Abstract
PurposeEpigenetic 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.MethodsBy 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.ResultsWe 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.ConclusionIn 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.
Highlights
Advances in the analyses of the genomic landscape of human cancers have permitted the identification of different molecular alterations, including mutations, copy number variations, or gene rearrangements, which may be linked with the genesis and maintenance of tumors [1,2]
We identified KMT2D, SETD1A and SETD2, included in the lysine methyltransferase activity function, as linked with poor prognosis in invasive breast cancer
Genes regulated by KMT2D included RAC3, KRT23, or KRT14, among others, which are involved in cell communication and signal transduction
Summary
Advances in the analyses of the genomic landscape of human cancers have permitted the identification of different molecular alterations, including mutations, copy number variations, or gene rearrangements, which may be linked with the genesis and maintenance of tumors [1,2]. Very well-known exceptions include inhibition of protein kinase activity, when that alteration affects a kinase [2] This has been the case for agents targeting mutated or amplified protein kinases, such as EGFR or HER2 in lung and breast cancers [3,4,5]. Alterations in proteins involved in epigenetic regulation can affect genetic programs that can in turn impact on several cellular functions Such genomic alterations can translate into different diseases, from cancer to neurological alterations or aging disorders, among others [8,9]. Inhibition of epigenetic proteins can have a wide effect impacting on the expression of multiple genes, affecting multiple pathways at the same time [10] In this context, agents that target epigenetic enzymes have been recently described and are currently in clinical development [11]. Not very well known, KMT2D can act in some circumstances as a tumor suppressor gene maintaining the expression of relevant proteins involved in genomic stability [14]
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