CBFB Mutations and MAGI3–AKT3 Fusions Recur In Breast Cancer

Breast cancers are clinically and molecularly heterogeneous, and it is becoming clear that sequencing of many samples from many sources representing each breast cancer subtype will be needed to catalog the many low-frequency recurring somatic alterations and identify subsets of patients that may benefit from particular targeted therapies. Banerji and colleagues performed whole-exome sequencing on 103 primary, treatment-naïve tumors and matched normal samples from patients in Mexico or Vietnam and whole-genome sequencing of an additional 22 matched tumor–normal pairs. Five of the 6 most commonly mutated genes, TP53, PIK3CA, AKT1, GATA3, and MAP3K1, had known links to breast cancer, but mutations in core-binding factor beta subunit (CBFB) had not previously been implicated in solid tumors. Interestingly, CBFB mutations were accompanied by deletions of the gene encoding its binding partner, RUNX1, suggesting that there is selective pressure for loss of transcriptional regulation by the CBFB–RUNX1 complex in some breast cancers. Further analysis of the whole-genome sequencing data identified a rearrangement between membrane-associated guanylate kinase, WW, and PDZ domain containing 3 (MAGI3) and v-akt murine thymoma viral oncogene homolog 3 (AKT3) resulting in an in-frame gene fusion. Screening of an additional 235 breast cancers revealed the presence of MAGI3–AKT3 in 8 samples, including 5 of 72 (7%) triple-negative breast cancers. Ectopic expression of the MAGI3–AKT3 protein product led to constitutive AKT3 kinase activity and activation of downstream targets. Notably, the activity of the MAGI3–AKT3 fusion protein could be blocked by an ATP-competitive, but not allosteric, small-molecule AKT inhibitor, suggesting a potential therapeutic option for the subset of breast cancers harboring a MAGI3–AKT3 fusion gene and highlighting the possibilities of large sequencing studies for personalized medicine.

Banerji S, Cibulskis K, Rangel-Escareno C, Brown KK, Carter SL, Frederick AM, et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature 2012;486:405–9.