KMT2C

Gene Summary

Gene:KMT2C; lysine methyltransferase 2C
Aliases: HALR, MLL3, KLEFS2
Location:7q36.1
Summary:This gene is a member of the myeloid/lymphoid or mixed-lineage leukemia (MLL) family and encodes a nuclear protein with an AT hook DNA-binding domain, a DHHC-type zinc finger, six PHD-type zinc fingers, a SET domain, a post-SET domain and a RING-type zinc finger. This protein is a member of the ASC-2/NCOA6 complex (ASCOM), which possesses histone methylation activity and is involved in transcriptional coactivation. [provided by RefSeq, Jul 2008]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase 2C
Source:NCBIAccessed: 31 August, 2019

Ontology:

What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: KMT2C (cancer-related)

Lan Y, Zhao E, Luo S, et al.
Revealing clonality and subclonality of driver genes for clinical survival benefits in breast cancer.
Breast Cancer Res Treat. 2019; 175(1):91-104 [PubMed] Related Publications
PURPOSE: Genomic studies have revealed that genomic aberrations play important roles in the progression of this disease. The aim of this study was to evaluate the associations between clinical survival outcomes of the clonality and subclonality status of driver genes in breast cancer.
METHODS: We performed an integrated analysis to infer the clonal status of 55 driver genes in breast cancer data from TCGA. We used the chi-squared test to assess the relations between clonality of driver gene mutations and clinicopathological factors. The Kaplan-Meier method was performed for the visualization and the differences between survival curves were calculated by log-rank test. Univariate and multivariate Cox proportional hazards regression models were used to adjust for clinicopathological factors.
RESULTS: We identified a high proportion of clonal mutations in these driver genes. Among them, there were 17 genes showing significant associations between their clonality and multiple clinicopathologic factors. Performing survival analysis on BRCA patients with clonal or subclonal driver gene mutations, we found that clonal ERBB2, FOXA1, and KMT2C mutations and subclonal GATA3 and RB1 mutations predicted shorter overall survival compared with those with wild type. Furthermore, clonal ERBB2 and FOXA1 mutations and subclonal GATA3 and RB1 mutations independently predicted for shorter overall survival after adjusting for clinicopathological factors. By longitudinal analysis, the clonality of ERBB2, FOXA1, GATA3, and RB1 significantly predicted patients' outcome within some specific BRCA tumor stages and histological subtypes.
CONCLUSIONS: In summary, these clonal or subclonal mutations of driver genes have implications for diagnosis, prognosis, and treatment with BRCA patients.

MacFawn I, Wilson H, Selth LA, et al.
Grainyhead-like-2 confers NK-sensitivity through interactions with epigenetic modifiers.
Mol Immunol. 2019; 105:137-149 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Natural Killer (NK) cells suppress tumor initiation and metastasis. Most carcinomas are heterogeneous mixtures of epithelial, mesenchymal and hybrid tumor cells, but the relationships of these phenotypes to NK susceptibility are understood incompletely. Grainyhead-like-2 (GRHL2) is a master programmer of the epithelial phenotype, that is obligatorily down-regulated during experimentally induced Epithelial-Mesenchymal Transition (EMT). Here, we utilize GRHL2 re-expression to discover unifying molecular mechanisms that link the epithelial phenotype with NK-sensitivity. GRHL2 enhanced the expression of ICAM-1, augmenting NK-target cell synaptogenesis and NK killing of target cells. The expression of multiple interferon response genes, including ICAM1, anti-correlated with EMT. We identified two novel GRHL2-interacting proteins, the histone methyltransferases KMT2C and KMT2D. Mesenchymal-epithelial transition, NK-sensitization and ICAM-1 expression were promoted by GRHL2-KMT2C/D interactions and by GRHL2 inhibition of p300, revealing novel and potentially targetable epigenetic mechanisms connecting the epithelial phenotype with target cell susceptibility to NK killing.

Zámečníkova A, Al Bahar S
A Novel and Cytogenetically Cryptic t(7;21)(q36.1;q22) Disrupting RUNX1 in Acute Myeloid Leukemia.
Cytogenet Genome Res. 2018; 156(3):140-143 [PubMed] Related Publications
Translocations involving the RUNX1 transcription factor gene are frequently identified in leukemia patients, but the partner genes have been characterized in only about half of these cases. We report here a novel RUNX1 partner gene, KMT2C (MLL3), in a patient with de novo acute myeloid leukemia, having a novel and cytogenetically cryptic t(7;21)(q36.1;q22) leading to disruption of RUNX1 and KMT2C. This is the third cryptic RUNX1 rearrangement in myeloid and the fourth in hematologic malignancies.

Cui M, Hu Y, Bi Y, et al.
Preliminary exploration of potential molecular therapeutic targets in recurrent and metastatic parathyroid carcinomas.
Int J Cancer. 2019; 144(3):525-532 [PubMed] Related Publications
Parathyroid carcinoma (PC) is a rare endocrine malignancy. Surgical resection is curative for local lesions, while effective therapies are lacking for recurrent or metastatic PCs. To study whether targeted therapies could be applied in recurrent or metastatic PCs, potential therapeutic targets were identified with next-generation sequencing (NGS). DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) sections from 19 recurrent or metastatic PC samples. A panel of 560 genes was sequenced with NGS to identify genomic alterations at an average sequencing depth of 581×. In total, 190 genomic alterations were identified. Nine PC samples (47%) harbored at least one potentially actionable genomic alteration including in the after genes: ROS1 (5/19; 26%), PTEN (3/19; 16%), TSC1 (2/19; 11%), PIK3CA (1/19; 5%), AKT1 (1/19; 5%), MTOR (1/19; 5%), ERBB2 (1/19; 5%), NTRK1 (1/19; 5%), IDH1 (1/19; 5%) and FGFR3 (1/19; 5%). CDC73 mutations were detected in 9/19 (47%) PC samples. Additional recurrent genomic alterations were identified in MSH2 (15/19; 79%), AR (9/19; 47%), BCR (8/19; 42%), SLC45A3 (6/19; 32%), MAGI1 (5/19; 26%), ZNF521 (4/19; 21%), KMT2C (4/19; 21%) and NOTCH4 (4/19; 21%). Our study identified a relatively high frequency of potentially actionable genomic alterations in PC patients in a Chinese population for the first time. A series of recurrent mutant genes was detected as well. Our study contributes to both the selection of novel targeted therapies for PC and further molecular understanding of this refractory malignancy.

