MYCL

Gene Summary

Gene:MYCL; v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog
Aliases: LMYC, L-Myc, MYCL1, bHLHe38
Location:1p34.2
Summary:-
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:protein L-Myc
HPRD
Source:NCBIAccessed: 06 August, 2015

Ontology:

What does this gene/protein do?
Show (5)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 06 August 2015 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.

  • In Situ Hybridization
  • Nucleic Acid Hybridization
  • Adolescents
  • TP53
  • DNA-Binding Proteins
  • Gene Amplification
  • Transcription Factors
  • Neuroblastoma
  • Heterozygote
  • Proto-Oncogene Proteins
  • Neoplasm Proteins
  • Cerebellar Neoplasms
  • Neoplasm Recurrence, Local
  • Colorectal Cancer
  • DNA Probes
  • Cancer DNA
  • Thyroid Cancer
  • Telomerase
  • Immunoenzyme Techniques
  • Cancer Gene Expression Regulation
  • Genetic Markers
  • Chromosome Mapping
  • Proto-Oncogene Proteins c-myc
  • Precancerous Conditions
  • Disease Progression
  • Chromosome Deletion
  • Chromosome Aberrations
  • myc Genes
  • Medulloblastoma
  • Childhood Cancer
  • Microsatellite Repeats
  • Tumor Markers
  • Lung Cancer
  • Chromosome 1
  • Polymerase Chain Reaction
  • Loss of Heterozygosity
  • Bladder Cancer
  • Cervical Cancer
  • Proto-Oncogenes
  • Restriction Fragment Length Polymorphism
Tag cloud generated 06 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (8)

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: MYCL (cancer-related)

Chayka O, D'Acunto CW, Middleton O, et al.
Identification and pharmacological inactivation of the MYCN gene network as a therapeutic strategy for neuroblastic tumor cells.
J Biol Chem. 2015; 290(4):2198-212 [PubMed] Free Access to Full Article Related Publications
The MYC family of transcription factors consists of three well characterized members, c-MYC, L-MYC, and MYCN, deregulated in the majority of human cancers. In neuronal tumors such as neuroblastoma, MYCN is frequently activated by gene amplification, and reducing its expression by RNA interference has been shown to promote growth arrest and apoptosis of tumor cells. From a clinical perspective, RNA interference is not yet a viable option, and small molecule inhibitors of transcription factors are difficult to develop. We therefore planned to identify, at the global level, the genes interacting functionally with MYCN required to promote fitness of tumor cells facing oncogenic stress. To find genes whose inactivation is synthetically lethal to MYCN, we implemented a genome-wide approach in which we carried out a drop-out shRNA screen using a whole genome library that was delivered into isogenic neuroblastoma cell lines expressing or not expressing MYCN. After the screen, we selected for in-depth analysis four shRNAs targeting AHCY, BLM, PKMYT1, and CKS1B. These genes were chosen because they are directly regulated by MYC proteins, associated with poor prognosis of neuroblastoma patients, and inhibited by small molecule compounds. Mechanistically, we found that BLM and PKMYT1 are required to limit oncogenic stress and promote stabilization of the MYCN protein. Cocktails of small molecule inhibitors of CKS1B, AHCY, BLM, and PKMYT1 profoundly affected the growth of all neuroblastoma cell lines but selectively caused death of MYCN-amplified cells. Our findings suggest that drugging the MYCN network is a promising avenue for the treatment of high risk, neuroblastic cancers.

Khan S, Greco D, Michailidou K, et al.
MicroRNA related polymorphisms and breast cancer risk.
PLoS One. 2014; 9(11):e109973 [PubMed] Free Access to Full Article Related Publications
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval (CI): 0.88-0.96), rs1052532 (OR 0.97; 95% CI: 0.95-0.99), rs10719 (OR 0.97; 95% CI: 0.94-0.99), rs4687554 (OR 0.97; 95% CI: 0.95-0.99, and rs3134615 (OR 1.03; 95% CI: 1.01-1.05) located in the 3' UTR of CASP8, HDDC3, DROSHA, MUSTN1, and MYCL1, respectively. DROSHA belongs to miRNA machinery genes and has a central role in initial miRNA processing. The remaining genes are involved in different molecular functions, including apoptosis and gene expression regulation. Further studies are warranted to elucidate whether the miRNA binding site SNPs are the causative variants for the observed risk effects.

