Medical genetics of cancer

Question 1

Sporadic cancers

Answer 1

75-80% of cancers
Random mutations in a somatic cells within an individual’s lifetime
DNA damage from exogenous and endogenous sources
Age is main risk factor

Question 2

Familial cancers

Answer 2

Cluster in families but not caused by inheritance of a single gene
Many different mutations with low penetrance and lifestyle factors (multifactorial)

Question 3

Hereditary cancers

Answer 3

5-10% of cancers
Usually autosomal dominant inheritance 
All cells will contain the mutation
Mostly tumour suppressor genes
Functional allele allows cell to function but if this is lost then cancer is likely to develop

Question 4

BRCA1/2 function

Answer 4

BRCA1 phosphorylated by ATM in response to DSBs
Phosphorylated BRCA1 activated DNA repair via homologous recombination with BRCA2 and Rad51.
BRCA1 also recruits Rad50-Mre11-NBS complex to sites of DNA damage

Question 5

BRCA1/2 loss

Answer 5

Leads to genomic instability
Oncogene changes may not be repaired
Hereditary breast-ovarian cancer syndrome leading to breast, ovarian, pancreatic and prostate cancer

Question 6

Interventions following BRCA1/2 testing

Answer 6

Earlier and more frequent cancer screening
Risk-reducing medication
Risk-reducing surgery

Treatment options may be different with those without BRCA1 mutation

Question 7

Synthetic lethality

Answer 7

BRCA1/2 mutant alone increases cancer risk but allows cell survival
PARP inhibition also decreases SSB break repair but allows cell survival

PARP inhibitors for patients with BRCA1/2 leads to severe DNA damage and cancer cell death