Sun Y, Zhou B, Mao F, et al.
HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis.
Cancer Cell. 2018; 34(4):643-658.e5 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.

Tan TZ, Rouanne M, Tan KT, et al.
Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors.
Eur Urol. 2019; 75(3):423-432 [PubMed] Related Publications
BACKGROUND: Previous molecular subtyping for bladder carcinoma (BLCA) involved <450 samples, with diverse classifications.
OBJECTIVE: To identify molecular subtypes by curating a large BLCA dataset.
DESIGN, SETTING, AND PARTICIPANTS: Gene expression publicly available were combined and reanalyzed. The dataset contained 2411 unique tumors encompassing non-muscle-invasive (NMIBC) and muscle-invasive BLCA (MIBC). Subtypes were reproduced on The Cancer Genome Atlas, UROMOL, and IMvigor210.
INTERVENTION: Subtypes were assigned by gene expression.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analyses were performed for subtype-clinical outcome correlations; Chi-square/Fisher exact tests were used for subtype-clinicopathological parameters associations.
RESULTS AND LIMITATIONS: We identified six molecular subtypes with different overall survival (OS) and molecular features. Subtype Neural-like (median OS, 87 mo) is prevalent in MIBC and characterized by high WNT/β-catenin signaling. HER2-like (107.7 mo) is distributed evenly across NMIBC and MIBC, with higher ERBB2 amplification and signaling. Papillary-like (>135 mo), an NMIBC subtype enriched in urothelial differentiation genes, shows a high frequency of actionable FGFR3 mutations, amplifications, and FGFR3-TACC3 fusion. Luminal-like (91.7 mo), predominantly NMIBC, has higher MAPK signaling and more KRAS and KMT2C/D mutations than other subtypes. Mesenchymal-like (MES; 86.6 mo) and Squamous-cell carcinoma-like (SCC; 20.6 mo) are predominant in MIBC. MES is high in AXL signaling, whereas SCC has elevated PD1, CTLA4 signaling, and macrophage M2 infiltration. About 20% of NMIBCs show MIBC subtype traits and a lower 5-yr OS rate than Papillary-like NMIBC (81% vs 96%). The main limitations of our study are the incomplete clinical annotation, and the analyses were based on transcriptome subset due to comparisons across gene expression quantification technologies.
CONCLUSIONS: BLCA can be stratified into six molecular subtypes. NMIBC, with a high risk of progression, displays the molecular features of MIBC.
PATIENT SUMMARY: Biomarkers are urgently needed to guide patient treatment selection and avoid unnecessary toxicities in those who fail to respond. We believe molecular subtyping is a promising way to tailor disease management for those who will benefit most.

Hylebos M, Op de Beeck K, van den Ende J, et al.
Molecular analysis of an asbestos-exposed Belgian family with a high prevalence of mesothelioma.
Fam Cancer. 2018; 17(4):569-576 [PubMed] Related Publications
Familial clustering of malignant mesothelioma (MM) has been linked to the presence of germline mutations in BAP1. However, families with multiple MM patients, without segregating BAP1 mutation were described, suggesting the existence of other predisposing genetic factors. In this study, we report a previously undescribed Belgian family, in which BAP1 was found to be absent in the epithelial malignant mesothelial cells of the index patient. Whole exome analysis did not reveal a germline or somatic BAP1 variant. Also, no germline or somatic copy number changes in the BAP1 region could be identified. However, germline variants, predicted to be damaging, were detected in 11 other 'Cancer census genes' (i.e. MPL, RBM15, TET2, FAT1, HLA-A, EGFR, KMT2C, BRD3, NOTCH1, RB1 and MYO5A). Of these, the one in RBM15 seems to be the most interesting given its low minor allele frequency and absence in the germline DNA of the index patient's mother. The importance of this 'Cancer census gene' in familial MM clustering needs to be evaluated further. Nevertheless, this study strengthens the suspicion that, next to germline BAP1 alterations, other genetic factors might predispose families to the development of MM.

