causes of cancer

what is a carcinogen

• an agent that significantly increases the risk of developing cancer

  • initiators→ chemically modifies or damages DNA

  • promoters→ induce proliferation and DNA replication

categories of carcinogens

• chemical

• viruses

• radiation

• hormones

• bacteria

• asbestos

chemical carcinogen example

• non common structural feature

• polycyclic aromatic hydrocarbons (smoking)→ lung cancer

• rubber and dye works→ bladder cancer

virus carcinogen examples

• cervix→ HPV

• burkitt lymphoma→ EBV

• nasopharyngeal carcinoma→ EBV

• kaposi sarcoma→ HHV8

• merkel cell carcinoma→ MCV

• T-cell leukaemia→ human T lymphotropic virus-1

examples of cancers caused by radiation

• basal cell

• squamous cell

• melanoma

• merkel cell

• thyroid tumours

examples of hormones causing cancers

• exogenous oestrogens

  • can cause endometrial and breast cancers

examples of cancers caused by bacteria

e.g. H.Pylori linked with development of gastric cancers

initiation in cancer formation

• chemical modification of DNA
  replication and misincorporation

promotion in cancer formation

• stimulate DNA replication for mutation fixation

• stimulate clonal expansion of mutated cells→ enables accumulation of further mutations

mutational consequences

• gain of function→ activation of proto-oncogenes

• loss of function→ inactivation of tumour suppressor genes

inactivation of TSG through methylation

mechanisms of chemicals

• most chemicals are metabolically inactive

• procarcinogens e.g. aromatic amines

  • require enzymatic activation before reacting with DNA

  • depends on agent and site of enzyme

• alkylating agents→ direct DNA damage

• free radicals

mechanism of ionising radiation

• UV light, ionising radiation

• direct damage to DNA

• promotion effect

mechanisms of oncogenic viruses

• insertion of additional viral oncogenic genes into the host cell, or enhancement of already existing oncogenic genes

smoking

• leads to 100 fold increase in head and neck cancer in combination with promotion from alcohol

alcohol

• linked to e.g. oral, oesophageal, bowel, liver cancer

• converted to acetaldehyde→ can cause DNA damage

• increases oestrogen and testosterone levels

• increases uptake of carcinogenic chemicals into upper GI cells

• reduces folate→ required for accurate DNA replication

• can kill surface epithelium→ unscheduled proliferation

risk factors for breast cancer

• increased insulin exposure

  • alcohol consumption

  • age of 1st pregnancy> 30 years

  • early menarche, late menopause

  • post menopausal obesity

  • hormone replacement therapy

  • oral contraceptive

role of oestrogen in breast cancer

1. binds to oestrogen receptors on mitogenic genes

2. causes cell proliferation

3. errors during DNA replication→ mutations

4. mutations can lead to breast cancer

chronic inflammation and cancer

• inflammatory response

  • DNA damage from free radicals released by immune cells

  • growth factor induced cell division to repair tissue damage→ promotion

DNA damaging agents

• X-rays

• oxygen radicals

• alkylating agents

• spontaneous reactions

• UV light

• polycyclic aromatic hydrocarbons

• X rays

• anti-tumour agents e.g. cis-Pt

• replication errors

DNA repair processes

• base-excision repair

• nucleotide excision repair

• recombinational repair

• mismatch repair

gene/environment effects

1. carcinogen exposure

2. (metabolic activation e.g. cytochrome p450s)

   1. detoxification and excretion e.g. glutathione→ avoids cancer

3. DNA damage

4. DNA replication

5. mutation

6. progression

7. cancer

defence against carcinogenesis

• antioxidants

• liver

• DNA repair/modification

common cancer predisposition syndromes

• familial breast and ovarian cancer syndrome

• HNPCC/lynch syndrome

• FAP

familial breast and ovarian cancer syndrome

• BRCA1 and BRCA2 on chr17 and chr13

• inherit one faulty copy of gene→ autosomal dominant

lynch syndrome

• hereditary non polyposis colorectal cancer

• mismatch repair genes

familial adenomatous polyposis

• mutation of APC gene

• chromosome 5

common genetic abnormalities seen in tumours

• base pair substitution

• frameshift

• deletion or insertion

• gene amplification

• chromosomal translocation

• chromosomal inversion

• aneuploidy