Session 9 Flashcards
How many cases of cancer are preventable?
38%
What are the intrinsic causes of cancer?
- Heredity
- Age and prolonged lifespan (constant accumulation of mutation and lower immunodefences of people)
- Sex (hormones)
What are the extrinsic causes of cancer?
- Environment (chemicals, radiation, infection)
- Behaviour
How can cancer be prevented?
- Smoking (biggest factor!)
- Maintaining a healthy weight
- Sun safety
- Balanced diet
- Less alcohol
- Activity
What cancers can be prevented by smoking?
Mouth, pharynx, noes, oesophagus
Liver, stomach, kidney,
Some leukaemia
What are the EXTRINSIC factors of carcinogenesis?*
- Chemicals
- Viruses
- Radiation
- Infection
Will cause initiation and promotion
What are INTRINSIC factors of carcinogenesis?*
- Inherited mutation (initiation and promotion)
- Chronic inflammation (promotion)
What factors of carcinogenesis are mutations?*
Can be both extrinsic and intrinsic:
- Monoclonal population
- Gaining additional mutation to progress
- Deregulated cell signalling pathways results in hallmarks of cancer
What percentage of cancer risk do environmental/extrinsic factors count for?*
85% (reduction past generations of migrants so environmental factors)
What can be the hereditary causes of cancer?
- Autosomal dominant genes: ‘guaranteed’ cancer
- Less frequent genes (eg. having a first degree relative) = more neoplastic phenotype
What chemical used in dye manufacturing causes cancer and how does it do that?
2-NAPTHYLAMINE
- Long delay (decades) between carcinogen exposure and malignant neoplasm onset
- Risk depends on total carcinogen dosage
- Sometimes organ specificity (bladder)
- Present in cigarettes and so smokers at increased risks
How does chemical carcinogenesis occur?*
- Initiation and promotion
- Initiators come first and then are followed by promoters
- Promoters take many years (growth, growth factor pathways, proliferation)
What chemicals can cause cancer?
- Alkylating agents (vinyl chloride)
- Benzopyrene (cigarette smoke)
- Asbestos
- Aflatoxin
- 2-naphthylamine (aromatic amine)
- Aromating agents
- N-nitroso compounds (created in stomach on nitrite exposure)
What is radiation and what are some examples of radiation?
Any type of energy travelling through space, some forms being mutagenic by causing direct DNA damage or generating free radicals (hydroxyl radicals)
- Alpha, beta particles, gamma rays, X rays, UV rays
(25% of malignant neoplasms)
Beware of medical testing (CT, X rays)
How can infections cause cancer?
- Directly affecting genes that control cell growth (eg. HPV)
- Indirectly by causing chronic tissue injury and regeneration acting as a promoter for pre-existing mutation or causing new mutation (eg. Hepatitis B by chronic inflammation )
What can cause cancer by reduced immunity?
HIV
How does HPV cause cancer and what cancers is it associated with?
- Makes E6 and E7 proteins
- Virus infects cells and ensures they don’t die
- Then hijacks DNA to make more virus
- E6 inhibits p53 (tumour suppressor) so preventing apoptosis
- Hijacks cell cycle by interfering with retinoblastoma protein which is a cell cycle checkpoint
How do you test if something is a carcinogen?*
Use media with minimal histidine and a high number of revertants (his- to his+) suggests that it causes mutation
What is an initiator?
Anything that can cause a mutation
What is a promotor?
Anything that causes the expansion of initiator population
What is a pro-carcinogen?
Pro-carcinogen is converted into a carcinogen by cytochrome P450 in the liver
What is a complete carcinogen?
A carcinogen capable of being an initiator and promoter
What is familial retinoblastoma?
Cancer of the eye that is inherited (family) - about 40% of retinoblastomas
What are the 2 types of retinoblastoma?
- Bilateral - earlier (greater increase due to gene inheritance, 40%)
- One eye - later (sporadic due to mutation, needs 2 sporadic hits and is happening later in one eye, 60%)
How does familial inheritance cause retinoblastoma?
- First hit at germline as one abnormal cell
- Hit 2 occurs as going through life
= Retinoblastoma
How does sporadic mutation cause retinoblastoma? (2-hit hypothesis)
- 2 normal cells into germline
- Over time get one hit
- Time passes, get second hit
= Retinoblastoma
What is the retinoblastoma gene?
2 forms: active hypophosphorylated and inactive hyperphosphorylated
- Negative regulator of G1/S checkpoint
- Allows continuous proliferation
What is the RAS gene?
The most common type of abnormality involving human tumours and proto-oncogenes
- Mutated in 15-20% of all malignant neoplasms
- Higher (90%) in some cancers, eg. pancreatic adenocarcinomas
How does the RAS gene work normally?*
- RAS encodes a small G protein binding to GTP
- Conformational changes
- Enters cell, makes cyclin D
- Activates CDK
- Retinoblastoma gets hyperphosphorylated and allows cell to progress to the next point of the cell cycle
What happens when RAS gets a mutation?
eg. point mutation allows RAS to be permanently switched on
- Permanently activates RB gene
- Constant proliferation
= Cancer
How do proto-oncogenes and tumour suppressor genes work?*
Together but opposing function
RAS = proto-oncogene, tumour suppressor gene is trying to stop it from happening
Where must abnormalities occur to create cell cycle restriction?
ACCUMULATION
- Proto-oncogene: one abnormality
- Tumour suppressor: two abnormalities
What can proto-oncogenes encode?*
SLIDE 26
What genes prevent accumulation of DNA damage?
Caretaker genes (some neoplasms caused by indirectly affecting DNA repair)
What is hereditary non-polyposis colon cancer? (HNPCC)
An autosomal dominant syndrome that is associated with colon cancer, where the germline mutation affects one of several DNA mismatch repair genes
What is xeroderma pigmentosa (XP)?
An autosomal recessive disease due to mutation affecting DNA nucleotide excision repair
What are the effects of xeroderma pigmentosa?
- Skin that is very sensitive to UV damage
- Developing skin cancer at a very young age
What genes cause familial breast carcinoma?*
BRCA1/BRCA2 genes which are normally unrelated to each other and are expressed in the breast
What are BRCA genes involved in?
Repairing double strand DNA breaks
What are the signs that the breast carcinoma is a BRCA mutation?
- DNA damage cannot be repaired and mutations accumulate
- Breast cancer development at a younger age
What do chromosome aggregations contribute to in malignancies?
Accelerated mutation rate (genetic instability)
What genes maintain stability?
Caretaker genes (tumour suppressor genes)
How does 80% of colorectal cancer develop?*
Gradual accumulation of gene abnormalities
dysplasia - intermediate then late adenoma - carcinoma - metastases
How many mutations do malignant neoplasms usually consist of?
Around 10 but variable by tumour type and individual
What are the hallmarks of cancer?
- Self-sufficient growth signals (proliferate with no need for stimuli)
- Resistance to growth stop (tumour suppressor faulty)
- Limitless cell division number (telomerase activation)
- Sustained angiogenesis (VEGF)
- Resistance to apoptosis
- Ability to invade and produce mets (EXCLUSIVE TO MALIGNANT NEOPLASMS)
