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

Sara Morcillo-Garcia, Maria del Mar Noblejas-Lopez, Cristina Nieto-Jimenez, Javier Perez-Peña, Miriam Nuncia-Cantarero, B. Györffy, Eitan Amir, Atanasio Pandiella, Eva M. Galan-Moya, Alberto Ocana

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere0209134
JournalPloS one
Volume14
Issue number4
DOIs
Publication statusPublished - Apr 1 2019

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methyltransferases
Epigenomics
histones
epigenetics
breast neoplasms
Tumors
Genes
Breast Neoplasms
genes
prognosis
Signal transduction
cell communication
neoplasms
Methyltransferases
transcriptomics
Cell Communication
Lysine
Machinery
signal transduction
histone methyltransferase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Morcillo-Garcia, S., Noblejas-Lopez, M. D. M., Nieto-Jimenez, C., Perez-Peña, J., Nuncia-Cantarero, M., Györffy, B., ... Ocana, A. (2019). Genetic mutational status of genes regulating epigenetics: Role of the histone methyltransferase KMT2D in triple negative breast tumors. PloS one, 14(4), [e0209134]. https://doi.org/10.1371/journal.pone.0209134

Genetic mutational status of genes regulating epigenetics : Role of the histone methyltransferase KMT2D in triple negative breast tumors. / Morcillo-Garcia, Sara; Noblejas-Lopez, Maria del Mar; Nieto-Jimenez, Cristina; Perez-Peña, Javier; Nuncia-Cantarero, Miriam; Györffy, B.; Amir, Eitan; Pandiella, Atanasio; Galan-Moya, Eva M.; Ocana, Alberto.

In: PloS one, Vol. 14, No. 4, e0209134, 01.04.2019.

Research output: Contribution to journalArticle

Morcillo-Garcia, S, Noblejas-Lopez, MDM, Nieto-Jimenez, C, Perez-Peña, J, Nuncia-Cantarero, M, Györffy, B, Amir, E, Pandiella, A, Galan-Moya, EM & Ocana, A 2019, 'Genetic mutational status of genes regulating epigenetics: Role of the histone methyltransferase KMT2D in triple negative breast tumors', PloS one, vol. 14, no. 4, e0209134. https://doi.org/10.1371/journal.pone.0209134
Morcillo-Garcia, Sara ; Noblejas-Lopez, Maria del Mar ; Nieto-Jimenez, Cristina ; Perez-Peña, Javier ; Nuncia-Cantarero, Miriam ; Györffy, B. ; Amir, Eitan ; Pandiella, Atanasio ; Galan-Moya, Eva M. ; Ocana, Alberto. / Genetic mutational status of genes regulating epigenetics : Role of the histone methyltransferase KMT2D in triple negative breast tumors. In: PloS one. 2019 ; Vol. 14, No. 4.
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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.",
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AU - Perez-Peña, Javier

AU - Nuncia-Cantarero, Miriam

AU - Györffy, B.

AU - Amir, Eitan

AU - Pandiella, Atanasio

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N2 - 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.

AB - 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.

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