title: Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance).
abstract: SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis. There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available. SCLC is rarely resected, limiting the number of samples available for genomic analyses of somatic mutations.
  
  
  
  To identify potential driver mutations in human SCLC we sequenced the whole exomes of 18 primary SCLCs and seven cell lines along with matched normal controls. We extended these data by resequencing a panel of genes across 40 primary SCLCs and 48 cell lines.
  
  
  
  We report frequent mutations in the lysine methyltransferase 2D gene (KMT2D) (also known as MLL2), a key regulator of transcriptional enhancer function. KMT2D exhibited truncating nonsense/frameshift/splice site mutations in 8% of SCLC tumors and 17% of SCLC cell lines. We found that KMT2D mutation in human SCLC cell lines was associated with reduced lysine methyltransferase 2D protein levels and reduced monomethylation of histone H3 lysine 4, a mark associated with transcriptional enhancers. We also found mutations in other genes associated with transcriptional enhancer control, including CREB binding protein gene (CREBBP), E1A binding protein p300 gene (EP300), and chromodomain helicase DNA binding protein 7 gene (CHD7), and we report mutations in additional chromatin remodeling genes such as polybromo 1 gene (PBRM1).
  
  
  
  These data indicate that KMT2D is one of the major mutated genes in SCLC, and they point to perturbation of transcriptional enhancer control as potentially contributing to SCLC.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Augert
authors.affiliation: Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Breanna
authors.initials: B
authors.lastname: Bates
authors.affiliation: Carnegie Institution, Department of Embryology, Baltimore, Maryland.
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.affiliation: Duke University School of Medicine and Alliance Data and Statistical Center, Durham, North Carolina.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Case Western Reserve Medical School, Division of Hematology and Oncology, Cleveland, Ohio.
authors.forename: Gary
authors.initials: G
authors.lastname: Wildey
authors.affiliation: Case Western Reserve Medical School, Division of Hematology and Oncology, Cleveland, Ohio.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington; Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Genome Sciences, University of Washington, Seattle, Washington. Electronic address: dmacpher@fhcrc.org.
authors.forename: David
authors.initials: D
authors.lastname: MacPherson
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome / Q000235:genetics*; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins
keywords: Genomics; KMT2D; MLL2; SCLC; Small cell lung cancer