RGD Reference Report - Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance). - Rat Genome Database

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Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance).

Authors: Augert, Arnaud  Zhang, Qing  Bates, Breanna  Cui, Min  Wang, Xiaofei  Wildey, Gary  Dowlati, Afshin  MacPherson, David 
Citation: Augert A, etal., J Thorac Oncol. 2017 Apr;12(4):704-713. doi: 10.1016/j.jtho.2016.12.011. Epub 2016 Dec 19.
RGD ID: 150523766
Pubmed: PMID:28007623   (View Abstract at PubMed)
PMCID: PMC5669801   (View Article at PubMed Central)
DOI: DOI:10.1016/j.jtho.2016.12.011   (Journal Full-text)


INTRODUCTION: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
KMT2DHumanlung small cell carcinoma  IAGP  RGD 
Kmt2dMouselung small cell carcinoma  ISOKMT2D (Homo sapiens) RGD 
Kmt2dRatlung small cell carcinoma  ISOKMT2D (Homo sapiens) RGD 

Objects Annotated

Genes (Rattus norvegicus)
Kmt2d  (lysine methyltransferase 2D)

Genes (Mus musculus)
Kmt2d  (lysine (K)-specific methyltransferase 2D)

Genes (Homo sapiens)
KMT2D  (lysine methyltransferase 2D)


Additional Information