KMT2C

Gene Summary

Gene:KMT2C; lysine methyltransferase 2C
Aliases: HALR, MLL3
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:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:histone-lysine N-methyltransferase 2C
Source:NCBIAccessed: 15 March, 2017

Ontology:

What does this gene/protein do?
Show (12)
Pathways:What pathways are this gene/protein implicaed in?
Show (1)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 15 March 2017 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.

  • Cell Cycle
  • Sequence Analysis, RNA
  • Wnt Signaling Pathway
  • MLL
  • Genetic Loci
  • Mutation
  • MicroRNAs
  • Alcohol Drinking
  • ras Proteins
  • Signal Transduction
  • Epigenetics
  • Chromatin
  • Histone-Lysine N-Methyltransferase
  • Phenotype
  • Skin Cancer
  • Cancer Gene Expression Regulation
  • Neoplasm Proteins
  • KMT2A
  • Genomics
  • Single Nucleotide Polymorphism
  • Serine-Arginine Splicing Factors
  • Adenosarcoma
  • DNA Sequence Analysis
  • Risk Factors
  • Phylogeny
  • Squamous Cell Carcinoma
  • RTPCR
  • Esophageal Cancer
  • Chromosome 7
  • Uterine Cancer
  • Neoplasm Metastasis
  • Genetic Predisposition
  • Carcinogenesis
  • Histones
  • Apoptosis
  • MLL3
  • DNA Mutational Analysis
  • Exome
  • High-Throughput Nucleotide Sequencing
  • Recombinational DNA Repair
  • DNA Copy Number Variations
Tag cloud generated 15 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

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)

Yang F, Gong Q, Shi W, et al.
Aberrant DNA methylation of acute myeloid leukemia and colorectal cancer in a Chinese pedigree with a MLL3 germline mutation.
Tumour Biol. 2016; 37(9):12609-12618 [PubMed] Related Publications
Unlike genetic aberrations, epigenetic alterations do not modify the deoxyribonucleic acid (DNA) coding sequence and can be reversed pharmacologically. Identifying a particular epigenetic alteration such as abnormal DNA methylation may provide better understanding of cancers and improve current therapy. In a Chinese pedigree with colorectal carcinoma and acute myeloid leukemia, we examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. DNA methylation status in the four cases, which all harbor a MLL3 germline mutation, differed from that of the normal control, and hypermethylation was more prevalent. Also, more CpG sites were hypermethylated in the acute-phase AML patient than in the AML patient in remission. Fifty-nine hyper- or hypomethylated genes were identified as common to all four cases. Genome-wide DNA methylation analysis demonstrated that differentially methylated sites among acute myeloid leukemia and colorectal carcinoma cases and the control were in both promoters (CpG island) and gene body regions (shelf/shore areas). Hypermethylation was more prevalent in cancer cases. The study supports the suggestion that the level of DNA methylation changes in AML progression.

Deb P, Bhan A, Hussain I, et al.
Endocrine disrupting chemical, bisphenol-A, induces breast cancer associated gene HOXB9 expression in vitro and in vivo.
Gene. 2016; 590(2):234-43 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
HOXB9 is a homeobox-containing gene that plays a key role in mammary gland development and is associated with breast and other types of cancer. Here, we demonstrate that HOXB9 expression is transcriptionally regulated by estradiol (E2), in vitro and in vivo. We also demonstrate that the endocrine disrupting chemical bisphenol-A (BPA) induces HOXB9 expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of ovariectomized (OVX) rats. Luciferase assay showed that estrogen-response-elements (EREs) in the HOXB9 promoter are required for BPA-induced expression. Estrogen-receptors (ERs) and ER-co-regulators such as MLL-histone methylase (MLL3), histone acetylases, CBP/P300, bind to the HOXB9 promoter EREs in the presence of BPA, modify chromatin (histone methylation and acetylation) and lead to gene activation. In summary, our results demonstrate that BPA exposure, like estradiol, increases HOXB9 expression in breast cells both in vitro and in vivo through a mechanism that involves increased recruitment of transcription and chromatin modification factors.

Lu YW, Zhang HF, Liang R, et al.
Colorectal Cancer Genetic Heterogeneity Delineated by Multi-Region Sequencing.
PLoS One. 2016; 11(3):e0152673 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Intratumor heterogeneity (ITH) leads to an underestimation of the mutational landscape portrayed by a single needle biopsy and consequently affects treatment precision. The extent of colorectal cancer (CRC) genetic ITH is not well understood in Chinese patients. Thus, we conducted deep sequencing by using the OncoGxOne™ Plus panel, targeting 333 cancer-specific genes in multi-region biopsies of primary and liver metastatic tumors from three Chinese CRC patients. We determined that the extent of ITH varied among the three cases. On average, 65% of all the mutations detected were common within individual tumors. KMT2C aberrations and the NCOR1 mutation were the only ubiquitous events. Subsequent phylogenetic analysis showed that the tumors evolved in a branched manner. Comparison of the primary and metastatic tumors revealed that PPP2R1A (E370X), SETD2 (I1608V), SMAD4 (G382T), and AR splicing site mutations may be specific to liver metastatic cancer. These mutations might contribute to the initiation and progression of distant metastasis. Collectively, our analysis identified a substantial level of genetic ITH in CRC, which should be considered for personalized therapeutic strategies.