Schaub FX, Cleveland JL
Tipping the MYC-MIZ1 balance: targeting the HUWE1 ubiquitin ligase selectively blocks MYC-activated genes.
EMBO Mol Med. 2014; 6(12):1509-11 [PubMed] Free Access to Full Article Related Publications
MYC family oncoproteins (MYC, N‐MYC and L‐MYC) function as basic helix‐loop‐helix‐leucine zipper (bHLH‐Zip) transcription factors that are activated (i.e., overexpressed) in well over half of all human malignancies (Boxer & Dang, 2001; Beroukhim et al, 2010). In this issue of EMBO Molecular Medicine, Eilers and colleagues (Peter et al, 2014) describe a novel approach to disable MYC, whereby inhibition of the ubiquitin ligase HUWE1 stabilizes MIZ1 and leads to the selective repression of MYC‐activated target genes.

Hoellein A, Fallahi M, Schoeffmann S, et al.
Myc-induced SUMOylation is a therapeutic vulnerability for B-cell lymphoma.
Blood. 2014; 124(13):2081-90 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Myc oncogenic transcription factors (c-Myc, N-Myc, and L-Myc) coordinate the control of cell growth, division, and metabolism. In cancer, Myc overexpression is often associated with aggressive disease, which is in part due to the destruction of select targets by the ubiquitin-proteasome system (eg, SCF(Skp2)-directed destruction of the Cdk inhibitor p27(Kip1)). We reasoned that Myc would also regulate SUMOylation, a related means of posttranslational modification of proteins, and that this circuit would play essential roles in Myc-dependent tumorigenesis. Here, we report marked increases in the expression of genes that encode regulators and components of the SUMOylation machinery in mouse and human Myc-driven lymphomas, resulting in hyper-SUMOylation in these tumors. Further, inhibition of SUMOylation by genetic means disables Myc-induced proliferation, triggering G2/M cell-cycle arrest, polyploidy, and apoptosis. Using genetically defined cell models and conditional expression systems, this response was shown to be Myc specific. Finally, in vivo loss-of-function and pharmacologic studies demonstrated that inhibition of SUMOylation provokes rapid regression of Myc-driven lymphoma. Thus, targeting SUMOylation represents an attractive therapeutic option for lymphomas with MYC involvement.

Varghese AM, Zakowski MF, Yu HA, et al.
Small-cell lung cancers in patients who never smoked cigarettes.
J Thorac Oncol. 2014; 9(6):892-6 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
INTRODUCTION: We describe clinical, pathologic, and molecular characteristics of never-smoker patients with small-cell lung cancers (SCLCs).
METHODS: We identified cases of SCLCs evaluated at our institution from 2005 to 2012. We collected smoking history, demographic, treatment, and survival data. EGFR, KRAS, PIK3CA, ALK testing, RB protein expression, and next generation sequencing were performed on available samples.
RESULTS: Two percent (23 of 1040) of patients with SCLCs were never-smokers. Eighty-three percent (19 of 23) had de novo SCLCs, whereas 17% had SCLC transformation as acquired resistance to erlotinib after treatment for EGFR-mutant lung carcinomas. Median survival from SCLC diagnosis was 23 months. Of de novo SCLCs, ALK rearrangement, KRAS mutations, EGFR mutations, and RB loss were identified in zero of five, zero of eight, two of eight, and six of seven, respectively. Two de novo samples underwent next generation sequencing. One had mutations in p53 and RB1 with amplification in TERT, and a second had mutations in CBL and GNAS with amplification in MYCL1.
CONCLUSIONS: Two percent of patients with SCLCs are never-smokers. Although transformation to SCLC can rarely occur in acquired resistance to erlotinib, 83% of never-smokers with SCLCs had de novo SCLC. RB loss was noted in 86% of cases. Multiplexed genotyping can be performed on tissues to identify potentially actionable oncogenic drivers.

