Targeting cancer Flashcards
What is a hereditary cancer?
A germline mutation: one that is present in gametes, present in every cell of offspring
- usually in tumour suppressor genes
Usually inherit a predisposition to cancer with the risk increasing over lifetime
Most cancers are polygenic (+infection + environment) although exceptions exist
What is retinoblastoma?
What is the causative mutation?
How does the presentation differ between the familial and sporadic form?
A rare childhood cancer
Tumour caused by mutations in Rb tumour suppressor gene
Familial form (40%) affects younger children and is often bilateral, may be multifocal Sporadic form (60%) is unilateral
Describe the difference in the distribution of the mutant protein gene in retinoblastoma in the familial and sporadic form
What does this mean for the likelihood of tumorgenesis?
Familial form
- child inherits a germline copy of mutant Rb gene: every retinal cell bears this mutant allele
- high probability of spontaneous mutation in other allele
Sporadic form
- spontaneous mutations in both copies of the Rb gene must occur in the same retinal cell for tumorgenesis
- low probabiltiy
What is the function of the Rb gene?
Encodes the retinoblastoma protein pRb
- regulates cell cycle progression
- inhibits transcription of cell cycle proteins by binding to the transcription factor E2F
How does a mutation in the Rb gene contribute to carcinogenesis?
In the absence of functional pRb:
- cell cycle progression uncontrolled
- DNA replication even in presence of damaged DNA
- increases replication rates
- predisposes to further mutations
What are BRCA1 and BRCA2?
Large nuclear proteins involved in repair of DNA double strand breaks
BRCA1 is additionally a cell cycle checkpoint signaller and involved in transcriptional regulation
Why are BRCA1 and BRCA2 deficient cells at an increased risk of further mutations?
Cells deficient in either protein show “genomic instability”
What is the lifetime risk of cancer in those with BRCA1 and BRCA2 mutations?
BRCA 1
- 94% of breast or ovarian
- 60-80% of breast cancer
- increased risk of colon and prostate cancer
BRCA2
- breast cancer risk: 60-80%
- ovarian cancer risk: 10-50%
Together account for 5-10% of all breast cancers
What is “risk”?
- relative to population risk
- it will vary between populations
What factors are used to calculate risk?
- age
- FHx
- personal risk factors
- use a risk estimate models
What is does it mean to be
a) low risk
b) moderate risk
c) high risk
a) = population risk
In breast cancer that is <3% aged 40-50/lifetime risk <17%
b) 3-8% aged 40-50
lifetime risk 17-30%
c) risk >8% aged 40-50
lifetime risk >30%
How are patients at low risk of breast cancer managed?
- mammographic screening from age 50
- breast awareness
- lifestyle information
How are patients at moderate risk of breast cancer managed?
under 40
- information, counselling
40-49
- annual mammography
How are patients at high risk of breast cancer managed?
- refer to specialist clinic, genetic counselling
- genetic testing IF affected family member agrees
Give three “high risk” factors
- Jewish ancestry
- multiple cancers at young age
- two relatives with BrCa <50
- three relative with BrCa <60
- four relatives with BrCa any age
- ovarian cancer + BrCa<50
- bilateral BrCa <50
- male BrCa + BrCa <50
