Sequence analysis of mutations and translocations across breast cancer subtypes

Abstract

This paper reports one of the largest breast cancer whole-exome and whole-genome sequencing efforts so far, identifying previously unknown recurrent mutations in CBFB, deletions of RUNX1 and recurrent MAGI1–AKT3 fusion; the fusion suggests that the use of ATP-competitive AKT inhibitors should be evaluated in clinical trials. This paper reports one of the largest whole-exome sequencing efforts in human breast cancers so far, complemented by whole-genome sequences of 22 breast cancer/normal pairs. The authors analysed diverse subtypes from patients in Mexico and Vietnam and identified recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1, as well as a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancers (those lacking oestrogen and progesterone receptors and ERBB2 expression). The fusion leads to constitutive activation of AKT kinase, which can be counteracted by treatment with a small-molecule inhibitor. Breast carcinoma is the leading cause of cancer-related mortality in women worldwide, with an estimated 1.38 million new cases and 458,000 deaths in 2008 alone1. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy2,3,4. Recurrent somatic alterations in breast cancer have been described, including mutations and copy number alterations, notably ERBB2 amplifications, the first successful therapy target defined by a genomic aberration5. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements6,7,8,9,10. Here we report the whole-exome sequences of DNA from 103 human breast cancers of diverse subtypes from patients in Mexico and Vietnam compared to matched-normal DNA, together with whole-genome sequences of 22 breast cancer/normal pairs. Beyond confirming recurrent somatic mutations in PIK3CA11, TP536, AKT112, GATA313 and MAP3K110, we discovered recurrent mutations in the CBFB transcription factor gene and deletions of its partner RUNX1. Furthermore, we have identified a recurrent MAGI3–AKT3 fusion enriched in triple-negative breast cancer lacking oestrogen and progesterone receptors and ERBB2 expression. The MAGI3–AKT3 fusion leads to constitutive activation of AKT kinase, which is abolished by treatment with an ATP-competitive AKT small-molecule inhibitor.