Rahnamoun H, Hong J, Sun Z, et al.
Mutant p53 regulates enhancer-associated H3K4 monomethylation through interactions with the methyltransferase MLL4.
J Biol Chem. 2018; 293(34):13234-13246 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Monomethylation of histone H3 lysine 4 (H3K4me1) is enriched at enhancers that are primed for activation and the levels of this histone mark are frequently altered in various human cancers. Yet, how alterations in H3K4me1 are established and the consequences of these epigenetic changes in tumorigenesis are not well understood. Using ChIP-Seq in human colon cancer cells, we demonstrate that mutant p53 depletion results in decreased H3K4me1 levels at active enhancers that reveal a striking colocalization of mutant p53 and the H3K4 monomethyltransferase MLL4 following chronic tumor necrosis factor alpha (TNFα) signaling. We further reveal that mutant p53 forms physiological associations and direct interactions with MLL4 and promotes the enhancer binding of MLL4, which is required for TNFα-inducible H3K4me1 and histone H3 lysine 27 acetylation (H3K27ac) levels, enhancer-derived transcript (eRNA) synthesis, and mutant p53-dependent target gene activation. Complementary

Yap YS, Munusamy P, Lim C, et al.
Breast cancer in women with neurofibromatosis type 1 (NF1): a comprehensive case series with molecular insights into its aggressive phenotype.
Breast Cancer Res Treat. 2018; 171(3):719-735 [PubMed] Related Publications
PURPOSE: The purpose of the study was to improve the understanding of NF1-associated breast cancer, given the increased risk of breast cancer in this tumour predisposition syndrome and the limited data.
METHODS: We identified 18 women with NF1 and breast cancer at our institution. Clinical and pathologic characteristics of NF1-associated breast cancers were compared with 7132 breast cancers in patients without NF1 from our institutional database. Next generation sequencing was performed on DNA from blood and breast cancer specimens available. Blood specimens negative for NF1 mutation were subjected to multiplex ligation-dependent probe amplification (MLPA) to identify complete/partial deletions or duplications. Expression of neurofibromin in the NF1-associated breast cancers was evaluated using immunohistochemistry.
RESULTS: There was a higher frequency of grade 3 (83.3% vs 45.4%, p = 0.005), oestrogen receptor (ER) negative (66.7% vs 26.3%, p < 0.001) and human epidermal growth factor receptor 2 (HER2)-positive (66.7% vs 23.4%, p < 0.001) tumours among NF1 patients compared to non-NF1 breast cancers. Overall survival was inferior in NF1 patients in multivariable analysis (hazard ratio 2.25, 95% CI 1.11-4.60; p = 0.025). Apart from germline NF1 mutations (11/16; 69%), somatic mutations in TP53 (8/10; 80%), second-hit NF1 (2/10; 20%), KMT2C (4/10; 40%), KMT2D (2/10; 20%), and PIK3CA (2/10; 20%) were observed. Immunohistochemical expression of neurofibromin was seen in the nuclei and/or cytoplasm of all specimens, but without any consistent pattern in the intensity or extent.
CONCLUSIONS: This comprehensive series of NF1-associated breast cancers suggests that their aggressive features are related to germline NF1 mutations in cooperation with somatic mutations in TP53, KMT2C and other genes.

Hu ZY, Xie N, Tian C, et al.
Identifying Circulating Tumor DNA Mutation Profiles in Metastatic Breast Cancer Patients with Multiline Resistance.
EBioMedicine. 2018; 32:111-118 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
PURPOSE: In cancer patients, tumor gene mutations contribute to drug resistance and treatment failure. In patients with metastatic breast cancer (MBC), these mutations increase after multiline treatment, thereby decreasing treatment efficiency. The aim of this study was to evaluate gene mutation patterns in MBC patients to predict drug resistance and disease progression.
METHOD: A total of 68 MBC patients who had received multiline treatment were recruited. Circulating tumor DNA (ctDNA) mutations were evaluated and compared among hormone receptor (HR)/human epidermal growth factor receptor 2 (HER2) subgroups.
RESULTS: The baseline gene mutation pattern (at the time of recruitment) varied among HR/HER2 subtypes. BRCA1 and MED12 were frequently mutated in triple negative breast cancer (TNBC) patients, PIK3CA and FAT1 mutations were frequent in HR+ patients, and PIK3CA and ERBB2 mutations were frequent in HER2+ patients. Gene mutation patterns also varied in patients who progressed within either 3 months or 3-6 months of chemotherapy treatment. For example, in HR+ patients who progressed within 3 months of treatment, the frequency of TERT mutations significantly increased. Other related mutations included FAT1 and NOTCH4. In HR+ patients who progressed within 3-6 months, PIK3CA, TP53, MLL3, ERBB2, NOTCH2, and ERS1 were the candidate mutations. This suggests that different mechanisms underlie disease progression at different times after treatment initiation. In the COX model, the ctDNA TP53 + PIK3CA gene mutation pattern successfully predicted progression within 6 months.
CONCLUSION: ctDNA gene mutation profiles differed among HR/HER2 subtypes of MBC patients. By identifying mutations associated with treatment resistance, we hope to improve therapy selection for MBC patients who received multiline treatment.

Park ES, Yan JP, Ang RA, et al.
Isolation and genome sequencing of individual circulating tumor cells using hydrogel encapsulation and laser capture microdissection.
Lab Chip. 2018; 18(12):1736-1749 [PubMed] Related Publications
Circulating tumor cells (CTCs) are malignant cells released into the bloodstream with the potential to form metastases in secondary sites. These cells, acquired non-invasively, represent a sample of highly relevant tumor tissue that is an alternative to difficult and low-yield tumor biopsies. In recent years, there has been growing interest in genomic profiling of CTCs to enable longitudinal monitoring of the tumor's adaptive response to therapy. However, due to their extreme rarity, genotyping CTCs has proved challenging. Relevant mutations can be masked by leukocyte contamination in isolates. Heterogeneity between subpopulations of tumor cells poses an additional obstacle. Recent advances in single-cell sequencing can overcome these limitations but isolation of single CTCs is prone to cell loss and is prohibitively difficult and time consuming. To address these limitations, we developed a single cell sample preparation and genome sequencing pipeline that combines biophysical enrichment and single cell isolation using laser capture microdissection (LCM). A key component of this process is the encapsulation of enriched CTC sample in a hydrogel matrix, which enhances the efficiency of single-cell isolation by LCM, and is compatible with downstream sequencing. We validated this process by sequencing of single CTCs and cell free DNA (cfDNA) from a single patient with castration resistant prostate cancer. Identical mutations were observed in prostate cancer driver genes (TP53, PTEN, FOXA1) in both single CTCs and cfDNA. However, two independently isolated CTCs also had identical missense mutations in the genes for ATR serine/threonine kinase, KMT2C histone methyltransferase, and FANCC DNA damage repair gene. These mutations may be missed by bulk sequencing libraries, whereas single cell sequencing could potentially enable the characterization of key CTC subpopulations that arise during metastasis.

