- Several germline mutations have been shown to increase cancer risk
- More than 50 genetic abnormalities have been identified
- Most are inherited in autosomal dominant fashion
- Cancer genetics are important as:
- Genes involved are important in normal growth and development
- Improve our knowledge of cancer biology
- Allow identification of high-risk patients who will benefit from preventative therapies
- Most genetic abnormalities involve tumour suppressor genes
- Code for proteins that are important in normal growth and development
- Hereditary cancer syndromes result from germline mutation in one copy of the suppressor gene
- Somatic mutation in the second copy of the gene results in the development of cancer
Breast cancer genetics
- 12% women will develop breast cancer in their life-time
- 5% breast and ovarian cancers due to germ-line mutation
BRCA1 and BRCA2 genes
- BRCA1 and BRCA2 are tumour suppressor genes
- Commonest abnormality is in BRCA1 gene found on long arm of chromosome 17
- Mutation seen in 50% of families with 4 or more affected members < 60 years
- More than 100 BRCA mutations described
- Highest carrier rate is in Ashkenazi Jews
- If a patient is BRCA1 positive she has:
- 50% risk of developing breast cancer by 50 years
- 85% risk of developing breast cancer by 70 years
- 70% risk of developing contralateral breast cancer
- 50% life time risk of developing ovarian cancer
Treatment
- How should BRCA1 and BRCA2 positive patients be managed ?
- Possible options include:
- Intensive screening with annual mammography from an early age
- Chemoprophylaxis with tamoxifen
- Prophylactic mastectomy
- Reduces but does not completely abolish risk of breast cancer
- Risk of ipsilateral and contralateral recurrence is higher in BRCA1 and BRCA2 carriers
Bibliography
Emery J, Lucassen A, Murphy M. Common hereditary cancers and implications for primary
care. Lancet 2001; 358: 56-63.
Haffty B G, Harrold E, Khan A J et al. Outcome of conservatively managed early-onset
breast cancer by BRCA1/2 status. Lancet 2002; 359: 1471-1477.
Taylor M R G. Genetic testing for inherited breast and ovarian cancer syndromes: important
concepts for the primary care physician. Postgrad Med J 2001; 77: 11-15. |