDACs are disregulated?
Over de-acetylation and and inactivation of tumour supressor genes
True or False “ miRNA can be tumour-promoting and tumour-supressing”
True
What type of biomarker can miRNA be?
Predictive biomarkers