Sequence analysis of mutations and translocations across breast cancer subtypes.

Nature
Authors
Keywords
Abstract

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 alone. This malignancy represents a heterogeneous group of tumours with characteristic molecular features, prognosis and responses to available therapy. 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 aberration. Previous DNA sequencing studies of breast cancer genomes have revealed additional candidate mutations and gene rearrangements. 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 PIK3CA, TP53, AKT1, GATA3 and MAP3K1, 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.

Year of Publication
2012
Journal
Nature
Volume
486
Issue
7403
Pages
405-9
Date Published
2012 Jun 20
ISSN
1476-4687
URL
DOI
10.1038/nature11154
PubMed ID
22722202
PubMed Central ID
PMC4148686
Links
Grant list
CA089393 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
R01 CA122099 / CA / NCI NIH HHS / United States
P50 CA089393 / CA / NCI NIH HHS / United States
U24 CA143845 / CA / NCI NIH HHS / United States
Howard Hughes Medical Institute / United States
CA122099 / CA / NCI NIH HHS / United States