Breast cancers are caused by combinations of at least 40 different driver mutations.
Major finding: Breast cancers are caused by combinations of at least 40 different driver mutations.
Concept: Infrequently mutated genes account for almost half of all driving genetic events in breast cancer.
Impact: The identification of previously unrecognized cancer genes provides insight into breast cancer etiology.
Although the genomes of some breast tumors have been analyzed, a comprehensive understanding of the driver mutations and mutational landscape of breast cancer is lacking. Stephens and colleagues performed genome-wide copy number analysis and exome sequencing of protein-coding genes and microRNAs in 100 primary breast tumors and searched for nonrandom clusters of somatic mutations likely to disrupt protein function. Genes identified by this analysis were sequenced in an additional 250 breast cancers, and mutations in multiple genes not previously linked to breast cancer, such as ARID1B, CASP8, MAP3K1, MAP3K13, NCOR1, SMARCD1, and CDKN1B, were identified as likely driver events. Point mutations or copy number changes in 40 genes were identified, with a high degree of variation in the number of driver mutations in each tumor. Genetic alterations in the 7 most frequently mutated cancer-related genes accounted for 58% of the driver mutations identified, which meant that infrequent mutations in at least 33 other genes represented 42% of the genetic events that contribute to breast cancer initiation and progression. The identification of 73 different combinations of mutated genes among the 100 tumors also implies that most breast cancers are genetically unique, which is supported by the great variation observed in the total number of mutations among the tumors. Of note, several tumors had a distinctive mutation spectrum characterized by cytosine mutations within TpC dinucleotides, suggesting that a common mutational mechanism may contribute to the development of these tumors. Together, these findings highlight the complexity and diversity of breast cancer and indicate that many different treatment and prevention strategies may be necessary.