Breast and Ovarian Cancer

Abstract

espite years of intensive study and substantial progress in understanding susceptibility to breast and ovarian cancer, these diseases remain important causes of death in women.However, several recent critical advances -sequencing of the human genome and the development of high-throughput techniques for identifying DNA-sequence variants, changes in copy numbers, and global expression profiles -have dramatically accelerated the pace of research aimed at preventing and curing these diseases.We review some of the important discoveries in the genetics of breast and ovarian cancer, ongoing studies to isolate additional susceptibility genes, and early work on molecular profiling involving microarrays.In the United States, 10 to 20 percent of patients with breast cancer and patients with ovarian cancer have a first-or second-degree relative with one of these diseases. 1Two major genes associated with susceptibility to breast and ovarian cancer -breast cancer susceptibility gene 1 ( BRCA1 ) and breast cancer susceptibility gene 2 ( BRCA2 ) -have been identified to date. 2,3Mutations in either of these genes confer a lifetime risk of breast cancer of between 60 and 85 percent and a lifetime risk of ovarian cancer of between 15 and 40 percent. 4,5However, mutations in these genes account for only 2 to 3 percent of all breast cancers, 6,7 and susceptibility alleles in other genes, such as TP53, PTEN, and STK11/LKB1, are even less common causes of breast and ovarian cancer (Fig. 1).The prediction that there are common DNA-sequence variants that confer a small but appreciable enhanced risk of cancer has been validated with the recent discovery of the 1100delC mutation in the cell-cycle-checkpoint kinase gene ( CHEK2 ). 9 This mutation was found in 1.1 percent of women without breast cancer, 1.4 percent of women with a personal but no family history of breast cancer, and 4.2 percent of index patients from 718 families in which two or more members had been given a diagnosis of breast cancer before the age of 60 years but in which there was no detectable BRCA1 or BRCA2 mutation.This mutation doubles the risk of breast cancer among women and increases the risk among men by a factor of 10.CHEK2, an important component of the cellular machinery that recognizes and repairs damaged DNA, is activated after phosphorylation by the checkpoint gene ATM and in turn activates BRCA1.The role of ATM mutations in the predisposition to the early onset of breast cancer remains controversial, but some missense mutations do appear to increase susceptibility to breast cancer in humans 10 and mice. 11There is convincing evidence that additional high-penetrance genes that increase susceptibility to breast cancer exist.In contrast, it has been suggested that, other than BRCA1 and BRCA2, high-penetrance genes that confer susceptibility to ovarian cancer do not exist. 12An ovarian-cancer-susceptibility locus on chromosome 3p22-25 has d susceptibility to breast and ovarian cancer