Genetic predisposition to cancer Flashcards
How can protein function be altered?
- A premature stop codon shortens the protein which results in a non-functional or missing protein (half as much of protein as there should be)
- Gene alteration can reduce the amount of protein rather than getting rid of it altogether and cause reduction in function
Explain how tumours are accumulations of genetic faults
- Tumors are caused by a clonal expansion of a cell that contains a mutation within its DNA
- If a gene alteration occurs in a normal cell then replication of that cell also results in replication of the alteration
- With every replication event, additional mutations can accrue
- End up with a multi-hit situation within the cell that can go on to form a tumour
What are Somatic mutations?
An alteration in DNA that occurs after conception.
- Occur in any cell in the body other than germ cells
- Non-inheritable
- Cause the vast majority of cancers
What are Germline mutations?
Mutation within germ cells - egg or sperm inherits new gene alteration that is then present in all cells of the offspring
- Heritable
- Cause cancer family syndromes
- Once the offspring has the mutation then they can pass it on (tends to be dominant so is passed on = becomes familial)
How do oncogenes regulate normal cell growth?
Oncogenes in their proto-oncogene state drive the cell cycle forward, allowing cells to proceed from one cell cycle stage to the next.
What happens after a mutation in a proto-oncogene?
Once proto-oncogenes are altered to become oncogenes, there is uncontrolled cell growth that contributes to tumour growth.
1 mutation is sufficient for role in cancer development
Retinoblastoma
It is a rare form of childhood eye cancer where there is uncontrolled proliferation of growth from the retina. It can be familial and sporadic
Children who inherit the retinoblastoma gene (‘first hit’) at birth, are 100,000 times more likely to develop a second, cancer causing mutation
Describe the ‘two hit’ phenomena
- 1st mutation or ‘hit’ makes you a susceptible carrier
- People with a hereditary susceptibility to cancer inherit this ‘first hit’ at conception
- Others may receive it later on in life - at birth or after birth
- 2nd mutation or ‘hit’ leads to cancer - in either case, a second mutation leads to cancer. Tumour suppressor genes fail and progression to cancer
What is the main mechanism for familial cancer?
Faulty DNA mismatch - if the DNA is not repaired then it’s copied and you get an insertion mutation
What is Lynch Syndrome / Hereditary Non-Polyposis Colon Cancer (HNPCC)?
An autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer (second most common).
- Caused by a mutation in DNA mismatch repair genes
- Adenoma to carcinoma sequence for polyp formation so there is a great opportunity for prevention due to this multi-step progression - can intervene early
Which 2 main cancers does Lynch syndrome/HNPCC put you at increased risk of?
- Colon cancer - tends to be in proximal (ascending) colon
- Endometrial cancer
Inheritence of BRCA1 and 2 genes puts you at increased risk of which cancers?
In women: Breast and ovarian
In males: prostate and breast cancer
Autosomal dominant inheritance
- Each child has a 50% chance of inheriting the mutation
- No ‘skipped generations’
- Equally transmitted by men and women
When should you suspect a hereditary cancer syndrome?
- Cancer in 2 or more close relatives (on same side of family)
- Early age at diagnosis
- Multiple primary tumors
- Bilateral or multiple rare cancers
- Characteristic pattern of tumours (e.g. breast and ovary)
- Evidence of autosomal dominant transmission
What is involved in a clinical genetics consultation?
- Go through family history
- Risk estimation
- Explanation of basis of risk
- Interventions
- increased awareness of symptoms / signs
- lifestyle - diet, smoking, exercise,
- Prevention – oestrogen, aspirin use
- screening
- prophylactic surgery
- Genetic testing - consider in high risk