Hembree TN, Teer JK, Hakam A, Chiappori AA
Genetic Investigation of Uterine Carcinosarcoma: Case Report and Cohort Analysis.
Cancer Control. 2016; 23(1):61-6 [PubMed] Related Publications
BACKGROUND: Uterine carcinosarcoma, a rare gynecological malignancy, often presents at the advanced stage with a poor prognosis because current therapies have not improved rates of survival. Genetic characterization of this tumor may lead to novel, specifically targeted drug targets to provide better treatment options for patients with this malignancy.
METHODS: We present a case of a woman aged 61 years with uterine carcinosarcoma and retrospectively analyzed 100 study patients with uterine carcinosarcoma. From this group, 9 study patients underwent targeted sequencing of 1,321 genes.
RESULTS: All 9 study patients had at least 1 mutation in JAK2, KRAS, PIK3CA, CTNNB1, PTEN, FBXW7, TP53, and ERBB2; of these, TP53 was the most frequently mutated gene (6/9). In addition, ARID1A and KMT2C, which have been described and identified as part of a set of chromatin-remodeling genes, were also found in our analyses. From our 100-person cohort clinical analyses, study patients with stage 1 cancer had a median survival rate of 33 months (95% confidence interval, 19-109) compared with a median survival rate of 6 months (95% confidence interval, 3-12) in those with stage 4 disease.
CONCLUSIONS: Disease stage alone predicted the rate of clinical survival. Up to 50% in the study group were identified at having early stage disease (stage 1/2), indicating improved rates of overall detection compared with previously reported data. Our mutational analysis findings add to the number of tumors in which these mutations have been found and suggest that chromatin-remodeling dysregulation may play a role in the tumorigenesis of carcinosarcoma.

Marouf C, Göhler S, Filho MI, et al.
Analysis of functional germline variants in APOBEC3 and driver genes on breast cancer risk in Moroccan study population.
BMC Cancer. 2016; 16:165 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
BACKGROUND: Breast cancer (BC) is the most prevalent cancer in women and a major public health problem in Morocco. Several Moroccan studies have focused on studying this disease, but more are needed, especially at the genetic and molecular levels. Therefore, we investigated the potential association of several functional germline variants in the genes commonly mutated in sporadic breast cancer.
METHODS: In this case-control study, we examined 36 single nucleotide polymorphisms (SNPs) in 13 genes (APOBEC3A, APOBEC3B, ARID1B, ATR, MAP3K1, MLL2, MLL3, NCOR1, RUNX1, SF3B1, SMAD4, TBX3, TTN), which were located in the core promoter, 5'-and 3'UTR or which were nonsynonymous SNPs to assess their potential association with inherited predisposition to breast cancer development. Additionally, we identified a ~29.5-kb deletion polymorphism between APOBEC3A and APOBEC3B and explored possible associations with BC. A total of 226 Moroccan breast cancer cases and 200 matched healthy controls were included in this study.
RESULTS: The analysis showed that12 SNPs in 8 driver genes, 4 SNPs in APOBEC3B gene and 1 SNP in APOBEC3A gene were associated with BC risk and/or clinical outcome at P ≤ 0.05 level. RUNX1_rs8130963 (odds ratio (OR) = 2.25; 95 % CI 1.42-3.56; P = 0.0005; dominant model), TBX3_rs8853 (OR = 2.04; 95 % CI 1.38-3.01; P = 0.0003; dominant model), TBX3_rs1061651 (OR= 2.14; 95 % CI1.43-3.18; P = 0.0002; dominant model), TTN_rs12465459 (OR = 2.02; 95 % confidence interval 1.33-3.07; P = 0.0009; dominant model), were the most significantly associated SNPs with BC risk. A strong association with clinical outcome were detected for the genes SMAD4 _rs3819122 with tumor size (OR = 0.45; 95 % CI 0.25-0.82; P = 0.009) and TTN_rs2244492 with estrogen receptor (OR = 0.45; 95 % CI 0.25-0.82; P = 0.009).
CONCLUSION: Our results suggest that genetic variations in driver and APOBEC3 genes were associated with the risk of BC and may have impact on clinical outcome. However, the reported association between the deletion polymorphism and BC risk was not confirmed in the Moroccan population. These preliminary findings require replication in larger studies.

Yeh CH, Bai XT, Moles R, et al.
Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia.
Mol Cancer. 2016; 15:15 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
BACKGROUND: Epigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated.
METHOD: Here we used whole genome next generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4.
RESULTS: TET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Interestingly, NGS revealed nonsense mutations accompanied by loss of heterozygosity (LOH) in TET2 and MLL3, which was further confirmed by cloning and direct sequencing of DNA from uncultured cells. Finally, direct sequencing of matched control and tumor samples revealed that TET2 mutation was present only in ATL tumor cells.
CONCLUSIONS: Our results suggest that inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced ATL.

Chen D, Gong L, Jiang Q, et al.
Interaction between MLL3 genetic polymorphisms, smoking, and alcohol drinking in laryngeal cancer: a case-control study.
Cancer Med. 2016; 5(3):527-33 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
A previous study indicated that MLL3 genetic polymorphisms were associated with human cancer. However, whether MLL3 genetic variants are associated with the risk of laryngeal cancer is not clear. This study investigated the association between MLL3 gene polymorphisms and laryngeal cancer in a Chinese population. Four polymorphisms of the MLL3 gene (rs6943984, rs4725443, rs3800836, rs6464211) were genotyped using the TaqMan method in 592 patients with larynx cancer and 602 age- and sex-matched noncancer controls. We found that rs6943984 and rs4725443 of the MLL3 gene were significantly associated with the risk of larynx cancer after Bonferroni correction. The minor allele A for rs6943984 was associated with increased larynx cancer risk (P < 0.001, OR = 1.960, 95% CI = 1.587-2.420). C allele frequency (0.151) for rs4725443 was significantly higher in the case group than the control group (0.072, P < 0.001). Haplotype analyses showed that haplotypes A-T-A-C and G-T-G-C increased the risk of laryngeal cancer (OR = 2.406, 95% CI: 1.820-3.180, P < 0.001; OR = 1.399, 95% CI: 1.180-1.659, respectively), and haplotypes G-T-A-C and G-T-G-T significantly reduced the risk of laryngeal cancer (OR = 0.332, 95% CI: 0.271-0.408, P < 0.001; OR = 0.742, 95% CI: 0.607-0.908, respectively). We also found that MLL3 rs6943984 and rs4725443 polymorphisms had synergistic effects with smoking or alcohol drinking for the risk of laryngeal cancer. This study indicated that MLL3 genetic polymorphisms and haplotypes were associated with larynx cancer in a Chinese population. There was a mutually synergistic effect between smoking, alcohol drinking, and MLL3 gene polymorphisms for laryngeal cancer.