Gala K, Li Q, Sinha A, et al.
KMT2C mediates the estrogen dependence of breast cancer through regulation of ERα enhancer function.
Oncogene. 2018; 37(34):4692-4710 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Estrogen receptor alpha (ERα) is a ligand-activated nuclear receptor that directs proliferation and differentiation in selected cancer cell types including mammary-derived carcinomas. These master-regulatory functions of ERα require trans-acting elements such as the pioneer factor FOXA1 to establish a genomic landscape conducive to ERα control. Here, we identify the H3K4 methyltransferase KMT2C as necessary for hormone-driven ERα activity and breast cancer proliferation. KMT2C knockdown suppresses estrogen-dependent gene expression and causes H3K4me1 and H3K27ac loss selectively at ERα enhancers. Correspondingly, KMT2C loss impairs estrogen-driven breast cancer proliferation but has no effect on ER- breast cells. Whereas KMT2C loss disrupts estrogen-driven proliferation, it conversely promotes tumor outgrowth under hormone-depleted conditions. In accordance, KMT2C is one of the most frequently mutated genes in ER-positive breast cancer with KMT2C deletion correlating with significantly shorter progression-free survival on anti-estrogen therapy. From a therapeutic standpoint, KMT2C-depleted cells that develop hormone-independence retain their dependence on ERα, displaying ongoing sensitivity to ERα antagonists. We conclude that KMT2C is a key regulator of ERα activity whose loss uncouples breast cancer proliferation from hormone abundance.

Cavalieri S, Perrone F, Miceli R, et al.
Efficacy and safety of single-agent pan-human epidermal growth factor receptor (HER) inhibitor dacomitinib in locally advanced unresectable or metastatic skin squamous cell cancer.
Eur J Cancer. 2018; 97:7-15 [PubMed] Related Publications
BACKGROUND: In recurrent or metastatic (R/M) skin squamous cell cancer (sSCC) not amenable to radiotherapy (RT) or surgery, chemotherapy (CT) has a palliative intent and limited clinical responses. The role of oral pan-HER inhibitor dacomitinib in this setting was investigated within a clinical trial.
METHODS: Patients with diagnosis of R/M sSCC were treated. Dacomitinib was started at a dose of 30 mg daily (QD) for 15 d, followed by 45 mg QD. Primary end-point was response rate (RR). Tumour samples were analysed through next-generation sequencing using a custom panel targeting 36 genes associated with sSCC.
RESULTS: Forty-two patients (33 men; median age 77 years) were treated. Most (86%) received previous treatments consisting in surgery (86%), RT (50%) and CT (14%). RR was 28% (2% complete response; 26% partial response), disease control rate was 86%. Median progression-free survival and overall survival were 6 and 11 months, respectively. Most patients (93%) experienced at least one adverse event (AE): diarrhoea, skin rash (71% each), fatigue (36%) and mucositis (31%); AEs grade 3-4 occurred in 36% of pts. In 16% of cases, treatment was discontinued because of drug-related toxicity. TP53, NOTCH1/2, KMT2C/D, FAT1 and HER4 were the most frequently mutated genes. BRAF, NRAS and HRAS mutations were more frequent in non-responders, and KMT2C and CASP8 mutations were restricted to this subgroup.
CONCLUSIONS: In sSCC, dacomitinib showed activity similar to what was observed with anti-epidermal growth factor receptor agents, and durable clinical benefit was observed. Safety profile was comparable to previous experiences in other cancers. Molecular pt selection could improve therapeutic ratio.

Inaba T, Honda H, Matsui H
The enigma of monosomy 7.
Blood. 2018; 131(26):2891-2898 [PubMed] Related Publications
Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models.

Fantini D, Glaser AP, Rimar KJ, et al.
A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer.
Oncogene. 2018; 37(14):1911-1925 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80%), Kmt2d (70%), and Kmt2c (90%) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.

Zhang L, Liu Y, Wang M, et al.
EZH2-, CHD4-, and IDH-linked epigenetic perturbation and its association with survival in glioma patients.
J Mol Cell Biol. 2017; 9(6):477-488 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Glioma is a complex disease with limited treatment options. Recent advances have identified isocitrate dehydrogenase (IDH) mutations in up to 80% lower grade gliomas (LGG) and in 76% secondary glioblastomas (GBM). IDH mutations are also seen in 10%-20% of acute myeloid leukemia (AML). In AML, it was determined that mutations of IDH and other genes involving epigenetic regulations are early events, emerging in the pre-leukemic stem cells (pre-LSCs) stage, whereas mutations in genes propagating oncogenic signal are late events in leukemia. IDH mutations are also early events in glioma, occurring before TP53 mutation, 1p/19q deletion, etc. Despite these advances in glioma research, studies into other molecular alterations have lagged considerably. In this study, we analyzed currently available databases. We identified EZH2, KMT2C, and CHD4 as important genes in glioma in addition to the known gene IDH1/2. We also showed that genomic alterations of PIK3CA, CDKN2A, CDK4, FIP1L1, or FUBP1 collaborate with IDH mutations to negatively affect patients' survival in LGG. In LGG patients with TP53 mutations or IDH1/2 mutations, additional genomic alterations of EZH2, KMC2C, and CHD4 individually or in combination were associated with a markedly decreased disease-free survival than patients without such alterations. Alterations of EZH2, KMT2C, and CHD4 at genetic level or protein level could perturb epigenetic program, leading to malignant transformation in glioma. By reviewing current literature on both AML and glioma and performing bioinformatics analysis on available datasets, we developed a hypothetical model on the tumorigenesis from premalignant stem cells to glioma.

