STUDY OF A SINGLE BRCA2 MUTATION WITH HIGH CARRIER FREQUENCY IN A SMALL POPULATION

Germ-line changes in the cancer-predisposition gene BRCA2 are found in a small proportion of breast cancers. Mutations in the BRCA2 gene hav e been studied mainly in families with high risk of breast cancer in f emales, and male breast cancer also has been associated with BRCA2 mut ations. The importance of germ-line BRCA2 mutations in individuals wit hout a family history of breast cancer is unknown. The same BRCA2 muta tion has been found in 16/21 Icelandic breast cancer families, indicat ing a founder effect. We determined the frequency of this mutation, 99 9del5, in 1,182 Icelanders, comprising 520 randomly selected individua ls from the population and a series of 632 female breast cancer patien ts (61.4% of patients diagnosed during the study period) and all male breast cancer patients diagnosed during the past 40 years. We detected the 999del5 germ-line mutation in 0.6% of the population, in 7.7% of female breast cancer patients, and in 40% of males with breast cancer. The mutation was strongly associated with onset of female breast canc er at age <50 years, but its penetrance and expression are varied. A n umber of cancers other than breast cancer were found to be increased i n relatives of mutation carriers, including those with prostate and pa ncreatic cancer. Furthermore, germ-line BRCA2 mutation can be present without a strong family history of breast cancer. Comparison of the ag e at onset for mother/daughter pairs with the 999de15 mutation and bre ast cancer indicates that age at onset is decreasing in the younger ge neration. Increase in breast cancer incidence and lower age at onset s uggest a possible contributing environmental factor.