title: Genomic analyses of gynaecologic carcinosarcomas reveal frequent mutations in chromatin remodelling genes.
abstract: Malignant mixed Müllerian tumours, also known as carcinosarcomas, are rare tumours of gynaecological origin. Here we perform whole-exome analyses of 22 tumours using massively parallel sequencing to determine the mutational landscape of this tumour type. On average, we identify 43 mutations per tumour, excluding four cases with a mutator phenotype that harboured inactivating mutations in mismatch repair genes. In addition to mutations in TP53 and KRAS, we identify genetic alterations in chromatin remodelling genes, ARID1A and ARID1B, in histone methyltransferase MLL3, in histone deacetylase modifier SPOP and in chromatin assembly factor BAZ1A, in nearly two thirds of cases. Alterations in genes with potential clinical utility are observed in more than three quarters of the cases and included members of the PI3-kinase and homologous DNA repair pathways. These findings highlight the importance of the dysregulation of chromatin remodelling in carcinosarcoma tumorigenesis and suggest new avenues for personalized therapy.
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.affiliation: Blueprint Medicines, Cambridge, Massachusetts 02142, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: McCord
authors.affiliation: Blueprint Medicines, Cambridge, Massachusetts 02142, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Cerami
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lagowski
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Devon
authors.initials: D
authors.lastname: Kelly
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Samuel V
authors.initials: SV
authors.lastname: Angiuoli
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Sausen
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kann
authors.affiliation: Personal Genome Diagnostics, Baltimore, Maryland 21224, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Shukla
authors.affiliation: Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon 97239, USA.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Makar
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Wood
authors.affiliation: 1] The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA [2] Swim Across America Laboratory and the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins, Baltimore, Maryland 21287, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Diaz
authors.affiliation: Blueprint Medicines, Cambridge, Massachusetts 02142, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D002296:Carcinosarcoma / Q000235:genetics; D002843:Chromatin / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone; D004252:DNA Mutational Analysis; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D015723:Gene Library; D016158:Genes, p53; D011905:Genes, ras / Q000235:genetics; D005833:Genital Neoplasms, Female / Q000235:genetics* / Q000378:metabolism; D023281:Genomics; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000092468:Bromodomain Containing Proteins
chemical_list: D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D012097:Repressor Proteins; D014157:Transcription Factors; C112476:ARID1A protein, human; C497837:ARID1B protein, human; C492319:BAZ1A protein, human; D000092468:Bromodomain Containing Proteins; C452979:KMT2C protein, human; C509761:SPOP protein, human