Cancer Flashcards
What are the broad categories of cancer and their nomenclature?
Benign (tissue + oma): neither invaded nor metastasised
- Can be encompassed in a capsule
Malignant (carcinoma): capable of metastasis and invading into other tissues
- Metastasis = formation of new tumour colonies (major death causing (>90%))
What are the ways that cancer can impact normal function?
- Pressure: pituitary gland/medulla, depressing vital function; blockage of vessels/airways/digestion
- Erosion of bone = fractures
- Epithelial ulceration: bleeding from colorectal tumours
- Competition with normal function: failure of bone marrow
- Metabolic changes: Cachexia = ‘general wasting’ and production of tumour specific products
How can cancer be detected?
Clinical symptoms:
- Cachexia
- Indirect: bleeding, blocked colon, pain
- Palpation of breast tissue
Clinical tests:
- X-ray
- Screening (cervical cancer)
Tumour mapping:
- Single cell sequencing
- Spatial transcriptomics (including ssRNAseq): to determine which cell types are where in tumour
What are mutagens and how do they increase cancer risk?
Initiators which increase genetic instability: directly damaging DNA and increasing mutation rate (higher transformation risk)
Examples:
- UV light (causing thymidine dimers)
- Smoking (benzopyrene, β-naphthylamine)
- Environmental carcinogens (weedkiller; agent orange)
- Toxins produced by infectious agents (aspergillus aflatoxin activated by oxidases)
- Interruption of gene by integrating virus (rare)
- NMU (alkylating: AT-GC mutations)
How do components of cigarettes increase transformation risk?
Benzopyrene (contains benzene rings):
1. Binds Ahr causing CYP1A1 translation
2. Addition of adducts to guanines caused
3. If not removed by NER then A ➡ T visa versa likely
β-naphthylamine:
1. Normally glycosylated to clear in urine
2. Reactivated by human enzyme glucaronidase
3. Adducts formed
Give some specific environmental carcinogens. What are the mechanisms by which they cause disease?
Agent Orange (containing TCDD):
- Causes translation of CYP1A1 and increased ROS
- Proliferation and increased DNA damage (both initiator and promotor)
NMU:
- Alkylating agent
- Transfers methyl group causing AT ➡ GC transitions
Aflatoxin produced by aspergillus:
- Alkylating agent
- Adduct formation causing disheveled DNA and interrupting repair mechanisms
What are promotors and how do they increase transformation risk?
Change cell behaviour, increasing the probability of a mutation of an individual cell or a population of cells (or increasing population size):
- Carcinogens causing inflammation (asbestos, TPA)
- Microbes causing inflammation (aspergillus, TB)
- Infection with a transforming pathogen (HPV, Rous’ SV, EBV)
Detail the ways that infection can cause transformation of a cell; give examples:
Gene modification: Proto-oncogene protomors: HPV, HSV, EBV
- Carry proto-oncogenes (H-ras; K-ras) with a range of actions
- Discovered by Rous’ experiments using filtered sarcoma homogenate injected into chicken wing – sarcoma developed weeks later
Change cell behaviour (create environment to facilitate survival)
- Loss of contact inhibition (HPV)
- High growth density/growth without attachment
- Immortality
- Growth factor independence/resistance to signals causing stasis of growth/death.
Change to behaviour of cell population:
- Malaria causing B cell proliferation/activation (synergy between EBV and malaria)
What are gatekeeper and caretaker mutations?
Gatekeeper = involved in growth/division:
- Oncogenes/tumour suppressor genes
- E.g. pRb, p53
Caretaker = involved in maintenance of genome:
- SSBR, NER, BER, NHEJ, MMR
What is a classic tumour suppressor gene? Describe an example.
Recessive tumour suppressor gene.
Retinoblastoma gene (for Rb protein (pRb)):
- pRb normally inhibits DNA replication at G1/S checkpoint
- When cyclin D builds up it activated cdk4/6
- These phosphorylate pRb, inhibiting it.
Mutations in RB1 gene (inactivating it) or genes overactivating cdk4/cyclin D can cause overphosphorylation (and cancer)
What is an abnormal tumour suppressor gene? Describe an example.
