Causes and Risk Factors Flashcards
How many cancers in the UK are estimated to be preventable? Can the cause be identified once diagnosed? 11:56
- 42%
- Usually not possible to identify the precise cause for individual cause
What are the preventable risk factors for cancer?
- Smoking
- Diet
- Exercise
- Infection
- Pollution
- Alcohol
(Lifestyle/environmental)
What types of mutation can occur that may result in cancer?
Permanent change in DNA sequences (passed from cell to cell):
- Single nucleotide changes/point mutations (most common)
- Insertions/deletions/amplifications
- Chromosome rearrangements/losses/gains
What are the common mutagens that may lead to cancer?
Usually carcinogens:
- Tobacco
- UV
- IR (ionising radiation)
- Chemotherapeutics drugs
What conditions increase cell proliferation, and thus in turn increase the rate of tumour progression (i.e. tumour promoters)? What do they have in common?
- Inflammation (esp. chronic, e.g. from asbestos)
- Alcohol
- Chemical promoters
- Menstruation
»> Increase cell proliferation WITHOUT changes in gene sequences
How is chronic inflammation a major risk factor in cancer?
Promotes mutagenesis
- ROS, RNS (Nitrogen); produced during inflammation; to combat pathogens, but damages self too
Promotes tumour progression
- NF-kB induces cytokines (TNF-α, IL-1 etc.); prevents apoptosis (tipping balance towards proliferation)
Promotes metastasis
- Activated neutrophils secrete TNF-α; tumor necrosis factor (causes apoptosis as well)
- Angiogenesis & migration
What effect do ROS/RNS typically have once released during inflammation?
- Oxidised bases and abasic sites (apurinic, apyrimidinic, AP)
- Single strand breaks and double strand breaks can also occur
»> If not repaired and cell does not apoptose = mutation
Describe smoking as a risk factor for cancer.
- Biggest avoidable/preventable cause
- 20X increased risk of lung cancer
- > 60 chemicals that damage DNA
» P53/KRAS (signal transduction protein downstream; RAS?) G > T change can encode different DNA, telling cells to proliferate
How does benzo(a)pyrene from smoking contribute towards cancer?
- Itself not carcinogenic
- But converted to epoxide inside cell
»> Can lead to detrimental point mutation if not apoptosed
How is infection implicated in cancer risk? Give examples.
- 16% caused by infection; 3% in the UK, >30% in sub-Saharan America
- Viruses, bacteria, animals
E.g.:
• H. pylori
• HPV (cervical)
• HCV, HBV (hepatic)
• EBV
• Herpes Type B
• Parasitic flatworms
• HTLV-1
How do oncoviruses (e.g. HPV, HCV, HBV) cause cancer?
HPV (human papilloma virus)
- 70% of cervical cancer cases
- Produces oncogenic proteins E6 & E7; interfering w/host cell proliferation signalling
»> E6 targets p53 for degradation (ubiquitination?)
»> E6 inhibits Rb (phosphorylates?)
HCV, HBV (hepatitis C/B virus)
- Inflammation (cirrhosis; of the liver)
How does H. pylori infection contribute to cancer risk?
Helicobacter pylori (bacterium)
- 50% of world’s population infected
- Gastric & duodenal ulcers (inflammation; risk)
- Increases ROS and RNS in stomach; free radicals DNA damage; mutation
»> Associated w/gastric carcinoma and mucosa associated lymphoid tissue (MALT) lymphoma
How do parasites cause cancer?
Flatworms, tapeworms (and their eggs) can cause inflammation:
- Schistosoma haematobium (flatworm) infection; bladder cancer
- Opisthorchis viverrini (flatworm); bile duct cancer
- Tapeworms in other mammals e.g. cats
- Malaria (protozoa) associated w/Burkitt’s lymphoma
What are transmissible cancers?
- Dogs and tasmanian devils can spread cancers by contact (though some of the animal population has developed resistance)
- Transmitted during surgery e.g. if surgeon exposed
What types of ionising radiation are there? How do they cause cancer? Give examples.
