Genetics-Predisposition to Cancer Flashcards
What does a normal piece of DNA produce?
A normal protein
What would a piece of DNA with an alteration in a single base or with a base removed produce?
A non-functioning protein
Or it would shorten the protein via a premature stop codon
What would a piece of DNA with a single base alteration produce?
A protein that doesn’t work as well
What is 5-10% of breast cancer due to?
A single hereditary gene mutation
What is 5-10% of ovarian cancer due to?
A hereditary single gene alteration
What is 10-30% of colorectal cancer due to?
familial basis through polygenic inheritance
What is 5% of colorectal cancer due to?
A single gene Lynch syndrome
What does a single gene Lynch syndrome cause?
Hereditary non-polyposis colorectal cancer
What is a tumour caused by?
clonal expansion of a cell that contains a mutation within its DNA
How does a mutating tumour with a high rate of growth and metastatic potential develop?
Within a cell a gene alteration occurs
This genetic alteration is replicated
With each replication, different mutations can occur
this results in a mutating tumour
What then created a tumour?
An accumulation of genetic faults
Where do somatic mutations occur?
non-germline tissues
What type of mutations cause the most cancers?
Somatic mutations
Are somatic mutations hereditary?
No, they are non-hereditary
How do germline mutations occur?
They are inherited from single alteration in egg or sperm
Are germline mutations hereditary or non-hereditary?
Hereditary
What do germline mutations cause?
Cancer family syndromes
Where are the germline mutations present in the body?
In all cells, regardless of the cancer it causes
What do oncogenes control?
The first part of the cell growth cycle
What occurs in the S phase (synthesis)?
Second part of the cell cycle
What occurs as S phase in the cell cycle?
Tumour suppressor genes act
DNA repair genes act
What is the percentage chance of germline mutations being passed on?
50% chance
Alteration in which phase of the cell cycle predisposes to familial cancer?
Alterations in the S phase
In which type of cancer are oncogenes more common?
In Sporadic types of cancer
What do normal cells do?
Regulate cell growth
What does a normal oncogene do?
Regulates cell growth
What does a mutation in an oncogene lead to?
Accelerated cell division
How many mutations in an oncogene is required to cause cancer?
One mutation is enough
What happens when oncogene ABL fuses with BCR gene?
Leads to a fusion protein BCR-ABL
BCR-ABL drives the formation of leukemia
What does a mutation in one copy of a gene cause the person to be?
A susceptible carries
What are the steps in multistep carcinogenesis?
- Normal epithelium
- Hyper-proliferative epithelium
- Early adenoma
- Inter-mediate adenoma
- Late adenoma
- Carcinoma
- Metastasis
What is one of the main mechanisms for familial cancer?
Familial DNA mismatch repair
What is the mechanism of familial DNA mismatch repair?
DNA is copied, get an extra base
Failure of mismatch repair gene
Unrepaired DNA is copied, causing a mutation
This is known as an insertion mutation- can be a trigger to cancer
How
- Mutations in genes that code for mismatch repair is the mutation in HNPCC
- A number of genes that code for mismatch repair can be mutated
- Tumour is usually in proximal colon
How is there a good chance for prevention in colorectal cancer?
Adenoma-carcinoma sequence for polyp formation
What are the 2 main clincial features of colorectal cancer?
Age of onset variable but normally around 45
Tumour occurs in proximal colon
Which cancers does Lynch syndrome increase the chance of?
- Endometrial cancer
- Urinary tract cancer
- Ovarian cancer
- Gastric cancer
What are BRCA1 and BRCA2 associated with?
Familial breast and ovarian cancer
Which cancers are BRCA1 and BRCA2 associated with?
Breast and Ovarian cancer
How does having the BRCA1 gene increase risk of developing breast cancer?
Increases chance by 60-80%
About 50% get second primary breast cancer
What percentage of women get Ovarian cancer with the BRCA1 gene?
50% get ovarian cancer
What percentage of women get Ovarian cancer with the BRCA2 gene?
20% get ovarian cancer
What does BRCA2 increase the chance of developing in men?
Increased risk of breast and prostate cancer
What type of inheritance does familial cancer have?
Autosomal dominant inheritance
What does autosomal dominant inheritance mean?
- Each child has a 50% chance of inheriting the mutation
- No skipped generation
- Equally transmitted by men and women
What is Mendelian Risk?
In a dominant high penetrance syndrome
• Offspring of an affected individual has a 50% chance of carrying the mutation and getting the condition
• Their offspring will only have a 25% chance of carrying the mutation
When should you suspect hereditary cancer?
- Cancer in 2 or more close relatives (on same side of family)
- Early age at diagnosis
- Multiple primary tumors in the same person
- Bilateral or multiple rare cancers
- Characteristic pattern of tumours (e.g. breast and ovary)
- Evidence of autosomal dominant transmission
What happens in a Clinical Genetics Consultation?
- Go through family history
- Risk estimation
- Explanation of basis of risk
- Genetic testing- if high risk
What interventions might you suggest to someone at risk of cancer?
- Increased awareness of signs and symptoms
- Lifestyle: Diet, smoking, exercise
- Prevention: Oestrogen, aspirin
- Screening
- Prophylactic surgery
When would you first do a mammography for breast cancer?
5 years younger than the first cancer in the family
If there was a high risk of someone developing breast cancer what would you suggest?
Annual breast examination by the doctor
What would you offer to patients who were at moderate risk of breast cancer?
Mammography 2 yrly from 35-40, yrly from 40-50
What would you offer to patients who were at moderate risk of breast cancer?
Mammography 2 yrly from 35-40,
yearly from 40-64
What genetic testing might you consider in high risk patients for breast and ovarian cancer?
BRCA1 and BRCA2 genetic testing
What would significantly reduce the chance of a carrier developing breast cancer?
Mastectomy- removal of breast tissue
Reduces chance of breast cancer to 5%
What is done to eliminate the risk of primary ovarian cancer?
Prophylactic oophorectomy
What does Prophylactic oophorectomy do?
Induces surgical menopause so women given HRT till 50
How often is a colonoscopy carried out in a gene carrier for CRC?
2 yearly from 25
How often is a colonoscopy carried out in someone who is at moderate to high risk of CRC?
5 yearly from 50 to 70
How often is a colonoscopy carried out in someone who is at low to moderate risk of CRC?
Once at 55
What is someone who is a gene carrier for CRC told to take prophylactically?
Prophylactic aspirin
How can it be determined if a cancer is lynch syndrome associated?
Test for mismatch repair gene proteins via immunohistochemistry (IHC) or microsatellite instability testing (MSI)