Yadav S, DE Sarkar N, Kumari N, et al.
Targeted Gene Sequencing of Gallbladder Carcinoma Identifies High-impact Somatic and Rare Germline Mutations.
Cancer Genomics Proteomics. 2017 Nov-Dec; 14(6):495-506 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
BACKGROUND: Gallbladder carcinoma (GBC) is a subtype of biliary tract malignancy with poor prognosis and high fatality rate. The present study was designed to uncover somatic and rare germline mutations in GBC to reveal the disease biology and understand the clinical importance of mutation profile in terms of prognostics and actionability.
MATERIALS AND METHODS: We performed ultra-deep sequencing across 409 cancer-related genes in 11 GBC patients of North-Indian descent. NGS data analysis was performed using Ion Reporter and several other publicly available resources and databases.
RESULTS: We identified 184 nonsynonymous somatic and 60 rare germline mutations in bona-fide cancer drivers such as SMAD family member 4 (SMAD4), lysine methyltransferase 2C (KMT2C), and tumor protein p53 (TP53). All the early-onset cases or hypermutated cases harbored mutation(s) in critical DNA-repair genes. Additionally, we detected 9 novel genes with high-impact somatic mutations in GBC.
CONCLUSION: Our results indicated the significance of inherited rare germline mutations in DNA-repair pathway genes in addition to acquired somatic mutations in GB carcinogenesis.

Cavalieri S, Stathis A, Fabbri A, et al.
Uncommon somatic mutations in metastatic NUT midline carcinoma.
Tumori. 2017; 103(Suppl. 1):e5-e8 [PubMed] Related Publications
INTRODUCTION:: NUT midline carcinoma (NMC) is a rare and aggressive epithelial cancer arising from median organs. It is driven by chromosomal translocation t(15;19) involving the rearrangement of NUT (nuclear protein in testis) and BRD4 (bromodomain 4) genes leading to fusion oncoprotein BRD4-NUT.
CASE PRESENTATION:: We report the case of a woman who was previously treated with induction chemotherapy, surgery, radiotherapy and adjuvant trastuzumab for HER-2 positive invasive ductal carcinoma of the breast. After 6 months of follow-up a lung nodule appeared. A biopsy showed an adenocarcinoma fetal type/lung blastoma, so a left inferior lobectomy was performed: NMC harboring BRD4-NUT rearrangement was diagnosed. After 9 months of follow-up, bone and soft tissue metastases occurred, so the patient was given radiotherapy. Next-generation sequencing technology identified somatic mutations in deleted in colorectal cancer (DCC), mixed lineage leukemia protein 3 (MLL3), and splicing factor 3B subunit 1 (SF3B1) genes in NMC cells from both primitive cancer and metastases. The patient was treated with the experimental BRD4 inhibitor for 10 months, until the disease progressed to the lung and bone. After spinal cord compression, the patient was offered palliative radiotherapy to bone and eventually died aged 39 years.
CONCLUSIONS:: To the best of our knowledge, our case is the first DCC, MLL3, and SF3B1 mutated NUT midline carcinoma reported in the literature. If these mutations were confirmed to play a role in this neoplasm, clinical trials analyzing targeted therapies should be considered, eg. colorectal cancer-like chemotherapies for DCC mutations, hypomethylating agents for MLL3 mutations or SF3B1 inhibitors in case of specific somatic mutations.

Kayser S, Feszler M, Krzykalla J, et al.
Clinical impact of KMT2C and SPRY4 expression levels in intensively treated younger adult acute myeloid leukemia patients.
Eur J Haematol. 2017; 99(6):544-552 [PubMed] Related Publications
OBJECTIVE: To evaluate the prognostic impact of gene expression levels (ELs) of two tumor suppressor genes, sprouty 4 (SPRY4, located on 5q) and lysine methyltransferase 2C (KMT2C, located on 7q) in correlation with clinical characteristics and genetic abnormalities assessed at initial diagnosis in acute myeloid leukemia (AML).
METHOD: Gene expression levels were measured on cDNA by RT-qPCR from diagnostic bone marrow samples of 275 intensively treated adult AML patients (median age, 48 years).
RESULTS: KMT2C ELs were significantly lower in abn7q/-7 (P = .001), whereas SPRY4 ELs were not associated with abn5q/-5. Higher KMT2C and SPRY4 ELs were significantly associated with lower genetic risk groups as defined by the European LeukemiaNet classification. Additionally, KMT2C ELs were lower in cytogenetically normal patients with DNMT3A (P = .01) or FLT3-ITD mutations (P = .05). KMT2C ELs were not associated with prognosis, whereas higher SPRY4 ELs showed a favorable impact on event-free (EFS, P = .01), relapse-free (RFS, P = .01) and in-trend on overall survival (P = .06) for cytogenetically abnormal patients, which was confirmed in multivariable analysis for EFS (HR, 0.84; 95%-CI, 0.73-0.97; P = .02) and RFS (HR, 0.85; 95%-CI, 0.73-0.98; P = .02).
CONCLUSION: Our data indicate that KMT2C ELs are associated with specific genetic features and that SPRY4 ELs may add prognostic information.

