Causes of cancer Flashcards
What is another phrase for cancer progression?
Darwinian clonal evolution
Each mutation gives a survival or fitness advantage to the neoplastic cell in that particular environment
What are the three major sources of risk factors?
Populations/ occupational risk/ direct accidental exposure
How is cigarette smoking linked to cancer?
Smoking 10 a day increases risk by x10
Cause 30% cancer UK (higher with passive smoking)
What are the environmental factors?
Chemicals/ radiation/ Infectious agents
What are the occupational risks?
- Historically= scrotal cancer chimney sweeps/ bladder cancer in dye industry workers
- Contemporary= Cervix and anal sex workers/ mesothelioma building and construction (asbestos)
Examples of direct exposure radiation
Hiroshima
iatrogenic contrast medium in diagnostic radiology radiation for thyroid disease in childhood X-rays during pregnancy- leukaemia
What are chemical carcinogens?
Mutagens, most are metabolically inactive pro-carcinogens, need to be activated to an active form= ultimate carcinogen, highly reactive electrophilic molecules, directly damages DNA
What specificity do chemical carcinogens show?
Tissue/ stage/ species
Examples of synthetic chemical carcinogens
Require in vivo activation
- polycyclic hydrocarbons (tar and cigarette)
- aromatic amines and azo dyes (removal of glucuronyl groups= cancer)
Examples of naturally occurring chemical carcinogens
- Nitrosamines (amines+nitrates stomach acid)
- Aflatoxin (peanut contaminant)
What are the types of radiation?
-Ionising (alpha, beta, gamma, x-rays, neutrons)
Radiation exposure measured as energy absorbed per unit of tissue, 1 gray= 100 rads
Damages DNA by making tracks of free radicals
-UV light (photo-activates adjacent pyrimidines- dimers)
Nucleotide excision repair pathway
Describe the epidemiology of retrospective human carcinogens
- Bladder cancer (dye workers)
- Pleural Malignant Mesothelioma= asbestos
- Bronchus Squamous Cell Carcinoma= cigarette smoke
- Tongue Squamous Cell Carcinoma= pipe smoke
- Head and Neck Squamous Cell Carcinoma= tobacco chewers
What are the infectious agents?
- Parasites (Schistosoma haematobium= bladder wall, chronic inflammation)
- Bacteria (Helicobacter pylori- gastric carcinoma and lymphoma)
- Viruses (prevented by prophylactic immunisation)
What human viral infections are associated with cancers?
- Carcinoma cervix= HPV 16,18
- Hepatocellular carcinoma= hepatitis B and C
- Kaposi’s sarcoma= human herpesvirus type 8
- Adult T cell leukaemia= human T cell lymphotropic virus type 1
- Nasopharyngeal carcinoma/ Burkitt’s lymphoma/ Post-transplant lymphoproliferative disorder/ Hodgkin’s lymphoma= EBV (Epstein- Barr virus)
What is Koch’s postulates?
Classical demonstration that infection causes disease
Agent isolated from each case of disease/ isolate grown in culture as clone isolate/ disease induced in animals by inoculation of cultured isolate
Difficult/ impossible for putative human tumour viruses
What is the alternative to Koch’s postulates?
- Detect viral genomes in each cancer biopsy
- Clone the viral genome from a cancer biopsy
- Transfect cloned viral genomes into normal cells and show biological effect (immortalisation)
What is promoter activity?
Multiple proliferative events will increase the risk of mutation and fix (make permanent) these mutations
Probability of mutation increases with cell division
What oncogenes are activated in Burkitt’s lymphoma?
c-myc due to t(8;14)
Rare cancer in children in African Malarial Zone
How do retroviruses activate oncogenes?
- Transduction
- Insertional mutagenesis (proviruses integrated close to oncogenes)
- Transactivation (virus protein acts as transcription factor)
How is HTLV-1 thought to act by?
Transactivation of genes encoding cell cycle competence factors in T cells (IL-2)
Tax protein of HTLV-1 may also activate genes important in the spindle assembly checkpoint
All rare events but if viral gene expression persists then rare events become more probable
How does HPV (16/18) inactivate tumour suppressor genes?
Two viral oncogenes in viral genome E7 and E6
E7 binds unphosphorylated pRB (releasing E2F), deregulating pathway
E6 binds and targets p53 for degradation
How does HHV-8 inactivate tumour suppressor genes?
Encodes a homologue of cyclin D that phosphorylates Rb
Encodes a homologue of bcl-2 that inhibits apoptosis
What is the link between HPV and cervical carcinomas?
99.7%
Mucosal HPV infection can cause vulval/ vaginal, anal, penile and oral/ throat pre-cancerous lesions and genital warts
What is the history of HPV?
1976= koilocytes found in low grade CIN= characteristic cells of wart virus HPV so link 1983/4= HPV DNA detected and cloned in cervical cancer- 16/18 not 1 (skin) or 6/11 (genital warts)
How is HPV common?
Transmitted by intimate contact
80% sexually active women will be exposed to the virus by age 50
Most infections regress spontaneously 6-12 months after
Persistent infection= cancer/ other dieases
How is HPV associated with cervical cancer?
HPV DNA sequences from 15 HPV types are detected in over 99% of cancers
HPV 16 most prevalent (50-60%)
HPV 18 10-30% in Europe, more prevalent in Africa
Same HPV DNA sequences detected in 90% high grade CIN (CIN 2/3)
Describe a HPV particle
Non-enveloped, double stranded DNA viruses 8kb circular genome At least 100 genotypes Epitheliotropic Associated with warts and neoplasia
What is high risk HPV?
Cause high grade CIN- 40% progress to cancer
DNA sequences detected in both squamous cell carcinoma and adenocarcinoma of cervix
What are the three main areas for HPV testing application?
- Triage of patients with low-grade abnormalities
- Primary screening
- Follow-up after treatment
What are the key features of HPV testing application?
- The effect of age
- The role of type-specific persistence
- The high negative predictive value
Why are HPV 16 and 18 transforming viruses?
Immortalise primary genital keratinocytes in culture
E6 activates telomerase
How are neutralising antibodies involved in HPV prevention?
Directed against the L1 capsid protein but generation of such L1 protein requires the tertiary or native structure of the protein- can’t grow in tissue culture
How are HPV vaccines made?
Virus-like particles (VLP)
-Cut L1 gene from virus DNA
-Paste DNA into DNA of another microbe (yeast/baculovirus)
-Grow recombinant microbe in large amounts
Chemistry of protein self-assembles into VLP