Have significant effect on cell when only one copy is mutated:
E.g. p53 TF
- Functions as a tetramer, hence most complexes contain some faulty protein
- Mutated copies have reduced ability to bind to DNA
- Reduces ability to induce apoptosis by activating Bcl2 protein, so damaged cells continue to reproduce
Can be hereditary E.g Familial adenomatous polyposis (APC mutation)
What are the types of genetic instability? Give examples of each:
Sequence instability = mutation:
- Failure to repair DNA damage E.g. MLH1 mutation causing MMR failure)
- Errors in mitosis E.g. pol epsilon mutation causing defective proof reading domain (high error rate)
Chromosomal instability:
- Failure to repair damage: BRCA1/2 mutations
- Errors in replication such as faulty spindle attachments/kinetochores: aneuploidy results
What are the different DNA repair mechanisms? What is BRCA involved in?
Excision repair: Nucleotide (NER)/base (BER):
- Deal with chemically modified bases E.g. UV-induced pyrimidine dimers
Mismatch repair (MMR): deals with mismatched bases or small loops:
- Caused by polymerase slip during replication of repeats ➡ deletion/insertion on one strand
- Inability to fix loops leads to shrinkage/expansion of short repeats (=microsatellites)
- MMR mutation in hereditary Lynch syndrome (mutation in MLH1/2)
Repair of strand breaks:
- Single stand break repair (SSBR)
- Homologous recombination (HR): relies on other copy (E.g. sister chromatid) as a template = faithful repair
- Non-homologous end-joining (NHEJ): results in loss of sequence fidelity (no template) often occurs at telomeres
BRCA1/2 are involved in HR causing breast cancer if mutated (can be hereditary).
What is the Vogelstein model of colorectal cancer development?
Suggest tumorigenesis is a sequence of mutations which together cause cancer (not one).
- Order and identity of acquisition affects speed of cancer formation.
Sequence of events:
1. Normal epithelium
2. Hyperplastic epithelium (due to APC mutation)
3. Adenoma due to DNA hypomethylation (epigenetic changes)
4. Carcinoma formation due to accumulation of mutations (activation of K-ras, loss of TSGs, loss of p53)
5. Invasion/metastasis
What is the modern interpretation of the Vogelstein model? Give an exemplar sequence:
- Epigenetic deregulation (E.g. due to infection)
- Disruption of onco/TSGs
- Transcriptional dysregulation due to mutation (repair cannot keep up with mutation rate)
- Metabolic deregulation
- Inflammation and microenvironment formed (immune suppressing and metabolically greedy with vascular growth)
E.g. Removal of proliferation brake (β-catenin) ➡ genetic instability (ras) ➡ immune system evasion mutation (e.g. TGF-β) ➡ removal of apoptosis activator (p53) ➡ carcinoma
Which cancers are hereditary/show a strong predisposition trend?
Hereditary Colon cancer:
- Adenomatous polyposis coli (APC): APC mutation affecting growth control = 80% of sporadic colorectal cancer
- Lynch syndrome: MLH1 mutation causing genetic instability in MMR gene (non polyposis colon cancer)
Hereditary predisposition to breast cancer:
- E.g. BRCA1/2 gene mutations causing problems in HR strand repair pathway (50-80% risk of breast cancer (compared to 15%)
- Even patients with restored BRCA2 the cancer is still lethal to patient (not purely due to mutation, but also due to genetic instability)
Retinoblastoma – RB1 mutation affecting growth control by allowing free entry to S phase causing rare childhood tumour.
Describe the Wnt signalling pathway:
- Wnt binding (to frizzled receptor) inhibits degradation of β-catenin
- β-cahenin (with TCF4) becomes active transcription factor
- Promotes proliferation through cell cycle entry (cyclin D, VEGF production)
Mutations (E.g. in wnt receptors) can lead to inappropriate inhibition of degradation
Describe the GF tyrosine kinase signalling pathway. How can mutations cause immortality?
Epidermal GF binding (to EGF receptor):
- RAS activation = promotes proliferation
- PIP2 to 3 conversion = PIP3 inhibits apoptosis
PIP3 normally broken down by PTEN
- Mutations in PTEN cause cancer
- Mutations can occur in all steps of the pathway
Describe the TGF-β signalling pathway:
- TGF-β binds TGF-β receptor
- Activation of SMADs (as TFs)
- Inhibition of proliferation (tumour suppressor)
Mutations cause release of proliferation inhibition and correlated with metastasis ability.
