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cancer, breast, mutations, article, nature, supplementary, sequencing, akt, gene, scholar, fusion, google, fig, cas, dna, samples, analysis, mutation, data, magiakt, ads, cancers, somatic, genomic, human, performed, usa, massachusetts, rearrangements, table, genes, subtypes, mexico, mutated, recurrent, wholeexome, cbfb, runx, expression, kinase, tumour, erbb, wholegenome, sample, domain, magi, institute, number, pikca, methods,

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nature portfolio privacy policy core-binding-factor beta subunit hormone-receptor-negative breast cancers29 advertising gerardo jimenez-sanchez oestrogen-receptor-positive breast cancers10 chimeric gene cbfb/pebp2b-mhy11 library construction uk/genetics/cgp/cosmic/ low-serum media reprints atp-competitive akt inhibitors triple-negative breast cancers v-erbb-related gene small-cell lung cancer dana-farber/harvard spore dana-farber cancer institute oestrogen-receptor-positive disease notch family-gene fusions25 antonio maffuz-aziz disrupts zinc-finger domains alfredo hidalgo-miranda target protein-coding regions predicted 5′-magi3–akt3-3′ fusion org/display/cgatools/mutect org/display/cgatools/indelocator org/display/cgatools/home social media nature biotechnol nature med shin nature magi3–akt3 fusion protein oestrogen-receptor-positive subtypes van de sluis mass-spectrometry-based genotyping commercial-share alike licence inferred segmental copy-ratios accession number phs000369 tumour/normal dna pairs higher copy-ratio allele magi3–akt3 overexpressing cells magi3–akt3 fusion gene oestrogen-receptor-positive samples allele-specific copy number small-molecule inhibitor protein-altering point mutations org/display/cgatools/mutsig received fellowship support 5′-magi3–akt3-3′ fusion event

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         headline:Sequence analysis of mutations and translocations across breast cancer subtypes
         description: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.
         datePublished:2012-06-20T00:00:00Z
         dateModified:2012-06-20T00:00:00Z
         pageStart:405
         pageEnd:409
         license:http://creativecommons.org/licenses/by-nc-sa/3.0/
         sameAs:https://doi.org/10.1038/nature11154
         keywords:
            Breast cancer
            Cancer genetics
            DNA sequencing
            Science
            Humanities and Social Sciences
            multidisciplinary
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                     name:Present addresses: Department of Medical Oncology, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada (S.B.); Global Biotech Consulting Group, Mexico City 01900, Mexico (G.J.-S.).
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ScholarlyArticle:
      headline:Sequence analysis of mutations and translocations across breast cancer subtypes
      description: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.
      datePublished:2012-06-20T00:00:00Z
      dateModified:2012-06-20T00:00:00Z
      pageStart:405
      pageEnd:409
      license:http://creativecommons.org/licenses/by-nc-sa/3.0/
      sameAs:https://doi.org/10.1038/nature11154
      keywords:
         Breast cancer
         Cancer genetics
         DNA sequencing
         Science
         Humanities and Social Sciences
         multidisciplinary
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         name:Nature
         issn:
            1476-4687
            0028-0836
         volumeNumber:486
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      author:
            name:Shantanu Banerji
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                  name:Harvard Medical School
                  address:
                     name:Harvard Medical School, Boston, USA
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                  name:Present addresses: Department of Medical Oncology, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada (S.B.); Global Biotech Consulting Group, Mexico City 01900, Mexico (G.J.-S.).
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                     name:Present addresses: Department of Medical Oncology, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada (S.B.); Global Biotech Consulting Group, Mexico City 01900, Mexico (G.J.-S.).,
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            address:
               name:The Broad Institute of MIT and Harvard, Cambridge, USA
               type:PostalAddress
            type:Organization
            name:Dana-Farber Cancer Institute
            address:
               name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School
            address:
               name:Harvard Medical School, Boston, USA
               type:PostalAddress
            type:Organization
            name:Dana-Farber Cancer Institute
            address:
               name:Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:Present addresses: Department of Medical Oncology, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada (S.B.); Global Biotech Consulting Group, Mexico City 01900, Mexico (G.J.-S.).,
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215,
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto de Enfermedades de la Mama FUCAM, Mexico City, Mexico
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto de Enfermedades de la Mama FUCAM, Mexico City, Mexico
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:Instituto de Enfermedades de la Mama FUCAM, Mexico City, Mexico
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:Harvard Medical School, Boston, USA
      name:Division of Hematology and Oncology, Massachusetts General Hospital, Boston, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:Department of Medicine, Brigham and Women’s Hospital, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:Depertment of Pathology, Massachusetts General Hospital, Boston, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:Department of Pathology, Brigham and Women's Hospital, Boston, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:Present addresses: Department of Medical Oncology, CancerCare Manitoba, Winnipeg, Manitoba R3E 0V9, Canada (S.B.); Global Biotech Consulting Group, Mexico City 01900, Mexico (G.J.-S.).,
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Harvard Medical School, Boston, USA
      name:Massachusetts Institute of Technology, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Harvard Medical School, Boston, USA
      name:Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Howard Hughes Medical Institute, Chevy Chase, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:Harvard Medical School, Boston, USA
      name:Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215,
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Instituto Nacional de Medicina Genómica, Mexico City, Mexico
      name:The Broad Institute of MIT and Harvard, Cambridge, USA
      name:Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA
      name:Harvard Medical School, Boston, USA
      name:Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, USA

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