TY - JOUR
T1 - Sequence analysis of mutations and translocations across breast cancer subtypes
AU - Banerji, Shantanu
AU - Cibulskis, Kristian
AU - Rangel-Escareno, Claudia
AU - Brown, Kristin K.
AU - Carter, Scott L.
AU - Frederick, Abbie M.
AU - Lawrence, Michael S.
AU - Sivachenko, Andrey Y.
AU - Sougnez, Carrie
AU - Zou, Lihua
AU - Cortes, Maria L.
AU - Fernandez-Lopez, Juan C.
AU - Peng, Shouyong
AU - Ardlie, Kristin G.
AU - Auclair, Daniel
AU - Bautista-Piña, Veronica
AU - Duke, Fujiko
AU - Francis, Joshua
AU - Jung, Joonil
AU - Maffuz-Aziz, Antonio
AU - Onofrio, Robert C.
AU - Parkin, Melissa
AU - Pho, Nam H.
AU - Quintanar-Jurado, Valeria
AU - Ramos, Alex H.
AU - Rebollar-Vega, Rosa
AU - Rodriguez-Cuevas, Sergio
AU - Romero-Cordoba, Sandra L.
AU - Schumacher, Steven E.
AU - Stransky, Nicolas
AU - Thompson, Kristin M.
AU - Uribe-Figueroa, Laura
AU - Baselga, Jose
AU - Beroukhim, Rameen
AU - Polyak, Kornelia
AU - Sgroi, Dennis C.
AU - Richardson, Andrea L.
AU - Jimenez-Sanchez, Gerardo
AU - Lander, Eric S.
AU - Gabriel, Stacey B.
AU - Garraway, Levi A.
AU - Golub, Todd R.
AU - Melendez-Zajgla, Jorge
AU - Toker, Alex
AU - Getz, Gad
AU - Hidalgo-Miranda, Alfredo
AU - Meyerson, Matthew
PY - 2012/6/21
Y1 - 2012/6/21
N2 - 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.
AB - 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.
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U2 - 10.1038/nature11154
DO - 10.1038/nature11154
M3 - Article
C2 - 22722202
AN - SCOPUS:84862523863
VL - 486
SP - 405
EP - 409
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7403
ER -