Anjanappa M, Hao Y, Simpson ER, et al.
A system for detecting high impact-low frequency mutations in primary tumors and metastases.
Oncogene. 2018; 37(2):185-196 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Tumor complexity and intratumor heterogeneity contribute to subclonal diversity. Despite advances in next-generation sequencing (NGS) and bioinformatics, detecting rare mutations in primary tumors and metastases contributing to subclonal diversity is a challenge for precision genomics. Here, in order to identify rare mutations, we adapted a recently described epithelial reprograming assay for short-term propagation of epithelial cells from primary and metastatic tumors. Using this approach, we expanded minor clones and obtained epithelial cell-specific DNA/RNA for quantitative NGS analysis. Comparative Ampliseq Comprehensive Cancer Panel sequence analyses were performed on DNA from unprocessed breast tumor and tumor cells propagated from the same tumor. We identified previously uncharacterized mutations present only in the cultured tumor cells, a subset of which has been reported in brain metastatic but not primary breast tumors. In addition, whole-genome sequencing identified mutations enriched in liver metastases of various cancers, including Notch pathway mutations/chromosomal inversions in 5/5 liver metastases, irrespective of cancer types. Mutations/rearrangements in FHIT, involved in purine metabolism, were detected in 4/5 liver metastases, and the same four liver metastases shared mutations in 32 genes, including mutations of different HLA-DR family members affecting OX40 signaling pathway, which could impact the immune response to metastatic cells. Pathway analyses of all mutated genes in liver metastases showed aberrant tumor necrosis factor and transforming growth factor signaling in metastatic cells. Epigenetic regulators including KMT2C/MLL3 and ARID1B, which are mutated in >50% of hepatocellular carcinomas, were also mutated in liver metastases. Thus, irrespective of cancer types, organ-specific metastases may share common genomic aberrations. Since recent studies show independent evolution of primary tumors and metastases and in most cases mutation burden is higher in metastases than primary tumors, the method described here may allow early detection of subclonal somatic alterations associated with metastatic progression and potentially identify therapeutically actionable, metastasis-specific genomic aberrations.

Murakami R, Matsumura N, Brown JB, et al.
Exome Sequencing Landscape Analysis in Ovarian Clear Cell Carcinoma Shed Light on Key Chromosomal Regions and Mutation Gene Networks.
Am J Pathol. 2017; 187(10):2246-2258 [PubMed] Related Publications
Previous studies have reported genome-wide mutation profile analyses in ovarian clear cell carcinomas (OCCCs). This study aims to identify specific novel molecular alterations by combined analyses of somatic mutation and copy number variation. We performed whole exome sequencing of 39 OCCC samples with 16 matching blood tissue samples. Four hundred twenty-six genes had recurrent somatic mutations. Among the 39 samples, ARID1A (62%) and PIK3CA (51%) were frequently mutated, as were genes such as KRAS (10%), PPP2R1A (10%), and PTEN (5%), that have been reported in previous OCCC studies. We also detected mutations in MLL3 (15%), ARID1B (10%), and PIK3R1 (8%), which are associations not previously reported. Gene interaction analysis and functional assessment revealed that mutated genes were clustered into groups pertaining to chromatin remodeling, cell proliferation, DNA repair and cell cycle checkpointing, and cytoskeletal organization. Copy number variation analysis identified frequent amplification in chr8q (64%), chr20q (54%), and chr17q (46%) loci as well as deletion in chr19p (41%), chr13q (28%), chr9q (21%), and chr18q (21%) loci. Integration of the analyses uncovered that frequently mutated or amplified/deleted genes were involved in the KRAS/phosphatidylinositol 3-kinase (82%) and MYC/retinoblastoma (75%) pathways as well as the critical chromatin remodeling complex switch/sucrose nonfermentable (85%). The individual and integrated analyses contribute details about the OCCC genomic landscape, which could lead to enhanced diagnostics and therapeutic options.

Kytola V, Topaloglu U, Miller LD, et al.
Mutational Landscapes of Smoking-Related Cancers in Caucasians and African Americans: Precision Oncology Perspectives at Wake Forest Baptist Comprehensive Cancer Center.
Theranostics. 2017; 7(11):2914-2923 [PubMed] Article available free on PMC after 08/10/2019 Related Publications

Chow RD, Guzman CD, Wang G, et al.
AAV-mediated direct in vivo CRISPR screen identifies functional suppressors in glioblastoma.
Nat Neurosci. 2017; 20(10):1329-1341 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
A causative understanding of genetic factors that regulate glioblastoma pathogenesis is of central importance. Here we developed an adeno-associated virus-mediated, autochthonous genetic CRISPR screen in glioblastoma. Stereotaxic delivery of a virus library targeting genes commonly mutated in human cancers into the brains of conditional-Cas9 mice resulted in tumors that recapitulate human glioblastoma. Capture sequencing revealed diverse mutational profiles across tumors. The mutation frequencies in mice correlated with those in two independent patient cohorts. Co-mutation analysis identified co-occurring driver combinations such as B2m-Nf1, Mll3-Nf1 and Zc3h13-Rb1, which were subsequently validated using AAV minipools. Distinct from Nf1-mutant tumors, Rb1-mutant tumors are undifferentiated and aberrantly express homeobox gene clusters. The addition of Zc3h13 or Pten mutations altered the gene expression profiles of Rb1 mutants, rendering them more resistant to temozolomide. Our study provides a functional landscape of gliomagenesis suppressors in vivo.

