Genetic mutational status of genes regulating epigenetics: Role of the histone methyltransferase KMT2D in triple negative breast tumors

Abstract

Purpose Epigenetic regulating proteins like histone methyltransferases produce variations in several functions, some of them associated with the generation of oncogenic processes. Mutations of genes involved in these functions have been recently associated with cancer, and strategies to modulate their activity are currently in clinical development. Methods By using data extracted from the METABRIC study, we searched for mutated genes linked with detrimental outcome in invasive breast carcinoma (n = 772). Then, we used downstream signatures for each mutated gene to associate that signature with clinical prognosis using the online tool “Genotype-2-Outcome” ( http://www.g-2-o.com ). Next, we performed functional annotation analyses to classify genes by functions, and focused on those associated with the epigenetic machinery. Results We identified KMT2D , SETD1A and SETD2 , included in the lysine methyltransferase activity function, as linked with poor prognosis in invasive breast cancer. KMT2D which codes for a histone methyltransferase that acts as a transcriptional regulator was mutated in 6% of triple negative breast tumors and found to be linked to poor survival. Genes regulated by KMT2D included RAC3 , KRT23 , or KRT14 , among others, which are involved in cell communication and signal transduction. Finally, low expression of KMT2D at the transcriptomic level, which mirror what happens when KMT2D is mutated and functionally inactive, confirmed its prognostic value. Conclusion In the present work, we describe epigenetic modulating genes which are found to be mutated in breast cancer. We identify the histone methyltransferase KMT2D, which is mutated in 6% of triple negative tumors and linked with poor survival.

Tumor Mutation Burden and Immune Invasion Characteristics in Triple Negative Breast Cancer: Genome High-Throughput Data Analysis

“…Its regulated genes include RAC3, KRT23, or KRT14 that are involved in cell communication and signal transduction. KMT2D was found to be related to poor survival rate, and low expression of KMT2D at the transcriptional level has prognostic value (33). PTEN is an important phosphatase that plays a role in the interweaving of genetics and epigenetic regulation.…”

The MLL3/4 H3K4 methyltransferase complex in establishing an active enhancer landscape

“…Somatic mutations in MLL3 and MLL4 were first identified by whole-genome sequencing in medulloblastoma (MB) [67][68][69][70] and non-Hodgkin lymphoma [71][72][73][74]. Mutations in MLL3 and/or MLL4 were later found in numerous human cancers and cancer cell lines, including leukemia [75,76], bladder [77,78], lung [79][80][81][82], liver [83], prostate [84], breast [85][86][87][88][89], ovarian [90], gastric [91], pancreatic [70,92], renal [93], and colorectal cancers [94,95]. Most of the somatic mutations in MLL3 or MLL4 appear to be inactivating mutations, highly suggesting their roles as tumor suppressors during tumor initiation and progression (Table 1).…”

The Rac3 GTPase in Neuronal Development, Neurodevelopmental Disorders, and Cancer

“…The gene KMT2D codes for a histone methyltransferase that acts as a transcriptional regulator. KMT2D is mutated in 6% of triple negative breast cancers and is strongly associated with poor survival [64]. Rac3 is one of the genes regulated by KMT2D, which becomes upregulated as a consequence of KMT2D mutations that lead to an abnormal protein that mimics a lack of expression of the KMT2D gene.…”