Huijbers IJ, Bin Ali R, Pritchard C, et al.
Rapid target gene validation in complex cancer mouse models using re-derived embryonic stem cells.
EMBO Mol Med. 2014; 6(2):212-25 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Human cancers modeled in Genetically Engineered Mouse Models (GEMMs) can provide important mechanistic insights into the molecular basis of tumor development and enable testing of new intervention strategies. The inherent complexity of these models, with often multiple modified tumor suppressor genes and oncogenes, has hampered their use as preclinical models for validating cancer genes and drug targets. In our newly developed approach for the fast generation of tumor cohorts we have overcome this obstacle, as exemplified for three GEMMs; two lung cancer models and one mesothelioma model. Three elements are central for this system; (i) The efficient derivation of authentic Embryonic Stem Cells (ESCs) from established GEMMs, (ii) the routine introduction of transgenes of choice in these GEMM-ESCs by Flp recombinase-mediated integration and (iii) the direct use of the chimeric animals in tumor cohorts. By applying stringent quality controls, the GEMM-ESC approach proofs to be a reliable and effective method to speed up cancer gene assessment and target validation. As proof-of-principle, we demonstrate that MycL1 is a key driver gene in Small Cell Lung Cancer.

Romero OA, Torres-Diz M, Pros E, et al.
MAX inactivation in small cell lung cancer disrupts MYC-SWI/SNF programs and is synthetic lethal with BRG1.
Cancer Discov. 2014; 4(3):292-303 [PubMed] Related Publications
Our knowledge of small cell lung cancer (SCLC) genetics is still very limited, amplification of L-MYC, N-MYC, and C-MYC being some of the well-established gene alterations. Here, we report our discovery of tumor-specific inactivation of the MYC-associated factor X gene, MAX, in SCLC. MAX inactivation is mutually exclusive with alterations of MYC and BRG1, the latter coding for an ATPase of the switch/sucrose nonfermentable (SWI/SNF) complex. We demonstrate that BRG1 regulates the expression of MAX through direct recruitment to the MAX promoter, and that depletion of BRG1 strongly hinders cell growth, specifically in MAX-deficient cells, heralding a synthetic lethal interaction. Furthermore, MAX requires BRG1 to activate neuroendocrine transcriptional programs and to upregulate MYC targets, such as glycolysis-related genes. Finally, inactivation of the MAX dimerization protein, MGA, was also observed in both non-small cell lung cancer and SCLC. Our results provide evidence that an aberrant SWI/SNF-MYC network is essential for lung cancer development.

Stessman HA, Mansoor A, Zhan F, et al.
Bortezomib resistance can be reversed by induced expression of plasma cell maturation markers in a mouse in vitro model of multiple myeloma.
PLoS One. 2013; 8(10):e77608 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Multiple myeloma (MM), the second most common hematopoietic malignancy, remains an incurable plasma cell (PC) neoplasm. While the proteasome inhibitor, bortezomib (Bz) has increased patient survival, resistance represents a major treatment obstacle as most patients ultimately relapse becoming refractory to additional Bz therapy. Current tests fail to detect emerging resistance; by the time patients acquire resistance, their prognosis is often poor. To establish immunophenotypic signatures that predict Bz sensitivity, we utilized Bz-sensitive and -resistant cell lines derived from tumors of the Bcl-X(L)/Myc mouse model of PC malignancy. We identified significantly reduced expression of two markers (CD93, CD69) in "acquired" (Bz-selected) resistant cells. Using this phenotypic signature, we isolated a subpopulation of cells from a drug-naïve, Bz-sensitive culture that displayed "innate" resistance to Bz. Although these genes were identified as biomarkers, they may indicate a mechanism for Bz-resistance through the loss of PC maturation which may be induced and/or selected by Bz. Significantly, induction of PC maturation in both "acquired" and "innate" resistant cells restored Bz sensitivity suggesting a novel therapeutic approach for reversing Bz resistance in refractory MM.