Morris V, Rao X, Pickering C, et al.
Comprehensive Genomic Profiling of Metastatic Squamous Cell Carcinoma of the Anal Canal.
Mol Cancer Res. 2017; 15(11):1542-1550 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Squamous cell carcinoma of the anal canal (SCCA) is a rare gastrointestinal malignancy with an increasing annual incidence globally. The majority of cases are linked to prior infection with the human papillomavirus (HPV). For patients with metastatic SCCA, no consensus standard treatment exists. Identification of relevant targeted agents as novel therapeutic approaches for metastatic SCCA has been limited by a lack of comprehensive molecular profiling. We performed whole-exome sequencing on tumor-normal pairs from 24 patients with metastatic SCCA. Tumor tissue from 17 additional patients was analyzed using a 263-gene panel as a validation cohort. Gene expression profiling was performed on available frozen tissue to assess for differential expression patterns. Based on these findings, patient-derived xenograft (PDX) models of SCCA were generated to test targeted therapies against PI3K and EGFR. Despite a low mutation burden, mutations in

Basturk O, Berger MF, Yamaguchi H, et al.
Pancreatic intraductal tubulopapillary neoplasm is genetically distinct from intraductal papillary mucinous neoplasm and ductal adenocarcinoma.
Mod Pathol. 2017; 30(12):1760-1772 [PubMed] Related Publications
Intraductal tubulopapillary neoplasm is a relatively recently described member of the pancreatic intraductal neoplasm family. The more common member of this family, intraductal papillary mucinous neoplasm, often carries genetic alterations typical of pancreatic infiltrating ductal adenocarcinoma (KRAS, TP53, and CDKN2A) but additionally has mutations in GNAS and RNF43 genes. However, the genetic characteristics of intraductal tubulopapillary neoplasm have not been well characterized. Twenty-two intraductal tubulopapillary neoplasms were analyzed by either targeted next-generation sequencing, which enabled the identification of sequence mutations, copy number alterations, and selected structural rearrangements involving all targeted (≥300) genes, or whole-exome sequencing. Three of these intraductal tubulopapillary neoplasms were also subjected to whole-genome sequencing. All intraductal tubulopapillary neoplasms revealed the characteristic histologic (cellular intraductal nodules of back-to-back tubular glands lined by predominantly cuboidal cells with atypical nuclei and no obvious intracellular mucin) and immunohistochemical (immunolabeled with MUC1 and MUC6 but were negative for MUC2 and MUC5AC) features. By genomic analyses, there was loss of CDKN2A in 5/20 (25%) of these cases. However, the majority of the previously reported intraductal papillary mucinous neoplasm-related alterations were absent. Moreover, in contrast to most ductal neoplasms of the pancreas, MAP-kinase pathway was not involved. In fact, 2/22 (9%) of intraductal tubulopapillary neoplasms did not reveal any mutations in the tested genes. However, certain chromatin remodeling genes (MLL1, MLL2, MLL3, BAP1, PBRM1, EED, and ATRX) were found to be mutated in 7/22 (32%) of intraductal tubulopapillary neoplasms and 27% harbored phosphatidylinositol 3-kinase (PI3K) pathway (PIK3CA, PIK3CB, INPP4A, and PTEN) mutations. In addition, 4/18 (18%) of intraductal tubulopapillary neoplasms had FGFR2 fusions (FGFR2-CEP55, FGFR2-SASS6, DISP1-FGFR2, FGFR2-TXLNA, and FGFR2-VCL) and 1/18 (5.5%) had STRN-ALK fusion. Intraductal tubulopapillary neoplasm is a distinct clinicopathologic entity in the pancreas. Although its intraductal nature and some clinicopathologic features resemble those of intraductal papillary mucinous neoplasm, our results suggest that intraductal tubulopapillary neoplasm has distinguishing genetic characteristics. Some of these mutated genes are potentially targetable. Future functional studies will be needed to determine the consequences of these gene alterations.

Weyand AC, Mody RJ, Rabah RM, Opipari VP
PD-1 inhibition in congenital pigment synthesizing metastatic melanoma.
Pediatr Blood Cancer. 2018; 65(1) [PubMed] Related Publications
A newborn female child was born with a congenital pigment synthesizing melanoma of the scalp. Further workup revealed metastatic disease within the liver, lungs, and left tibia. Whole exome sequencing was performed on multiple samples that revealed one somatic mutation, lysine methyltransferase 2C (KMT2C), at low allelic frequency but no v-Raf murine sarcoma viral oncogene homolog B (BRAF), NF-1 mutation. Programmed death ligand 1 was moderately expressed. Treatment was initiated with the programmed cell death protein 1 inhibitor nivolumab. The patient tolerated this treatment well with minimal toxicity. She is now over a year out from initial diagnosis, continuing on nivolumab, with stable disease.

Froimchuk E, Jang Y, Ge K
Histone H3 lysine 4 methyltransferase KMT2D.
Gene. 2017; 627:337-342 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Histone-lysine N-methyltransferase 2D (KMT2D), also known as MLL4 and MLL2 in humans and Mll4 in mice, belongs to a family of mammalian histone H3 lysine 4 (H3K4) methyltransferases. It is a large protein over 5500 amino acids in size and is partially functionally redundant with KMT2C. KMT2D is widely expressed in adult tissues and is essential for early embryonic development. The C-terminal SET domain is responsible for its H3K4 methyltransferase activity and is necessary for maintaining KMT2D protein stability in cells. KMT2D associates with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX in one protein complex. It acts as a scaffold protein within the complex and is responsible for maintaining the stability of UTX. KMT2D is a major mammalian H3K4 mono-methyltransferase and co-localizes with lineage determining transcription factors on transcriptional enhancers. It is required for the binding of histone H3K27 acetyltransferases CBP and p300 on enhancers, enhancer activation and cell-type specific gene expression during differentiation. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumor suppression. It is frequently mutated in developmental diseases, such as Kabuki syndrome and congenital heart disease, and various forms of cancer. Further understanding of the mechanism through which KMT2D regulates gene expression will reveal why KMT2D mutations are so harmful and may help generate novel therapeutic approaches.