Dobashi A, Tsuyama N, Asaka R, et al.
Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type.
Genes Chromosomes Cancer. 2016; 55(5):460-71 [PubMed] Related Publications
Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK-STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer-related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame-shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene.

Park C, Ha SY, Kim ST, et al.
Identification of the BRAF V600E mutation in gastroenteropancreatic neuroendocrine tumors.
Oncotarget. 2016; 7(4):4024-35 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Genomic profiles of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are still insufficiently understood, and the genetic alterations associated with drug responses have not been studied. Here, we performed whole exome sequencing of 12 GEP-NETs from patients enrolled in a nonrandomized, open-labeled, single-center phase II study for pazopanib, and integrated our results with previously published results on pancreas (n = 12) and small intestine NETs (n = 50). The mean numbers of somatic mutations in each case varied widely from 20 to 4682. Among 12 GEP-NETs, eight showed mutations of more than one cancer-related gene, including TP53, CNBD1, RB1, APC, BCOR, BRAF, CTNNB1, EGFR, EP300, ERBB3, KDM6A, KRAS, MGA, MLL3, PTEN, RASA1, SMARCB1, SPEN, TBC1D12, and VHL. TP53 was recurrently mutated in three cases, whereas CNBD1 and RB1 mutations were identified in two cases. Three GEP-NET patients with TP53 mutations demonstrated a durable response and one small intestinal grade (G) 1 NET patient with BRAF V600E mutation showed progression after pazopanib treatment. We found BRAF V600E (G1 NET from rectum and two G3 NETs from colon) and BRAF G593S (G2 NET from pancreas) missense mutations (9.1%) in an independent cohort of 44 GEP-NETs from the rectum (n = 26), colon (n = 7), pancreas (n = 4), small intestine (n = 3), stomach (n = 3) and appendix (n = 1) by Sanger sequencing. All tumor specimens were obtained before chemotherapy. In conclusion, BRAF V600E mutation is likely to result in resistance to pazopanib but may be a potentianally actionable mutation in metastatic GEP-NETs patients.

Goh G, Walradt T, Markarov V, et al.
Mutational landscape of MCPyV-positive and MCPyV-negative Merkel cell carcinomas with implications for immunotherapy.
Oncotarget. 2016; 7(3):3403-15 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine carcinoma, associated with the Merkel cell polyomavirus (MCPyV) in 80% of cases. To define the genetic basis of MCCs, we performed exome sequencing of 49 MCCs. We show that MCPyV-negative MCCs have a high mutation burden (median of 1121 somatic single nucleotide variants (SSNVs) per-exome with frequent mutations in RB1 and TP53 and additional damaging mutations in genes in the chromatin modification (ASXL1, MLL2, and MLL3), JNK (MAP3K1 and TRAF7), and DNA-damage pathways (ATM, MSH2, and BRCA1). In contrast, MCPyV-positive MCCs harbor few SSNVs (median of 12.5 SSNVs/tumor) with none in the genes listed above. In both subgroups, there are rare cancer-promoting mutations predicted to activate the PI3K pathway (HRAS, KRAS, PIK3CA, PTEN, and TSC1) and to inactivate the Notch pathway (Notch1 and Notch2). TP53 mutations appear to be clinically relevant in virus-negative MCCs as 37% of these tumors harbor potentially targetable gain-of-function mutations in TP53 at p.R248 and p.P278. Moreover, TP53 mutational status predicts death in early stage MCC (5-year survival in TP53 mutant vs wild-type stage I and II MCCs is 20% vs. 92%, respectively; P = 0.0036). Lastly, we identified the tumor neoantigens in MCPyV-negative and MCPyV-positive MCCs. We found that virus-negative MCCs harbor more tumor neoantigens than melanomas or non-small cell lung cancers (median of 173, 65, and 111 neoantigens/sample, respectively), two cancers for which immune checkpoint blockade can produce durable clinical responses. Collectively, these data support the use of immunotherapies for virus-negative MCCs.

