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Sequence analysis of mutations and translocations across breast cancer subtypes.


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.

SUBMITTER: Banerji S 

PROVIDER: S-EPMC4148686 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Sequence analysis of mutations and translocations across breast cancer subtypes.

Banerji Shantanu S   Cibulskis Kristian K   Rangel-Escareno Claudia C   Brown Kristin K KK   Carter Scott L SL   Frederick Abbie M AM   Lawrence Michael S MS   Sivachenko Andrey Y AY   Sougnez Carrie C   Zou Lihua L   Cortes Maria L ML   Fernandez-Lopez Juan C JC   Peng Shouyong S   Ardlie Kristin G KG   Auclair Daniel D   Bautista-Piña Veronica V   Duke Fujiko F   Francis Joshua J   Jung Joonil J   Maffuz-Aziz Antonio A   Onofrio Robert C RC   Parkin Melissa M   Pho Nam H NH   Quintanar-Jurado Valeria V   Ramos Alex H AH   Rebollar-Vega Rosa R   Rodriguez-Cuevas Sergio S   Romero-Cordoba Sandra L SL   Schumacher Steven E SE   Stransky Nicolas N   Thompson Kristin M KM   Uribe-Figueroa Laura L   Baselga Jose J   Beroukhim Rameen R   Polyak Kornelia K   Sgroi Dennis C DC   Richardson Andrea L AL   Jimenez-Sanchez Gerardo G   Lander Eric S ES   Gabriel Stacey B SB   Garraway Levi A LA   Golub Todd R TR   Melendez-Zajgla Jorge J   Toker Alex A   Getz Gad G   Hidalgo-Miranda Alfredo A   Meyerson Matthew M  

Nature 20120620 7403


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  ...[more]

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