2011年EMSO BRCA阳性乳腺癌临床实践指南

Familial susceptibility to breast cancer accounts for <25% of all breast cancer cases. BRCA1 and BRCA2 are high-penetrance breast cancer predisposition genes identified by genome-wide linkage analysis and positional cloning. Mutations in BRCA1/2 explain 20% of the familial clustering of breast cancer. Germline mutations in the other high-risk genes TP53, PTEN and STK11 are identified in <1% of breast cancer families and are usually associated with rare cancer syndromes (Li-Fraumeni, Cowden and Peutz–Jeghers syndromes, respectively). Screening of genes functionally related to BRCA1 and/or BRCA2 has identified mutations in CHEK2, ATM, BRIP1 and PALB2. Mutations in these genes are rare and confer

an intermediate risk of breast cancer, and therefore explain only a small proportion of the remaining predisposition. More recently, RAD51C has been discovered as a potentially high-risk cancer predisposition gene in breast/ovarian cancer families. Association studies have further identified 18 common variants associated with low-penetrance breast cancer predisposition. Despite these discoveries, the underlying cause of >70% of the familial breast cancer cases still remains unexplained.

The estimated population frequency of mutations in BRCA1/2 genes is 1/800–1/1000 per gene. Overall this equates to 15–20% of the excess familial risk of breast cancer. The prevalence of BRCA1 or BRCA2 germline mutations varies considerably among ethnic groups and geographical areas. Populationspecific mutations and recurrent mutations have been described among Ashkenazi Jews, in Iceland, The Netherlands, Sweden, Norway, Germany, France, Spain, Canada and countries of eastern and southern Europe.

BRCA1 and BRCA2 mutation frequencies in breast and ovarian cancer patients unselected for family history or age at onset are generally low (<1–7% for BRCA1 and 1–3% for BRCA2). Higher prevalence is associated with a family history of breast or ovarian cancer, young age at onset, male breast

cancer or multiple tumors (bilateral breast cancer or breast and ovarian cancer in the same patient). Based on pooled data from cases unselected for family history it is estimated that average cumulative risks in BRCA1 mutation carriers by age 70 years were 65% [confidence interval (CI) 44–78%] for breast cancer and 39% (18–54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31–56%) and 11% (2.4–19%).However, due to the high allelic heterogeneity of these genes,  the actual risk conferred by a particular mutation is likely to diverge from these estimates. The relative risk of male breast cancer is elevated for both genes, particularly BRCA2 (6%). An elevated risk of prostate cancer has also been shown in BRCA2 carriers, particularly in men aged <65 years. Other cancers at increased risk are pancreatic (up to 2%), stomach, and head  and neck.