Roussel MF, Robinson GW
Role of MYC in Medulloblastoma.
Cold Spring Harb Perspect Med. 2013; 3(11) [PubMed] Related Publications
Since its discovery as an oncogene carried by the avian acute leukemia virus MC29 in myelocytomatosis (Roussel et al. 1979) and its cloning (Vennstrom et al. 1982), c-MYC (MYC), as well as its paralogs MYCN and MYCL1, has been shown to play essential roles in cycling progenitor cells born from proliferating zones during embryonic development, and in all proliferating cells after birth. MYC deletion induces cell-cycle exit or cell death, depending on the cell type and milieu, whereas MYC and MYCN amplification or overexpression promotes cell proliferation and occurs in many cancers. Here, we review the relationship of MYC family proteins to the four molecularly distinct medulloblastoma subgroups, discuss the possible roles MYC plays in each of these subgroups and in the developing cells of the posterior fossa, and speculate on possible therapeutic strategies targeting MYC.

Iwakawa R, Takenaka M, Kohno T, et al.
Genome-wide identification of genes with amplification and/or fusion in small cell lung cancer.
Genes Chromosomes Cancer. 2013; 52(9):802-16 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
To obtain a landscape of gross genetic alterations in small cell lung cancer (SCLC), genome-wide copy number analysis and whole-transcriptome sequencing were performed in 58 and 42 SCLCs, respectively. Focal amplification of known oncogene loci, MYCL1 (1p34.2), MYCN (2p24.3), and MYC (8q24.21), was frequently and mutually exclusively detected. MYCL1 and MYC were co-amplified with other regions on either the same or the different chromosome in several cases. In addition, the 9p24.1 region was identified as being amplified in SCLCs without amplification of MYC family oncogenes. Notably, expression of the KIAA1432 gene in this region was significantly higher in KIAA1432 amplified cells than in non-amplified cells, and its mRNA expression showed strong correlations with the copy numbers. Thus, KIAA1432 is a novel gene activated by amplification in SCLCs. By whole-transcriptome sequencing, a total of 60 fusion transcripts, transcribed from 95 different genes, were identified as being expressed in SCLC cells. However, no in-frame fusion transcripts were recurrently detected in ≥2 SCLCs, and genes in the amplified regions, such as PVT1 neighboring MYC and RLF in MYCL1 amplicons, were recurrently fused with genes in the same amplicons or with those in different amplicons on either the same or different chromosome. Thus, it was indicated that amplification and fusion of several genes on chromosomes 1 and 8 occur simultaneously but not sequentially through chromothripsis in the development of SCLC, and amplification rather than fusion of genes plays an important role in its development.

Chen S, Zheng Z, Tang J, et al.
Association of polymorphisms and haplotype in the region of TRIT1, MYCL1 and MFSD2A with the risk and clinicopathological features of gastric cancer in a southeast Chinese population.
Carcinogenesis. 2013; 34(5):1018-24 [PubMed] Related Publications
To explore the association of polymorphisms in the region of three neighboring genes TRIT1, MYCL1 and MFSD2A with risk and clinicopathological features of gastric cancer, 19 tagging SNPs in this region were genotyped using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in a case-control study of 610 Chinese gastric cancer patients and 608 cancer-free controls. MFSD2A rs4233508 T>C CC genotype was associated with an increased risk of gastric cancer in younger patients and an increased risk of moderately/well-differentiated intestinal-type gastric cancer (adjusted odds ratio [OR], 1.74 and 1.50, respectively). TRIT1 rs11581557 T>G TG was associated with lymph node metastasis (TG versus TT/GG, adjusted OR, 1.64). MFSD2A rs12083239 GC genotype and TRIT1 rs2172362 or rs230310 homozygous genotype were associated with Lauren's classification (GC versus GG, adjusted OR, 1.69; GC versus GG/CC, adjusted OR, 1.74) and tumor site (rs2172362: CC versus CT, adjusted OR, 1.71; CC/TT versus CT, adjusted OR, 1.62; rs230310: CC versus CT, adjusted OR, 1.75; CC/TT versus CT, adjusted OR, 1.67) of gastric cancer, respectively. One TRIT1 haplotype, CCGT, was associated with lymph node metastasis and tumor site of gastric cancer (CCGT versus TTTT, adjusted OR, 1.91 and 1.55). This is believed to be the first report that several tagging SNPs and haplotypes in TRIT1, MYCL1 and MFSD2A region are significantly associated with risk and clinicopathological features of gastric cancer in a Chinese population. The findings might be useful for risk assessment and prognosis prediction of gastric cancer.

