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1.
Nature ; 486(7403): 405-9, 2012 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-22722202

RESUMO

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.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Mutação/genética , Translocação Genética/genética , Algoritmos , Neoplasias da Mama/patologia , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade beta de Fator de Ligação ao Core/genética , Análise Mutacional de DNA , Exoma/genética , Feminino , Fusão Gênica/genética , Humanos , Proteínas de Membrana/genética , México , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vietnã
2.
Genome Res ; 23(4): 727-35, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23382537

RESUMO

With the completion of the zebrafish genome sequencing project, it becomes possible to analyze the function of zebrafish genes in a systematic way. The first step in such an analysis is to inactivate each protein-coding gene by targeted or random mutation. Here we describe a streamlined pipeline using proviral insertions coupled with high-throughput sequencing and mapping technologies to widely mutagenize genes in the zebrafish genome. We also report the first 6144 mutagenized and archived F1's predicted to carry up to 3776 mutations in annotated genes. Using in vitro fertilization, we have rescued and characterized ~0.5% of the predicted mutations, showing mutation efficacy and a variety of phenotypes relevant to both developmental processes and human genetic diseases. Mutagenized fish lines are being made freely available to the public through the Zebrafish International Resource Center. These fish lines establish an important milestone for zebrafish genetics research and should greatly facilitate systematic functional studies of the vertebrate genome.


Assuntos
Técnicas de Inativação de Genes , Estudo de Associação Genômica Ampla , Genômica , Peixe-Zebra/genética , Alelos , Animais , Mapeamento Cromossômico/métodos , Biologia Computacional/métodos , Gammaretrovirus/fisiologia , Anotação de Sequência Molecular , Mutagênese Insercional , Mutação , Fenótipo , Integração Viral
3.
Proc Natl Acad Sci U S A ; 109(36): 14476-81, 2012 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-22908275

RESUMO

We assessed somatic alleles of six receptor tyrosine kinase genes mutated in lung adenocarcinoma for oncogenic activity. Five of these genes failed to score in transformation assays; however, novel recurring extracellular domain mutations of the receptor tyrosine kinase gene ERBB2 were potently oncogenic. These ERBB2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation or by covalent dimerization mediated by intermolecular disulfide bond formation. These distinct mechanisms of receptor activation converged upon tyrosine phosphorylation of cellular proteins, impacting cell motility. Survival of Ba/F3 cells transformed to IL-3 independence by the ERBB2 extracellular domain mutants was abrogated by treatment with small-molecule inhibitors of ERBB2, raising the possibility that patients harboring such mutations could benefit from ERBB2-directed therapy.


Assuntos
Adenocarcinoma/enzimologia , Neoplasias Pulmonares/enzimologia , Mutação/genética , Receptor ErbB-2/genética , Adenocarcinoma/genética , Adenocarcinoma de Pulmão , Alelos , Animais , Movimento Celular/fisiologia , Clonagem Molecular , Primers do DNA/genética , Dimerização , Immunoblotting , Neoplasias Pulmonares/genética , Camundongos , Células NIH 3T3 , Fosforilação , Estrutura Terciária de Proteína/genética , Retroviridae , Espectrometria de Massas em Tandem
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