Villacis RA, Miranda PM, Gomy I, et al.
Contribution of rare germline copy number variations and common susceptibility loci in Lynch syndrome patients negative for mutations in the mismatch repair genes.
Int J Cancer. 2016; 138(8):1928-35 [PubMed] Related Publications
In colorectal carcinoma (CRC), 35% of cases are known to have a hereditary component, while a lower proportion (∼ 5%) can be explained by known genetic factors. In this study, copy number variations (CNVs) were evaluated in 45 unrelated patients with clinical hypothesis of Lynch syndrome (Amsterdam or Bethesda criteria); negative for MLH1, MSH2, MSH6, PMS2, CHEK2*1100delC and TP53 pathogenic mutations; aiming to reveal new predisposing genes. Analyses with two different microarray platforms (Agilent 180K and Affymetrix CytoScan HD) revealed 35 rare CNVs covering 67 known genes in 22 patients. Gains (GALNT6 and GALNT11) and losses (SEMA3C) involving the same gene families related to CRC susceptibility were found among the rare CNVs. Segregation analysis performed on four relatives from one family suggested the involvement of GALNT11 and KMT2C in those at risk of developing CRC. Notably, in silico molecular analysis revealed that 61% (41/67) of the genes covered by rare CNVs were associated with cancer, mainly colorectal (17 genes). Ten common SNPs, previously associated with CRC, were genotyped in 39 index patients and 100 sporadic CRC cases. Although no significant, an increased number of risk alleles was detected in the index cases compared with the sporadic CRC patients. None of the SNPs were covered by CNVs, suggesting an independent effect of each alteration in cancer susceptibility. In conclusion, rare germline CNVs and common SNPs may contribute to an increased risk for hereditary CRC in patients with mismatch repair proficiency.

Piscuoglio S, Burke KA, Ng CK, et al.
Uterine adenosarcomas are mesenchymal neoplasms.
J Pathol. 2016; 238(3):381-8 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Uterine adenosarcomas (UAs) are biphasic lesions composed of a malignant mesenchymal (ie stromal) component and an epithelial component. UAs are generally low-grade and have a favourable prognosis, but may display sarcomatous overgrowth (SO), which is associated with a worse outcome. We hypothesized that, akin to breast fibroepithelial lesions, UAs are mesenchymal neoplasms in which clonal somatic genetic alterations are restricted to the mesenchymal component. To characterize the somatic genetic alterations in UAs and to test this hypothesis, we subjected 20 UAs to a combination of whole-exome (n = 6), targeted capture (n = 13) massively parallel sequencing (MPS) and/or RNA sequencing (n = 6). Only three genes, FGFR2, KMT2C and DICER1, were recurrently mutated, all in 2/19 cases; however, 26% (5/19) and 21% (4/19) of UAs harboured MDM2/CDK4/HMGA2 and TERT gene amplification, respectively, and two cases harboured fusion genes involving NCOA family members. Using a combination of laser-capture microdissection and in situ techniques, we demonstrated that the somatic genetic alterations detected by MPS were restricted to the mesenchymal component. Furthermore, mitochondrial DNA sequencing of microdissected samples revealed that epithelial and mesenchymal components of UAs were clonally unrelated. In conclusion, here we provide evidence that UAs are genetically heterogeneous lesions and mesenchymal neoplasms.

da Silva Almeida AC, Abate F, Khiabanian H, et al.
The mutational landscape of cutaneous T cell lymphoma and Sézary syndrome.
Nat Genet. 2015; 47(12):1465-70 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Sézary syndrome is a leukemic and aggressive form of cutaneous T cell lymphoma (CTCL) resulting from the malignant transformation of skin-homing central memory CD4(+) T cells. Here we performed whole-exome sequencing of tumor-normal sample pairs from 25 patients with Sézary syndrome and 17 patients with other CTCLs. These analyses identified a distinctive pattern of somatic copy number alterations in Sézary syndrome, including highly prevalent chromosomal deletions involving the TP53, RB1, PTEN, DNMT3A and CDKN1B tumor suppressors. Mutation analysis identified a broad spectrum of somatic mutations in key genes involved in epigenetic regulation (TET2, CREBBP, KMT2D (MLL2), KMT2C (MLL3), BRD9, SMARCA4 and CHD3) and signaling, including MAPK1, BRAF, CARD11 and PRKG1 mutations driving increased MAPK, NF-κB and NFAT activity upon T cell receptor stimulation. Collectively, our findings provide new insights into the genetics of Sézary syndrome and CTCL and support the development of personalized therapies targeting key oncogenically activated signaling pathways for the treatment of these diseases.

Patil V, Pal J, Somasundaram K
Elucidating the cancer-specific genetic alteration spectrum of glioblastoma derived cell lines from whole exome and RNA sequencing.
Oncotarget. 2015; 6(41):43452-71 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Cell lines derived from tumor tissues have been used as a valuable system to study gene regulation and cancer development. Comprehensive characterization of the genetic background of cell lines could provide clues on novel genes responsible for carcinogenesis and help in choosing cell lines for particular studies. Here, we have carried out whole exome and RNA sequencing of commonly used glioblastoma (GBM) cell lines (U87, T98G, LN229, U343, U373 and LN18) to unearth single nucleotide variations (SNVs), indels, differential gene expression, gene fusions and RNA editing events. We obtained an average of 41,071 SNVs out of which 1,594 (3.88%) were potentially cancer-specific. The cell lines showed frequent SNVs and indels in some of the genes that are known to be altered in GBM- EGFR, TP53, PTEN, SPTA1 and NF1. Chromatin modifying genes- ATRX, MLL3, MLL4, SETD2 and SRCAP also showed alterations. While no cell line carried IDH1 mutations, five cell lines showed hTERT promoter activating mutations with a concomitant increase in hTERT transcript levels. Five significant gene fusions were found of which NUP93-CYB5B was validated. An average of 18,949 RNA editing events was also obtained. Thus we have generated a comprehensive catalogue of genetic alterations for six GBM cell lines.

