The lysine‐specific methyltransferase
            <scp>KMT</scp>
            2C/
            <scp>MLL</scp>
            3 regulates
            <scp>DNA</scp>
            repair components in cancer

Ράμπιας, Θεόδωρος; Karagiannis, Dimitris; Avgeris, Margaritis; Polyzos, Alexander; Kokkalis, Antonis; Kanaki, Zoi; Kousidou, Evgenia; Tzetis, Maria; Kanavakis, Emmanouil; Stravodimos, Konstantinos; Manola, Kalliopi N.; Pantelias, Gabriel E.; Scorilas, Andreas; Klinakis, Apostolos

doi:10.15252/embr.201846821

Cited by 95 publications

(59 citation statements)

References 101 publications

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“…Mismatch repair deficiency and the associated hypermutability may indicate responsiveness to PD-1 blockade, as recently reported for metastatic dMMR breast cancer [42]. Rampias T et al [40] showed that inactivating KMT2C mutations (see above) caused sensitivity to PARP1/2 inhibition through synthetic lethality. Several other genes involved in LS-associated breast cancer may also be clinically actionable [43].…”

Section: Discussionmentioning

confidence: 66%

“…The histone lysine methyltransferases KMT2C (MLL3) and KMT2D (MLL2) (Figure 1) also belong to the driver genes detected by Nik-Zainal et al [38]. Mutations in these genes may alter the expression of other genes (e. g., inactivating KMT2C mutations were shown to downregulate genes involved in homologous recombination-mediated DNA repair, making the tumor cells chromosomally unstable [40];) or be harmful by other mechanisms (e. g., KMT2D mutations were found to increase mutational burden and genome instability in cancer through transcription stress [41],). Combined with our previous findings [15], frequent mutations in epigenetic regulatory genes appear to be a common feature of LS tumors, applicable to LS-OC and LS-CRC as well.…”

Section: Discussionmentioning

confidence: 93%

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Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

et al. 2020

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Inherited DNA mismatch repair (MMR) defects cause predisposition to colorectal, endometrial, ovarian, and other cancers occurring in Lynch syndrome (LS). It is unsettled whether breast carcinoma belongs to the LS tumor spectrum. We approached this question through somatic mutational analysis of breast carcinomas from LS families, using established LS-spectrum tumors for comparison. Somatic mutational profiles of 578 cancer-relevant genes were determined for LS-breast cancer (LS-BC, n = 20), non-carrier breast cancer (NC-BC, n = 10), LS-ovarian cancer (LS-OC, n = 16), and LS-colorectal cancer (LS-CRC, n = 18) from the National LS Registry of Finland. Microsatellite and MMR protein analysis stratified LS-BCs into MMR-deficient (dMMR, n = 11) and MMR-proficient (pMMR, n = 9) subgroups. All NC-BCs were pMMR and all LS-OCs and LS-CRCs dMMR. All but one dMMR LS-BCs were hypermutated (> 10 non-synonymous mutations/Mb; average 174/ Mb per tumor) and the frequency of MMR-deficiency-associated signatures 6, 20, and 26 was comparable to that in LS-OC and LS-CRC. LS-BCs that were pMMR resembled NC-BCs with respect to somatic mutational loads (4/9, 44%, hypermutated with average mutation count 33/Mb vs. 3/10, 30%, hypermutated with average 88 mutations/Mb), whereas mutational signatures shared features of dMMR LS-BC, LS-OC, and LS-CRC. Epigenetic regulatory genes were significantly enriched as mutational targets in LS-BC, LS-OC, and LS-CRC. Many top mutant genes of our LS-BCs have previously been identified as drivers of unselected breast carcinomas. In conclusion, somatic mutational signatures suggest that conventional MMR status of tumor tissues is likely to underestimate the significance of the predisposing MMR defects as contributors to breast tumorigenesis in LS.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 93%

Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

et al. 2020

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“…In addition, KMT2C was clearly associated with respiratory diseases according to the Open Targets Platform database. KMT2C, a member of the KMT2 family, is a putative tumor suppressor in several epithelial cells including pulmonary epithelial cells [65,66]. KMT2C knockdown has been shown to promote EMT, while forced expression of KMT2C decreased the expression of EMT-related proteins [67].…”

Section: Discussionmentioning

confidence: 99%

Peptidome Analysis of Umbilical Cord Mesenchymal Stem Cell (hUC-MSC) Conditioned Medium from Preterm and Term Infants

