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- HBC, hereditary breast cancer
- HBOC, hereditary breast/ovarian cancer
- SSCP, single strand conformational polymorphism
- PTT, protein truncation test
- OCCR, ovarian cancer cluster region
Breast cancer is the most common malignancy affecting women world wide.1 Approximately 1 in 10 women will develop breast cancer during their life time2 and 5-10% of all breast cancers, in particular those with an early age of onset, are the result of a genetic predisposition owing to the inheritance of a dominant susceptibility gene(s).
In the context of high risk families, one important gene is the BRCA2 gene located on chromosome 13q12-13. BRCA2 was localised to chromosome 13q by linkage analysis in 19943 and cloned in 1995.4,5 To date, more than 250 BRCA2 germline mutations have been identified in breast/ovarian cancer families.6 The majority of these mutations are nonsense mutations or frameshift mutations that generate premature termination codons.7 Recent studies on highly selected families with at least four cases of breast cancer suggest that BRCA2 accounts for the majority of breast cancer families where males as well as females are affected, for about one third of the families with female breast cancer alone, and only for a few families containing multiple cases of breast and ovarian cancer.8BRCA2 encodes a nuclear protein of 3418 amino acid residues that is postulated to play a role in the regulation of gene expression9 and in DNA double strand break repair and homologous recombination.10
Estimates of the cumulative breast cancer risks by the age of 70 in BRCA2 mutation carriers vary from 37-85%8,11 and the cumulative ovarian cancer risks from 16-27%.8,12 There is evidence for an increased risk of several other cancers including prostate cancer, pancreatic cancer, gall bladder and bile duct cancer, stomach cancer, and malignant melanoma.13 Analyses of BRCA2 mutation data have provided evidence that the risks of breast cancer and ovarian cancer are related to …