Garg M, Nagata Y, Kanojia D, et al.
Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse.
Blood. 2015; 126(22):2491-501 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Acute myeloid leukemia (AML) with an FLT3 internal tandem duplication (FLT3-ITD) mutation is an aggressive hematologic malignancy with a grave prognosis. To identify the mutational spectrum associated with relapse, whole-exome sequencing was performed on 13 matched diagnosis, relapse, and remission trios followed by targeted sequencing of 299 genes in 67 FLT3-ITD patients. The FLT3-ITD genome has an average of 13 mutations per sample, similar to other AML subtypes, which is a low mutation rate compared with that in solid tumors. Recurrent mutations occur in genes related to DNA methylation, chromatin, histone methylation, myeloid transcription factors, signaling, adhesion, cohesin complex, and the spliceosome. Their pattern of mutual exclusivity and cooperation among mutated genes suggests that these genes have a strong biological relationship. In addition, we identified mutations in previously unappreciated genes such as MLL3, NSD1, FAT1, FAT4, and IDH3B. Mutations in 9 genes were observed in the relapse-specific phase. DNMT3A mutations are the most stable mutations, and this DNMT3A-transformed clone can be present even in morphologic complete remissions. Of note, all AML matched trio samples shared at least 1 genomic alteration at diagnosis and relapse, suggesting common ancestral clones. Two types of clonal evolution occur at relapse: either the founder clone recurs or a subclone of the founder clone escapes from induction chemotherapy and expands at relapse by acquiring new mutations. Relapse-specific mutations displayed an increase in transversions. Functional assays demonstrated that both MLL3 and FAT1 exert tumor-suppressor activity in the FLT3-ITD subtype. An inhibitor of XPO1 synergized with standard AML induction chemotherapy to inhibit FLT3-ITD growth. This study clearly shows that FLT3-ITD AML requires additional driver genetic alterations in addition to FLT3-ITD alone.

Jiang Y, Malouf GG, Zhang J, et al.
Long non-coding RNA profiling links subgroup classification of endometrioid endometrial carcinomas with trithorax and polycomb complex aberrations.
Oncotarget. 2015; 6(37):39865-76 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
BACKGROUND: Integrative analysis of endometrioid endometrial carcinoma (EEC) using multiple platforms has distinguished four molecular subgroups. However, the landscape of expressed long non-coding RNAs (lncRNA) and their role in charting EEC subgroups and determining clinical aggressiveness remain largely unknown.
RESULTS: Using stringent criteria, we identified 1,931 expressed lncRNAs and predicted potential drivers through integrative analysis. Unsupervised clustering of lncRNA expression revealed three robust categories: basal-like, luminal-like and CTNNB1-enriched subgroups. Basal-like subgroup was enriched for aggressive tumors with higher pathological grade (p < 0.0001), TNM stage (p = 0.01), and somatic mutations in trithorax-group genes (MLL, MLL2 and MLL3); and it overexpressed polycomb genes EZH2 and CBX2. In contrast to the luminal-like subgroup, progesterone (PGR) and estrogen receptor (ESR1) genes were highly down-regulated in the EEC basal-like subgroup. Consistent with its enrichment for CTNNB1 mutations (69%), lncRNA profile of the CTNNB1-enriched EEC subgroup was highly similar to that of the CTNNB1-enriched liver cancer subgroup.
MATERIALS AND METHODS: We performed integrative analysis of lncRNAs in EEC using The Cancer Genome Atlas (TCGA) molecular RNAseq profiles of 191 primary tumors for which genomic data were also available. We established lncRNA subgroup classification, correlated it with chromatin modifying gene expression, and described correlations between our lncRNA classification and clinico-genomic tumor features.
CONCLUSIONS: Our results reveal the utility of systematic characterization of clinically annotated EEC in three clinically relevant subgroups. They also highlight the convergence of aberrations in polycomb- and trithorax-group genes in aggressive basal EEC subtypes, providing a rationale for further investigation of epigenetic therapy in this setting.

Katoh M
Mutation spectra of histone methyltransferases with canonical SET domains and EZH2-targeted therapy.
Epigenomics. 2016; 8(2):285-305 [PubMed] Related Publications
Germline mutations in canonical SET-methyltransferases have been identified in autism and intellectual disability syndromes and gain-of-function somatic alterations in EZH2, MLL3, NSD1, WHSC1 (NSD2) and WHSC1L1 (NSD3) in cancer. EZH2 interacts with AR, ERα, β-catenin, FOXP3, NF-κB, PRC2, REST and SNAI2, resulting in context-dependent transcriptional activation and repression. Pharmacological EZH2 inhibitors are currently in clinical trials for the treatment of B-cell lymphomas and solid tumors. EZH2 inhibitors might also be applicable in the treatment of SWI/SNF-mutant cancers, reflecting the reciprocal expression of and functional overlap between EZH2 and SMARCA4. Because of the risks for autoimmune diseases, cognitive impairment, cardiomyopathy and myelodysplastic syndrome, EZH2 inhibitors should be utilized for cancer treatment in patients receiving long-term surveillance but not for cancer chemoprevention.

