S9: neoplasia (3) + pathology in pictures

Question 1

List some intrinsic and extrinsic causes of mutation

Answer 1

Intrinsic: hereditary, age & sex (particularly hormones)
Extrinsic: environment (chemicals, radiation & infection) & behaviour

Question 2

List examples of extrinsic carcinogenic agents

Answer 2

Chemicals – asbestos, polycyclic hydrocarbons, aromatic amines (2-napthylamine & nitrosamines)
Radiation – ultraviolet & ionising radiation
Infections – HPV, EBV, hepatitis B & C viruses, human immunodeficiency virus, Helicobacter pylori & parasites

Question 3

Explain the association between HPV & cervical carcinoma

Answer 3

Makes 2 proteins E6 & E7
Virus infects the cell -> stops it from dying -> hijacks DNA to make more virus particles
E6 inhibits p53 – prevents cell from undergoing apoptosis
E7 hijacks cell cycle by interfering with retinoblastoma protein (important cell cycle checkpoint)

Question 4

Describe what radiation is and how it can cause cancer

Answer 4

Any type of energy travelling through space & some forms are mutagenic
Eg. alpha particles, beta particles, gamma rays, xrays, UV rays
Can damage DNA directly or indirectly by generating free radicals

Question 5

Describe how infections can cause cancer

Answer 5

Some can directly affect genes that control cell growth
Indirectly = causing chronic tissue injury & resulting regeneration acts either as a promoter for pre-existing mutation or causes new mutations from DNA replication errors
Direct effects – HPV
Indirect effects – hepatitis B virus
Reduced immunity – HIV

Question 6

What is asbestos and what cancers can it cause?

Answer 6

Naturally occurring fibre that was widely used in construction until the late 1990s
Used for insulation
Mesotheliomas, laryngeal cancer, lung cancer & ovarian cancer
Over many years, fibres cause inflammation and genetic changes that leads to cancer -> free radical damage

Question 7

List examples of oncogenes & tumour suppressor genes

Answer 7

Oncogenes = RAS, C-MYC & HER-2

Tumour suppressor genes = retinoblastoma & p53

Question 8

What is the RAS gene?

Answer 8

First human oncogene to be discovered
Mutated in approximately of all malignant neoplasms
Normally, a GF binds to a receptor -> activation of the pathway that contains RAS -> phosphorylates the retinoblastoma gene allowing for cell progression through the cell cycle
Mutation -> process is permanently activated meaning that the cells continually progress through the cell cycle & replicate

Question 9

What is the retinoblastoma gene?

Answer 9

Normally acts as a key negative regulator of G1/S cell cycle checkpoint
Inhibiting the retinoblastoma gene allows cells to progress through the cell cycle into S phase allowing for continued proliferation

Question 10

What is p53?

Answer 10

Apoptosis regulating gene
Normal function = prevents the cell from replicating by stopping the cell cycle at G1, or interphase, to give the cell time to repair
Mutation = results in impaired apoptosis & possible formation of tumours

Question 11

List the different things that a proto-oncogene can encode

Answer 11

Growth factors
Growth factor receptor 
Plasma membrane signal transducers 
Intracellular kinases 
Transcription factors
Cell cycle regulators
Apoptosis regulators

Question 12

What are caretaker genes?

Answer 12

Prevent accumulation of DNA damage
Some inherited cancer syndromes have germline mutations that become malignant neoplasms indirectly by affecting DNA repair eg. xeroderma pigmentosa, hereditary non-polyposis colon cancer syndrome & familial breast carcinoma

Question 13

What are 3 important points about carcinogenesis?

Answer 13

1) Long delay between carcinogen exposure & malignant neoplasm onset
2) Risk of cancer depends on total carcinogen dosage
3) Sometimes organ specificity for particular carcinogen -> direct interaction between the carcinogen & tissue that it effects eg. 2-napthylamine -> bladder -> bladder cancer

Question 14

Describe the processes of initiation and promotion

Answer 14

Sequence in which carcinogens are administered is critical
Initiators must be given first
Followed by second class of carcinogens
Complete carcinogen = initiator & promoter

Question 15

Describe the mutations in xeroderma pigmentosa, hereditary non-polyposis colon cancer syndrome & familial breast cancer

Answer 15

Xeroderma pigmentosa = autosomal recessive, mutations in 1/7 genes that affect DNA nucleotide excision repair -> very sensitive to UV damage & develop skin cancer at a young age
Hereditary non-polyposis colon cancer = autosomal dominant, associated with colon cancer -> germline mutation affects one of several DNA mismatch repair genes
Familial breast carcinoma = BRCA1/BRCA2, involved in repairing double strand DNA breaks

Question 16

Explain the adenoma-carcinoma sequence

Answer 16

Most well recognised mutational accumulation sequence
80% of sporadic colon tumours follow this pattern
Early adenoma -> intermediate adenoma -> late adenoma -> carcinoma
At each stage, a different gene is involved

Question 17

State the 6 hallmarks of cancer

Answer 17

1) Self-sufficiency in growth signals
2) Resistance to growth stop signals (TSGs)
3) Cell immortalisation
4) Sustained ability to induce new blood vessels
5) Resistance to apoptosis
6) Ability to invade and produce metastases

Question 18

Explain the two-hit hypothesis

Answer 18

Describes the need to have 2 hits to both alleles of a TSG to produce a neoplasm -> both alleles need to be inactivated
Familial cases – one hit is inherited & second hit is acquired (occur earlier)
Sporadic cases – both normal alleles must undergo a somatic mutation (occur later)