Ninomiya H, Kato M, Sanada M, et al.
Allelotypes of lung adenocarcinomas featuring ALK fusion demonstrate fewer onco- and suppressor gene changes.
BMC Cancer. 2013; 13:8 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: A subset of lung adenocarcinomas harboring an EML4-ALK fusion gene resulting in dominant oncogenic activity has emerged as a target for specific therapy. EML4-ALK fusion confers a characteristic histology and is detected more frequently in never or light smokers and younger patients.
METHODS: To gain insights into etiology and carcinogenic mechanisms we conducted analyses to compare allelotypes of 35 ALK fusion-positive and 95 -negative tumours using single nucleotide polymorphism (SNP) arrays and especially designed software which enabled precise global genomic profiling.
RESULTS: Overall aberration numbers (gains + losses) of chromosomal alterations were 8.42 and 9.56 in tumours with and without ALK fusion, respectively, the difference not being statistically significant, although patterns of gain and loss were distinct. Interestingly, among selected genomic regions, oncogene-related examples such as 1p34.3(MYCL1), 7q11.2(EGFR), 7p21.1, 8q24.21(MYC), 16p13.3, 17q12(ERBB2) and 17q25.1 showed significantly less gain. Also, changes in tumour suppressor gene-related regions, such as 9p21.3 (CDKN2A) 9p23-24.1 (PTPRD), 13q14.2 (RB1), were significantly fewer in tumours with ALK fusion.
CONCLUSION: Global genomic comparison with SNP arrays showed tumours with ALK fusion to have fewer alterations in oncogenes and suppressor genes despite a similar overall aberration frequency, suggesting very strong oncogenic potency of ALK activation by gene fusion.

Rudin CM, Durinck S, Stawiski EW, et al.
Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.
Nat Genet. 2012; 44(10):1111-6 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in ∼27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.

Hook KE, Garza SJ, Lira ME, et al.
An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735.
Mol Cancer Ther. 2012; 11(3):710-9 [PubMed] Related Publications
PF-03814735 is a novel, reversible inhibitor of Aurora kinases A and B that finished a phase I clinical trial for the treatment of advanced solid tumors. To find predictive biomarkers of drug sensitivity, we screened a diverse panel of 87 cancer cell lines for growth inhibition upon PF-03814735 treatment. Small cell lung cancer (SCLC) and, to a lesser extent, colon cancer lines were very sensitive to PF-03814735. The status of the Myc gene family and retinoblastoma pathway members significantly correlated with the efficacy of PF-03814735. Whereas RB1 inactivation, intact CDKN2A/p16, and normal CCND1/Cyclin D1 status are hallmarks of SCLC, activation or amplification of any of the three Myc genes (MYC, MYCL1, and MYCN) clearly differentiated cell line sensitivity within the SCLC panel. By contrast, we found that expression of Aurora A and B were weak predictors of response. We observed a decrease in histone H3 phosphorylation and polyploidization of sensitive lines, consistent with the phenotype of Aurora B inhibition. In vivo experiments with two SCLC xenograft models confirmed the sensitivity of Myc gene-driven models to PF-03814735 and a possible schedule dependence of MYC/c-Myc-driven tumors. Altogether our results suggest that SCLC and other malignancies driven by the Myc family genes may be suitable indications for treatment by Aurora B kinase inhibitors.