Fang B
RAS signaling and anti-RAS therapy: lessons learned from genetically engineered mouse models, human cancer cells, and patient-related studies.
Acta Biochim Biophys Sin (Shanghai). 2016; 48(1):27-38 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Activating mutations of oncogenic RAS genes are frequently detected in human cancers. The studies in genetically engineered mouse models (GEMMs) reveal that Kras-activating mutations predispose mice to early onset tumors in the lung, pancreas, and gastrointestinal tract. Nevertheless, most of these tumors do not have metastatic phenotypes. Metastasis occurs when tumors acquire additional genetic changes in other cancer driver genes. Studies on clinical specimens also demonstrated that KRAS mutations are present in premalignant tissues and that most of KRAS mutant human cancers have co-mutations in other cancer driver genes, including TP53, STK11, CDKN2A, and KMT2C in lung cancer; APC, TP53, and PIK3CA in colon cancer; and TP53, CDKN2A, SMAD4, and MED12 in pancreatic cancer. Extensive efforts have been devoted to develop therapeutic agents that target enzymes involved in RAS posttranslational modifications, that inhibit downstream effectors of RAS signaling pathways, and that kill RAS mutant cancer cells through synthetic lethality. Recent clinical studies have revealed that sorafenib, a pan-RAF and VEGFR inhibitor, has impressive benefits for KRAS mutant lung cancer patients. Combination therapy of MEK inhibitors with either docetaxel, AKT inhibitors, or PI3K inhibitors also led to improved clinical responses in some KRAS mutant cancer patients. This review discusses knowledge gained from GEMMs, human cancer cells, and patient-related studies on RAS-mediated tumorigenesis and anti-RAS therapy. Emerging evidence demonstrates that RAS mutant cancers are heterogeneous because of the presence of different mutant alleles and/or co-mutations in other cancer driver genes. Effective subclassifications of RAS mutant cancers may be necessary to improve patients' outcomes through personalized precision medicine.

He X, Zhang P
Serine/arginine-rich splicing factor 3 (SRSF3) regulates homologous recombination-mediated DNA repair.
Mol Cancer. 2015; 14:158 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
BACKGROUND: Our previous work found that serine/arginine-rich splicing factor 3 (SRSF3) was overexpressed in human ovarian cancer and the overexpression of SRSF3 was required for ovarian cancer cell growth and survival. The mechanism underlying the role of SRSF3 in ovarian cancer remains to be addressed.
METHODS: We conducted microarray analysis to profile the gene expression and splicing in SRSF3-knockdown cells and employed quantitative PCR and western blotting to validate the profiling results. We used chromatin immunoprecipitation to study transcription and the direct repeat green fluorescent protein reporter assay to study homologous recombination-mediated DNA repair (HRR).
RESULTS: We identified 687 genes with altered expression and 807 genes with altered splicing in SRSF3-knockdown cells. Among expression-altered genes, those involved in HRR, including BRCA1, BRIP1 and RAD51, were enriched and were all downregulated. We demonstrated that the downregulation of BRCA1, BRIP1 and RAD51 expression was caused by decreased transcription and not due to increased nonsense-mediated mRNA decay. Further, we found that SRSF3 knockdown impaired HRR activity in the cell and increased the level of γ-H2AX, a biomarker for double-strand DNA breaks. Finally, we observed that SRSF3 knockdown changed splicing pattern of KMT2C, a H3K4-specific histone methyltransferase, and reduced the levels of mono- and trimethylated H3K4.
CONCLUSION: These results suggest that SRSF3 is a new regulator of HRR process, which possibly regulates the expression of HRR-related genes indirectly through an epigenetic pathway. This new function of SRSF3 not only explains why overexpression of SRSF3 is required for ovarian cancer cell growth and survival but also offers a new insight into the mechanism of the neoplastic transformation.

Abba MC, Gong T, Lu Y, et al.
A Molecular Portrait of High-Grade Ductal Carcinoma In Situ.
Cancer Res. 2015; 75(18):3980-90 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Ductal carcinoma in situ (DCIS) is a noninvasive precursor lesion to invasive breast carcinoma. We still have no understanding on why only some DCIS lesions evolve to invasive cancer whereas others appear not to do so during the life span of the patient. Here, we performed full exome (tumor vs. matching normal), transcriptome, and methylome analysis of 30 pure high-grade DCIS (HG-DCIS) and 10 normal breast epithelial samples. Sixty-two percent of HG-DCIS cases displayed mutations affecting cancer driver genes or potential drivers. Mutations were observed affecting PIK3CA (21% of cases), TP53 (17%), GATA3 (7%), MLL3 (7%) and single cases of mutations affecting CDH1, MAP2K4, TBX3, NF1, ATM, and ARID1A. Significantly, 83% of lesions displayed numerous large chromosomal copy number alterations, suggesting they might precede selection of cancer driver mutations. Integrated pathway-based modeling analysis of RNA-seq data allowed us to identify two DCIS subgroups (DCIS-C1 and DCIS-C2) based on their tumor-intrinsic subtypes, proliferative, immune scores, and in the activity of specific signaling pathways. The more aggressive DCIS-C1 (highly proliferative, basal-like, or ERBB2(+)) displayed signatures characteristic of activated Treg cells (CD4(+)/CD25(+)/FOXP3(+)) and CTLA4(+)/CD86(+) complexes indicative of a tumor-associated immunosuppressive phenotype. Strikingly, all lesions showed evidence of TP53 pathway inactivation. Similarly, ncRNA and methylation profiles reproduce changes observed postinvasion. Among the most significant findings, we observed upregulation of lncRNA HOTAIR in DCIS-C1 lesions and hypermethylation of HOXA5 and SOX genes. We conclude that most HG-DCIS lesions, in spite of representing a preinvasive stage of tumor progression, displayed molecular profiles indistinguishable from invasive breast cancer.

Sausen M, Phallen J, Adleff V, et al.
Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients.
Nat Commun. 2015; 6:7686 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Pancreatic adenocarcinoma has the worst mortality of any solid cancer. In this study, to evaluate the clinical implications of genomic alterations in this tumour type, we perform whole-exome analyses of 24 tumours, targeted genomic analyses of 77 tumours, and use non-invasive approaches to examine tumour-specific mutations in the circulation of these patients. These analyses reveal somatic mutations in chromatin-regulating genes MLL, MLL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival. We observe alterations in genes with potential therapeutic utility in over a third of cases. Liquid biopsy analyses demonstrate that 43% of patients with localized disease have detectable circulating tumour DNA (ctDNA) at diagnosis. Detection of ctDNA after resection predicts clinical relapse and poor outcome, with recurrence by ctDNA detected 6.5 months earlier than with CT imaging. These observations provide genetic predictors of outcome in pancreatic cancer and have implications for new avenues of therapeutic intervention.

