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Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.

Liu L, Kimball S, Liu H, Holowatyj A, Yang ZQ - Oncotarget (2015)

Bottom Line: We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation.Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets.Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

ABSTRACT
Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.

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KMT2C and KMT2D mutational spectrum in breast cancer(A) Frequency of each mutation type for KMT2C from 958 breast cancer samples. The data were obtained from The Cancer Genome Atlas database via cBioPortal. (B) The images show protein domains and the positions of specific mutations of KMT2C and KMT2D. A red dot indicates a nonsense mutation, frameshift deletion, insertion, or splice; a green dot indicates a missense mutation; and a black dot indicates an inframe insertion or deletion.
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Figure 3: KMT2C and KMT2D mutational spectrum in breast cancer(A) Frequency of each mutation type for KMT2C from 958 breast cancer samples. The data were obtained from The Cancer Genome Atlas database via cBioPortal. (B) The images show protein domains and the positions of specific mutations of KMT2C and KMT2D. A red dot indicates a nonsense mutation, frameshift deletion, insertion, or splice; a green dot indicates a missense mutation; and a black dot indicates an inframe insertion or deletion.

Mentions: Because KMT2C and KMT2D are the most frequently mutated HMT genes in breast cancers, at rates of 6.99% and 2.40%, respectively (Table 2), we performed a comprehensive analysis of the KMT2C and KMT2D mutation spectrum in 958 breast cancer samples. As shown in Figure 3, we identified a total of 80 KMT2C mutations, consisting of 26 missense mutations, 23 nonsense mutations, 17 frameshift deletions, 12 frameshift insertions, 1 splice, and 1 inframe insertion. Eight tumor samples had two mutations, and two samples had four mutations in the KMT2C gene. For example, sample TCGA-AC-A23H contained three missense mutations (D3264N, E3724K, and D4344H) and one nonsense mutation (Q1218*). In the KMT2D gene, 25 mutations were identified, most of them missense mutations (Figure 3A). KMT2C and 2D are large proteins (approximately 5000 amino acids) that contain the zf-HC5HC2H, PHD, FYRN, and FYRC domains and the carboxy-terminal SET domain. Figure 3B shows the distribution of KMT2C and KMT2D mutations in 958 breast cancer samples across protein domains; most of the mutations are localized to the amino-terminal end of the SET domain. Previous studies demonstrated that mice lacking the KMT2C catalytic SET domain developed ureteric tumors, which supports its hypothesized role as a tumor suppressor [24]. Therefore, we predict that mutations at the amino terminus of KMT2C and KMT2D SET domains (Supplementary Table S3) might result in the truncation of the SET domain or loss of function of KMT2C and/or KMT2D methyltransferases, subsequently contributing to breast cancer initiation and progression.


Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.

Liu L, Kimball S, Liu H, Holowatyj A, Yang ZQ - Oncotarget (2015)

KMT2C and KMT2D mutational spectrum in breast cancer(A) Frequency of each mutation type for KMT2C from 958 breast cancer samples. The data were obtained from The Cancer Genome Atlas database via cBioPortal. (B) The images show protein domains and the positions of specific mutations of KMT2C and KMT2D. A red dot indicates a nonsense mutation, frameshift deletion, insertion, or splice; a green dot indicates a missense mutation; and a black dot indicates an inframe insertion or deletion.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385864&req=5

Figure 3: KMT2C and KMT2D mutational spectrum in breast cancer(A) Frequency of each mutation type for KMT2C from 958 breast cancer samples. The data were obtained from The Cancer Genome Atlas database via cBioPortal. (B) The images show protein domains and the positions of specific mutations of KMT2C and KMT2D. A red dot indicates a nonsense mutation, frameshift deletion, insertion, or splice; a green dot indicates a missense mutation; and a black dot indicates an inframe insertion or deletion.
Mentions: Because KMT2C and KMT2D are the most frequently mutated HMT genes in breast cancers, at rates of 6.99% and 2.40%, respectively (Table 2), we performed a comprehensive analysis of the KMT2C and KMT2D mutation spectrum in 958 breast cancer samples. As shown in Figure 3, we identified a total of 80 KMT2C mutations, consisting of 26 missense mutations, 23 nonsense mutations, 17 frameshift deletions, 12 frameshift insertions, 1 splice, and 1 inframe insertion. Eight tumor samples had two mutations, and two samples had four mutations in the KMT2C gene. For example, sample TCGA-AC-A23H contained three missense mutations (D3264N, E3724K, and D4344H) and one nonsense mutation (Q1218*). In the KMT2D gene, 25 mutations were identified, most of them missense mutations (Figure 3A). KMT2C and 2D are large proteins (approximately 5000 amino acids) that contain the zf-HC5HC2H, PHD, FYRN, and FYRC domains and the carboxy-terminal SET domain. Figure 3B shows the distribution of KMT2C and KMT2D mutations in 958 breast cancer samples across protein domains; most of the mutations are localized to the amino-terminal end of the SET domain. Previous studies demonstrated that mice lacking the KMT2C catalytic SET domain developed ureteric tumors, which supports its hypothesized role as a tumor suppressor [24]. Therefore, we predict that mutations at the amino terminus of KMT2C and KMT2D SET domains (Supplementary Table S3) might result in the truncation of the SET domain or loss of function of KMT2C and/or KMT2D methyltransferases, subsequently contributing to breast cancer initiation and progression.

Bottom Line: We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation.Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets.Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.

ABSTRACT
Histone lysine methyltransferases (HMTs), a large class of enzymes that catalyze site-specific methylation of lysine residues on histones and other proteins, play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of HMTs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of approximately 50 HMTs in breast cancer and identified associations among recurrent copy number alterations, mutations, gene expression, and clinical outcome. We identified 12 HMTs with the highest frequency of genetic alterations, including 8 with high-level amplification, 2 with putative homozygous deletion, and 2 with somatic mutation. Different subtypes of breast cancer have different patterns of copy number and expression for each HMT gene. In addition, chromosome 1q contains four HMTs that are concurrently or independently amplified or overexpressed in breast cancer. Copy number or mRNA expression of several HMTs was significantly associated with basal-like breast cancer and shorter patient survival. Integrative analysis identified 8 HMTs (SETDB1, SMYD3, ASH1L, SMYD2, WHSC1L1, SUV420H1, SETDB2, and KMT2C) that are dysregulated by genetic alterations, classifying them as candidate therapeutic targets. Together, our findings provide a strong foundation for further mechanistic research and therapeutic options using HMTs to treat breast cancer.

Show MeSH
Related in: MedlinePlus