Kawazu M, Kojima S, Ueno T, et al.
Integrative analysis of genomic alterations in triple-negative breast cancer in association with homologous recombination deficiency.
PLoS Genet. 2017; 13(6):e1006853 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
Triple-negative breast cancer (TNBC) cells do not express estrogen receptors, progesterone receptors, or human epidermal growth factor receptor 2. Currently, apart from poly ADP-ribose polymerase inhibitors, there are few effective therapeutic options for this type of cancer. Here, we present comprehensive characterization of the genetic alterations in TNBC performed by high coverage whole genome sequencing together with transcriptome and whole exome sequencing. Silencing of the BRCA1 gene impaired the homologous recombination pathway in a subset of TNBCs, which exhibited similar phenotypes to tumors with BRCA1 mutations; they harbored many structural variations (SVs) with relative enrichment for tandem duplication. Clonal analysis suggested that TP53 mutations and methylation of CpG dinucleotides in the BRCA1 promoter were early events of carcinogenesis. SVs were associated with driver oncogenic events such as amplification of MYC, NOTCH2, or NOTCH3 and affected tumor suppressor genes including RB1, PTEN, and KMT2C. Furthermore, we identified putative TGFA enhancer regions. Recurrent SVs that affected the TGFA enhancer region led to enhanced expression of the TGFA oncogene that encodes one of the high affinity ligands for epidermal growth factor receptor. We also identified a variety of oncogenes that could transform 3T3 mouse fibroblasts, suggesting that individual TNBC tumors may undergo a unique driver event that can be targetable. Thus, we revealed several features of TNBC with clinically important implications.

Melloni GEM, Mazzarella L, Bernard L, et al.
A knowledge-based framework for the discovery of cancer-predisposing variants using large-scale sequencing breast cancer data.
Breast Cancer Res. 2017; 19(1):63 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
BACKGROUND: The landscape of cancer-predisposing genes has been extensively investigated in the last 30 years with various methodologies ranging from candidate gene to genome-wide association studies. However, sequencing data are still poorly exploited in cancer predisposition studies due to the lack of statistical power when comparing millions of variants at once.
METHOD: To overcome these power limitations, we propose a knowledge-based framework founded on the characteristics of known cancer-predisposing variants and genes. Under our framework, we took advantage of a combination of previously generated datasets of sequencing experiments to identify novel breast cancer-predisposing variants, comparing the normal genomes of 673 breast cancer patients of European origin against 27,173 controls matched by ethnicity.
RESULTS: We detected several expected variants on known breast cancer-predisposing genes, like BRCA1 and BRCA2, and 11 variants on genes associated with other cancer types, like RET and AKT1. Furthermore, we detected 183 variants that overlap with somatic mutations in cancer and 41 variants associated with 38 possible loss-of-function genes, including PIK3CB and KMT2C. Finally, we found a set of 19 variants that are potentially pathogenic, negatively correlate with age at onset, and have never been associated with breast cancer.
CONCLUSIONS: In this study, we demonstrate the usefulness of a genomic-driven approach nested in a classic case-control study to prioritize cancer-predisposing variants. In addition, we provide a resource containing variants that may affect susceptibility to breast cancer.

Chakrabarty S, Varghese VK, Sahu P, et al.
Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia.
Br J Cancer. 2017; 117(1):136-143 [PubMed] Article available free on PMC after 08/10/2019 Related Publications
BACKGROUND: Long-standing ulcerative colitis (UC) leading to colorectal cancer (CRC) is one of the most serious and life-threatening consequences acknowledged globally. Ulcerative colitis-associated colorectal carcinogenesis showed distinct molecular alterations when compared with sporadic colorectal carcinoma.
METHODS: Targeted sequencing of 409 genes in tissue samples of 18 long-standing UC subjects at high risk of colorectal carcinoma (UCHR) was performed to identify somatic driver mutations, which may be involved in the molecular changes during the transformation of non-dysplastic mucosa to high-grade dysplasia. Findings from the study are also compared with previously published genome wide and exome sequencing data in inflammatory bowel disease-associated and sporadic colorectal carcinoma.
RESULTS: Next-generation sequencing analysis identified 1107 mutations in 275 genes in UCHR subjects. In addition to TP53 (17%) and KRAS (22%) mutations, recurrent mutations in APC (33%), ACVR2A (61%), ARID1A (44%), RAF1 (39%) and MTOR (61%) were observed in UCHR subjects. In addition, APC, FGFR3, FGFR2 and PIK3CA driver mutations were identified in UCHR subjects. Recurrent mutations in ARID1A (44%), SMARCA4 (17%), MLL2 (44%), MLL3 (67%), SETD2 (17%) and TET2 (50%) genes involved in histone modification and chromatin remodelling were identified in UCHR subjects.
CONCLUSIONS: Our study identifies new oncogenic driver mutations which may be involved in the transition of non-dysplastic cells to dysplastic phenotype in the subjects with long-standing UC with high risk of progression into colorectal neoplasia.

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