Sasaki MM, Skol AD, Bao R, et al.
Integrated genomic analysis suggests MLL3 is a novel candidate susceptibility gene for familial nasopharyngeal carcinoma.
Cancer Epidemiol Biomarkers Prev. 2015; 24(8):1222-8 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
BACKGROUND: Little is known about genetic factors associated with nasopharyngeal carcinoma (NPC). To gain insight into NPC etiology, we performed whole exome sequencing on germline and tumor DNA from three closely related family members with NPC.
METHODS: The family was ascertained through the Pediatric Familial Cancer Clinic at The University of Chicago (Chicago, IL). The diagnosis of NPC was confirmed pathologically for each individual. For each sample sequenced, 97.3% of the exome was covered at 5×, with an average depth of 44×. Candidate germline and somatic variants associated with NPC were identified and prioritized using a custom pipeline.
RESULTS: We discovered 72 rare deleterious germline variants in 56 genes shared by all three individuals. Of these, only three are in previously identified NPC-associated genes, all of which are located within MLL3, a gene known to be somatically altered in NPC. One variant introduces an early stop codon in MLL3, which predicts complete loss-of-function. Tumor DNA analysis revealed somatic mutations and Epstein-Barr virus (EBV) integration events; none, however, were shared among all three individuals.
CONCLUSIONS: These data suggest that inherited mutations in MLL3 may have predisposed these three individuals from a single family to develop NPC, and may cooperate with individually acquired somatic mutations or EBV integration events in NPC etiology.
IMPACT: Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC.

Kongpetch S, Jusakul A, Ong CK, et al.
Pathogenesis of cholangiocarcinoma: From genetics to signalling pathways.
Best Pract Res Clin Gastroenterol. 2015; 29(2):233-44 [PubMed] Related Publications
Cholangiocarcinoma (CCA) is a malignant tumour of bile duct epithelial cells with dismal prognosis and rising incidence. Chronic inflammation resulting from liver fluke infection, hepatitis and other inflammatory bowel diseases is a major contributing factor to cholangiocarcinogenesis, likely through accumulation of serial genetic and epigenetic alterations resulting in aberration of oncogenes and tumour suppressors. Recent studies making use of advances in high-throughput genomics have revealed the genetic landscape of CCA, greatly increasing our understanding of its underlying biology. A series of highly recurrent mutations in genes such as TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 and BAP1, which are known to be involved in cell cycle control, cell signalling pathways and chromatin dynamics, have led to investigations of their roles, through molecular to mouse modelling studies, in cholangiocarcinogenesis. This review focuses on the landscape genetic alterations in CCA and its functional relevance to the formation and progression of CCA.

Ford DJ, Dingwall AK
The cancer COMPASS: navigating the functions of MLL complexes in cancer.
Cancer Genet. 2015; 208(5):178-91 [PubMed] Related Publications
The mixed-lineage leukemia family of histone methyltransferases (MLL1-4, or KMT2A-D) were previously linked to cancer through the founding member, MLL1/KMT2A, which is often involved in translocation-associated gene fusion events in childhood leukemias. However, in recent years, a multitude of tumor exome sequencing studies have revealed that orthologues MLL3/KMT2C and MLL2/KMT2D are mutated in a significant percentage of a large variety of malignancies, particularly solid tumors. These unexpected findings necessitate a deeper inspection into the activities and functional differences between the MLL/KMT2 family members. This review provides an overview of this protein family and its relation to cancers, focusing on the recent links between MLL3/KMT2C and MLL2/4/KMT2D and their potential roles as tumor suppressors in an assortment of cell types.

Jusakul A, Kongpetch S, Teh BT
Genetics of Opisthorchis viverrini-related cholangiocarcinoma.
Curr Opin Gastroenterol. 2015; 31(3):258-63 [PubMed] Related Publications
PURPOSE OF REVIEW: We review the genetic, epigenetic and transcriptional landscape of liver fluke (Opisthorchis viverrini, Ov)-related cholangiocarcinoma (CCA). Its distinct alterations, as compared with non-Ov-related CCA may help shed light on its underlying molecular mechanisms.
RECENT FINDINGS: Recent whole-exome and targeted sequencing not only confirmed frequent mutations in known CCA-related genes including TP53 (44%), KRAS (16.7%) and SMAD4 (16.7%), but also revealed mutations in novel CCA-related genes associated with chromatin remodeling [BAP1 (2.8%), ARID1A (17.6%), MLL3 (13%) and IDH1/2 (2.8%)], WNT signaling [RNF43 (9.3%) and PEG3 (5.6%)] and KRAS/G protein signaling [GNAS (9.3%) and ROBO2 (9.3%)]. Interestingly, there is a significant difference in the frequency of mutated genes between Ov-related CCA and non-Ov-related CCA, such as p53 and IDH1/2, reflecting the impact of cause on pathogenesis. Altered DNA methylation and transcriptional profiles associated with xenobiotic metabolism and pro-inflammatory responses were also found in Ov-related CCA.
SUMMARY: Liver fluke-induced chronic inflammation plays a crucial role in cholangiocarcinogenesis, resulting in distinct signatures of genetic, epigenetic and transcriptional alterations. These alterations, when contrasted with non-Ov-related CCA, indicate a unique pathogenic process in Ov-related CCA and may have potential clinical implications on diagnostics, therapeutics and prevention.

