Neoplasm 3

Question 1

What is another name for ‘causes of cancer’

Answer 1

Carciogenesis

Question 2

What are intrinsic risks of cancer

Answer 2

• Age (old age)
• Sex (hormonal factors)
• Heredity (penetrance and frequency factors)

Question 3

What are extrinsic risks of cancer

Answer 3

• Environment and lifestyle
• High body max index
• Low fruit and vegetable intake
• Lack of physical activity
• Tobacco use
• Alcohol use

Question 4

Describe how chemicals can form a field of cancer cells

Answer 4

• Need initiators (mutagenic chemical carcinogens) and many promoters for carcinogen to develop
• Ames test shows that initiators are mutagens while promotors cause prolonged proliferation in target tissues
• Need promotors to form a field of mutagenic cells (progression)
• A germline mutation occurs fast as it differentiates into many cells

Question 5

Distinguish between pro-carcinogens and complete carcinogens

Answer 5

• Pro-carcinogen - only converted to carcinogens by the cytochrome P450 enzymes in the liver
• Complete carcinogens - act as both initiators and promotes

Question 6

Which radiation are we exposed to and how does it cause cancer

Answer 6

• Ionising radiation strips electrons from atoms (alpha, beta, gamma, x-rays)
  
  • Nuclear radiation includes alpha, beta and gamma
• UV radiation most important as everyday exposure leads to risk of skin cancer
  
  • Radon exposure and medical tests cause ionising radiation
• Damage DNA directly or indirectly by generating free radicals
  
  • Direct DNA damage - altered base, single/double strand DNA breaks

Question 7

Explain how infections cause cancer

Answer 7

• Directly affect genes that control growth
  
  • HPV produce proteins (E6, E7) which directly affect cancer producing genes
    
    • E6 inhibit p53 to prevent apoptosis
    • E7 inhibit pRb to allow free entry into cells cycle
    • Strongly linked to cervical carcinoma
• Indirectly cause chronic tissue injury, where the resulting regeneration acts either as a promoter for any pre-existing mutation or causes new mutation from DNA replication errors
  
  • Hepatitis B and C cause chronic liver cell injury and regeneration - potential for mutation
  • Bacteria and parasites can also indirectly lead to neoplasms
  • Helobacter pylori causes chronic gastric inflammation
  • Parasitic flukes cause inflammation in bile ducts and bladder mucosa - increase risk of gastric and bladder carcinomas
• Reduced immunity - HIV indirectly lowers immunity and allows potentially carcinogenic infections to occur

Question 8

What is the two hit hypothesis

Answer 8

• Inherited predisposition to neoplasia can occur through germline mutations
  
  • First hit delivered through germline and affects all cells in the body
  • Second hit is a somatic mutation
  • Eg. Retinoblastoma - autosomal dominant
• For sporadic mutations, no germline mutation so requires both hits to be somatic mutations on the same cell (rarer)

Question 9

Describe the actions of proto-oncogenes and tumour suppressor genes on neoplasm growth

Answer 9

• Tumour suppressor genes inhibit neoplastic growth
  
  • Need 2 hits to form neoplasm
  • One gene can still make protein to stop abnormal growth
  • Both alleles need to be inactivated
• Oncogenes enhance neoplastic growth and abnormally activated versions are proto-oncogenes
  
  • Only 1 hit needed
  • One gene will cause over proliferation of gene

Question 10

What is the role of caretaker genes

Answer 10

• Caretaker genes - tumour suppressor genes that maintain genetic stability
  
  • Genetic instability leads to high mutation rate
  • Chromosome segregation during mitosis can be abnormal in malignant cells and cause genetic instability

Question 11

What are examples of proto-oncogenes

Answer 11

• Growth factors
• Growth factor receptors
• Plasma membrane signal transducers - RAS
• Intracellular kinases
• Transcription factors
• Cell cycle regulators - cyclin D1
• Apoptosis regulators

Question 12

Outline how RAS can act as a proto-oncogene

Answer 12

• RAS oncogenes encodes a small G protein that relays signals into the cell that eventually pushes the cell past cell cycle restriction point
  
  • RAS proto-oncogene undergoes GDP-GTP switch which activates cyclin D to bind to CDK
  • Inhibits Rb gene to allow cell to enter cell cycle

Question 13

What are examples of tumour suppressor genes

Answer 13

• Rb genes restrains cell proliferation by inhibiting passage through restriction point
  
  • Inactivation of both RB alleles needed to allow unrestrained passage through restriction point
• P53 also acts a tumour suppressant gene which activates apoptosis

Question 14

Describe the inheritance of xeroderma pigmentosum

Answer 14

• Due to mutations in DNA repair genes
• Inherited cancer syndrome with germline mutations affecting DNA repair
• Autosomal recessive
• Mutation in any 1 of 7 genes that affects DNA nucleotide excision repair (NER)
• Patients very sensitive to UV damage and develop skin cancer at young age
• Leads to nucleotide instability

Question 15

Describe the inheritance of hereditary non-polyposis colon cancer (HNPCC) syndrome

Answer 15

• Autosomal dominant
• Associated with colon carcinoma
• Germline mutation affects 1 or several DNA mismatch repair genes
• Leads to microsatellite instability

Question 16

Describe the inheritance of familial breast carcinoma

Answer 16

• Associated with either BRCA1 or BRCA2 genes important in repairing double strand DNA breaks
• Mutations also found in sporadic malignant neoplasms
• Leads to chromosomal instability

Question 17

Explain the adenoma-carcinoma sequence

Answer 17

• Eg. Colonic adenoma leads to colon carcinoma
• Mutations accumulate from early adenomas -> later adenomas -> primary carcinomas -> metastatic carcinomas
• Steady accumulation of multiple mutations called progression

Question 18

What are the 3 main steps for cancer to evolve

Answer 18

• Cancer evolves by initiation and promotion to progression

- Number of mutations needed to fully evolve malignant neoplasms unknown but <10

Question 19

What are the 6 hallmarks of cancer + 1 enabling feature

Answer 19

• To become a fully evolved malignant neoplasms, it needs to alter its growth control
  1. Self sufficiency in growth signals
  2. Resistance to growth stop signals
  3. No limit on number of times a cell can divide (override telomere)
  4. Sustained ability to induce new blood vessels (angiogenesis)
  5. Resist apoptosis
  6. Ability to invade and produce metastases
• Genetic instability regarded as enabling characteristic

Question 20

Describe the overall process of carciogenesis

Answer 20

1. Somatic cells are exposed to environmental carcinogens (chemicals, radiation, infections) that are either initiators or promoters
2. Cumulates in a monoclonal population of mutant cells
   
   • In 5% of cancers, inherited germline mutation can be present
3. Some clones harbour mutations affecting a proto-oncogene or a tumour suppressor gene whose protein transcripts play crucial roles in cell signalling pathways affected by ‘hallmark’ changes
4. During progression, cells acquire further activated oncogenes or inactivated tumour suppressor genes
5. After many years or decades, results in population of cells that have acquired a set of mutations that produces all the ‘hallmarks of cancer’

Question 21

Describe some occupations associated with the development of tumours

Answer 21

• Dye industry
• Asbestos exposure
• Depends on length of exposure to chemicals