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.