Can dislodge electrons:
- Alpha emitters (H+ nucleus e.g. radon-222; accumulates in basements of buildings; colourless, odourless gas)
- Beta emitters (high energy electrons, emitted from nuclei e.g. potassium-40)
- Gamma radiation (high frequency EM radiation emitted from decaying nuclei e.g. potassium-40 AGAIN)
- X-rays (not as high frequency EM radiation from e-)
- Cosmic radiation (v. high energy charged particles from space; atmosphere gives protection
(UV radiation - lower energy, mostly non-ionising)
What effect does ionising radiation have?
- Causes DNA damage; directly, causing double strand breaks
- Or indirectly, producing ROS/RNS that attack DNA
What particular damage to DNA can UV radiation cause?
- Causes cyclo-pyrimidine dimers (Cs and Ts)
- Causes 6-4 photoproducts
»> Both between adjacent bases (not normally bonded, should be just j. chillin)
What other environmental mutagens are there, and the cancers they predispose?
• Occupational chemicals/waste products:
(Controlled to reduce exposure and prevent accidental release)
- Aromatic amines (bladder cancer)
- Benzene (leukaemias)
- Asbestos, carbon nanotubes (mesothelioma)
• Natural products
- Fungal toxins (aflatoxin; liver cancer associated w/chronic exposure)
• Medical mutagens
- Chemotherapy drugs (target DNA)
- Radiotherapy
- X-rays
- Diagnostic imaging
- Herbal products (e.g. Aristolochia; betel nut & oral cancer)
• Atmospheric particles
- Vehicle exhaust (PM10s from diesel fumes associated w/lung cancer)
How is diet linked to cancer risk?
- Mediterranean diet good, red meat bad
- Alcohol
How is red meat carcinogenic?
- Class 2A carcinogenic (WHO)
- HCAs (heterocyclic amines) from cooking
»> Processed red meat = Class 1 carcinogen
How is alcohol implicated in cancer risk?
- 4% of all cancers
- Possibly acetaldehyde (metabolite, causes DNA damage) = mutagenic
- Liver cancer in heavy drinker (cirrhosis/hepatitis; chronic inflammation)
- Irritant (tumour promoter) in oral & pharyngeal cancers in smokers (esp. more conc. alcoholic drinks on throat)
How does fibre have a protective role against cancer?
- Associated w/reduced colorectal cancer risks
- Protective; greater rate of passage, leads to more cells to promote apoptosis?)
What are the lifestyle factors implicated in risks/preventing cancer?
- Exercise; associated w/lower risk for many cancers (reducing obesity/stress)
- Stress
• Raised cortisol levels; immune suppression (allowing viruses etc to manifest?)
• Night working; disruption of circadian gene regulation - Obesity
• Especially in postmenopausal women (estrogen production shifts from ovaries to fat = proliferative signalling) - Reproduction (decreases self-proliferation)
• Reduces breast & ovarian cancer risk
• Lower estrogen & progesterone exposure
How does familial risk predispose cancer? Example?
- Cancer is a genetic disease, but not normally an inherited disease
- Mutations in oncogenes and tumour suppressor genes can only be passed on if they occur in germ cells (egg or sperm)
E.g. BRCA2 & BRCA3 (tumour suppressor) in breast cancer - Carrying a mutation = 5x higher risk of BC
- 60-90% vs. 12%
How often do errors occur during DNA replication?
- 1 in 1 billion nucleotides; mutations occurring for no obvious reason
- Frequency is still high even if error rate is low
How early is p53 triggered WRT mutations? What does it do?
- One modified base (one point mutation) enough to trigger p53:
• Cell cycle arrest
• Repair or apoptosis (protect organism)
How effective are our DNA repair pathways?
- <0.001% of base changes result in mutation
|»_space;> Most are repaired/apoptosed
What common mutagens have mammals evolved to being exposed to?
- UV
- IR
- Rocks/minerals
- Plant/fungal
»> We’ve had a long time to adapt