Wang

Zhang

et al. 2020

Preprint

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Background : The therapeutic role of mesenchymal stem cells (MSCs) has been widely confirmed in several animal models of premature infant diseases. Micromolecule peptides have shown promise for the treatment of premature infant diseases. However, the potential role of peptides secreted from MSCs has not been studied. The purpose of this study is to broaden the knowledge of the hUC-MSC secretome at the peptide level through peptidomic profile analysis. Methods : We used tandem mass tag (TMT) labeling technology followed by tandem mass spectrometry to compare the peptidomic profile of preterm and term umbilical cord MSC (hUC-MSC) conditioned medium (CM). Gene Ontology (GO) enrichment analysis and Ingenuity Pathway Analysis (IPA) were conducted to explore the differentially expressed peptides by predicting the functions of their precursor proteins. And we investigated the effects of differentially expressed peptides on human lung epithelial cells stimulated by hydrogen peroxide (H 2 O 2 ). Results : A total of 131 peptides derived from 106 precursor proteins were differentially expressed in the preterm hUC-MSC CM compared with the term group, comprising 37 up-regulated peptides and 94 down-regulated peptides. Bioinformatics analysis showed that these differentially expressed peptides may be associated with developmental disorders, inflammatory response and organismal injury. We also found that two differentially expressed peptides reduced the levels of TNFα and IL 1β mRNA in H 2 O 2 -treated human lung epithelial cells. Conclusions : In summary, this study provides further secretomics information on hUC-MSCs and provides a series of peptides that might have roles in premature infant diseases, which may be helpful for prevention and treatment.

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“…A meta-analysis of RNA-seq data from The Cancer Genome Atlas (TCGA) Consortium has shown that KMT2C expression is downregulated in NSCLC in comparison with normal tissue, and reduced KMT2C expression in patients with NSCLC was correlated with DNA hypermethylation within a CpG island (chr7:152435133-152437025, assembly GRCh38/hg38, ENCODE) of the KMT2C proximal promoter [30].…”

Section: Accepted Articlementioning

confidence: 99%

KMT2C promoter methylation in plasma‐circulating tumor DNA is a prognostic biomarker in non‐small cell lung cancer

et al. 2020

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MLL3 histone methyltransferase, encoded by the KMT2C gene, is a tumor suppressor that has an essential role in cell type-specific gene expression. We evaluated the prognostic significance of KMT2C promoter methylation as a circulating epigenetic biomarker in plasma cell-free DNA (cfDNA) in non-small cell lung cancer (NSCLC). We examined the methylation status of KMT2C promoter using a novel highly specific and sensitive real-time methylation-specific PCR (MSP) assay in: a) operable NSCLC: 48 fresh-frozen NSCLC tissues, their corresponding adjacent nonneoplastic tissues and 48 matched plasma samples; b) metastatic NSCLC: 91 plasma samples and c) 60 plasma samples from healthy donors (HD). KMT2C promoter methylation in plasma-cfDNA was detected in 7/48 (14.6%) patients with operable and in 18/91 (19.8%) patients with advanced NSCLC but in none (0/60, 0%) of the plasma samples from HD. In operable NSCLC, in corresponding adjacent non-neoplastic tissue samples, KMT2C promoter methylation was detected in 3/48 (6.3%) cases. Moreover, in operable NSCLC, KMT2C promoter methylation in plasma-cfDNA was related to reduced disease-free survival (DFS) (ΗR=0.239; p=0.001) and worse overall survival (OS) (HR=0.342, p=0.023). In metastatic NSCLC, KMT2C promoter methylation in plasma-cfDNA was related to worse progression-free survival (PFS) (HR=0.431; p=0.005) and worse OS (HR=0.306; p<0.001). Our data strongly suggest that detection of KMT2C promoter methylation in plasma cfDNA predicts poor prognosis in patients with both operable and metastatic NSCLC. KMT2C promoter methylation in plasma cfDNA therefore merits further evaluation and validation as a non-invasive circulating epigenetic biomarker.

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The lysine‐specific methyltransferase KMT 2C/ MLL 3 regulates DNA repair components in cancer

Cited by 95 publications

References 101 publications

Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

Does breast carcinoma belong to the Lynch syndrome tumor spectrum? – Somatic mutational profiles vs. ovarian and colorectal carcinomas

Peptidome Analysis of Umbilical Cord Mesenchymal Stem Cell (hUC-MSC) Conditioned Medium from Preterm and Term Infants

KMT2C promoter methylation in plasma‐circulating tumor DNA is a prognostic biomarker in non‐small cell lung cancer

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