Figueiredo DL, do Amaral Rabello D, Zanette DL, et al.
Assessment of MLL methyltransferase gene expression in larynx carcinoma.
Oncol Rep. 2015; 33(4):2017-22 [PubMed] Related Publications
Larynx cancer is the second most common type of cancer among all head and neck cancers. Deregulation of epigenetic effectors, including altered expression of histone methyltransferases from the MLL (mixed lineage leukemia) family, have been reported in many cancer types, yet little is known concerning their involvement in larynx cancer. Our objective was to determine the expression profile of MLL genes in larynx carcinoma and normal adjacent tissues and correlate this profile to tumor characteristics. We analyzed the expression profile of 5 MLL genes in 13 cases of larynx carcinoma and their adjacent non-tumor tissues using quantitative real-time PCR. MLL3 was significantly downregulated in tumor samples compared to their normal counterparts, and all MLL genes showed decreased expression in advanced tumors compared to tumors in the initial stage. Altered expression in a single MLL gene was associated with a similar alteration in the other MLL genes, revealing a strong correlation of expression in each individual patient. In conclusion, MLL genes may have similar transcriptional control, and decreased expression of these genes may contribute to larynx cancer progression.

Liu L, Kimball S, Liu H, et al.
Genetic alterations of histone lysine methyltransferases and their significance in breast cancer.
Oncotarget. 2015; 6(4):2466-82 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
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.

Graves CA, Jones A, Reynolds J, et al.
Neuroendocrine Merkel cell carcinoma is associated with mutations in key DNA repair, epigenetic and apoptosis pathways: a case-based study using targeted massively parallel sequencing.
Neuroendocrinology. 2015; 101(2):112-9 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
INTRODUCTION: Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma with a poorly understood molecular etiology. We implemented a comprehensive deep sequencing approach to identify mutations in the tumor DNA from a cohort of patients treated at our institution over the past 15 years. Our results indicate mutations that may constitute therapeutic targets in MCC.
METHODS: Five patients were treated for MCC within the study interval. Patients with adequate tissue (n = 4), positive neuroendocrine differentiation (chromogranin, synaptophysin, and cytokeratin 20), and histopathological confirmation of MCC were included in the study. DNA was extracted from archival tumor tissue samples and analyzed by massively parallel sequencing using a targeted, multiplex PCR approach followed by semiconductor sequencing.
RESULTS: We demonstrate high-penetrance nonsense mutations in PDE4DIP (n = 4) as well as various missense mutations in the DNA damage response (PRKDC, AURKB, ERCC5, ATR, and ATRX) and epigenetic modulating enzymes (MLL3).
CONCLUSION: We describe several mutations in potential disease-relevant genes and pathways. These targets should be evaluated in a larger cohort to determine their role in the molecular pathogenesis of MCC.

Hao C, Wang L, Peng S, et al.
Gene mutations in primary tumors and corresponding patient-derived xenografts derived from non-small cell lung cancer.
Cancer Lett. 2015; 357(1):179-85 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
Molecular annotated patient-derived xenograft (PDX) models are useful for the preclinical investigation of anticancer drugs and individualized anticancer therapy. We established 23 PDXs from 88 surgical specimens of lung cancer patients and determined gene mutations in these PDXs and their paired primary tumors by ultradeep exome sequencing on 202 cancer-related genes. The numbers of primary tumors with deleterious mutations in TP53, KRAS, PI3KCA, ALK, STK11, and EGFR were 43.5%, 21.7%, 17.4%, 17.4%, 13.0%, and 8.7%, respectively. Other genes with deleterious mutations in ≥3 (13.0%) primary tumors were MLL3, SETD2, ATM, ARID1A, CRIPAK, HGF, BAI3, EP300, KDR, PDGRRA and RUNX1. Of 315 mutations detected in the primary tumors, 293 (93%) were also detected in their corresponding PDXs, indicating that PDXs have the capacity to recapitulate the mutations in primary tumors. Nevertheless, a substantial number of mutations had higher allele frequencies in the PDXs than in the primary tumors, or were not detectable in the primary tumor, suggesting the possibility of tumor cell enrichment in PDXs or heterogeneity in the primary tumors. The molecularly annotated PDXs generated from this study could be useful for future translational studies.

Pickering CR, Zhou JH, Lee JJ, et al.
Mutational landscape of aggressive cutaneous squamous cell carcinoma.
Clin Cancer Res. 2014; 20(24):6582-92 [PubMed] Article available free on PMC after 30/09/2017 Related Publications
PURPOSE: Aggressive cutaneous squamous cell carcinoma (cSCC) is often a disfiguring and lethal disease. Very little is currently known about the mutations that drive aggressive cSCC.
EXPERIMENTAL DESIGN: Whole-exome sequencing was performed on 39 cases of aggressive cSCC to identify driver genes and novel therapeutic targets. Significantly, mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.
RESULTS: Despite the very high-mutational background caused by UV exposure, 23 candidate drivers were identified, including the well-known cancer-associated genes TP53, CDKN2A, NOTCH1, AJUBA, HRAS, CASP8, FAT1, and KMT2C (MLL3). Three novel candidate tumor suppressors with putative links to cancer or differentiation, NOTCH2, PARD3, and RASA1, were also identified as possible drivers in cSCC. KMT2C mutations were associated with poor outcome and increased bone invasion.
CONCLUSIONS: The mutational spectrum of cSCC is similar to that of head and neck squamous cell carcinoma and dominated by tumor-suppressor genes. These results improve the foundation for understanding this disease and should aid in identifying and treating aggressive cSCC.

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