Yan X, Li F, Dozmorov I, et al.
External Qi of Yan Xin Qigong induces cell death and gene expression alterations promoting apoptosis and inhibiting proliferation, migration and glucose metabolism in small-cell lung cancer cells.
Mol Cell Biochem. 2012; 363(1-2):245-55 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Small-cell lung cancer (SCLC) is a highly malignant carcinoma with poor long-term survival. Effective treatment remains highly demanded. In the present study, we demonstrated that External Qi of Yan Xin Qigong (YXQ-EQ) exerted potent cytotoxic effect towards SCLC cell line NCI-H82 via induction of apoptosis. Global gene expression profiling identified 39 genes whose expression was altered by YXQ-EQ in NCI-82 cells. Among them, semi-quantitative RT-PCR and real-time qPCR analyses confirmed that the gene expression levels of apoptotic proteins death-associated protein kinase 2 and cell death-inducing DFFA-like effector b were upregulated, whereas that of oncoproteins DEK and MYCL1, cell migration-promoting proteins CD24 and integrin-alpha 9, and glycolytic enzyme aldolase A were downregulated. These findings suggest that YXQ-EQ may exert anticancer effect through modulating gene expression in a way that facilitates cancer cell apoptosis while represses proliferation, metastasis, and glucose metabolism.

Ryan SL, Schwalbe EC, Cole M, et al.
MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma.
Acta Neuropathol. 2012; 123(4):501-13 [PubMed] Related Publications
The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.

Allen TD, Rodriguez EM, Jones KD, Bishop JM
Activated Notch1 induces lung adenomas in mice and cooperates with Myc in the generation of lung adenocarcinoma.
Cancer Res. 2011; 71(18):6010-8 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Notch1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) and, recently, have been found in non-small-cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated Notch1 in the lung by developing a transgenic mouse model in which activated Notch1 was overexpressed in the alveolar epithelium. The initial response to activated Notch1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas appeared in the transgenic mice but failed to progress to become carcinomas. Interestingly, Myc and MycL1 were expressed in the adenomas, suggesting that selection for enhanced Myc activity may facilitate tumorigenesis. Using mice engineered to coexpress activated Notch1 and Myc, we found that supplementing Myc expression resulted in increased frequency of Notch1 intracellular domain (N1ICD)-induced adenoma formation and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by Myc and/or activated Notch1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated Notch1 substitutes for RAS activation synergistically with Myc in the development of NSCLC. These tumor models should be valuable for exploring the role of activated Notch1 in the genesis of NSCLC and for testing therapies targeting either activated Notch1 or its downstream effectors.

Colombo F, Falvella FS, Galvan A, et al.
A 5'-region polymorphism modulates promoter activity of the tumor suppressor gene MFSD2A.
Mol Cancer. 2011; 10:81 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND: The MFSD2A gene maps within a linkage disequilibrium block containing the MYCL1-EcoRI polymorphism associated with prognosis and survival in lung cancer patients. Survival discrepancies between Asians and Caucasians point to ethnic differences in allelic frequencies of the functional genetic variations.
RESULTS: Analysis of three single-nucleotide polymorphisms (SNPs) mapping in the MFSD2A 5'-regulatory region using a luciferase reporter system showed that SNP rs12072037, in linkage disequilibrium with the MYCL1-EcoRI polymorphism and polymorphic in Asians but not in Caucasians, modulated transcriptional activity of the MFSD2A promoter in cell lines expressing AHR and ARNT transcription factors, which potentially bind to the SNP site.
CONCLUSION: SNP rs12072037 modulates MFSD2A promoter activity and thus might affect MFSD2A levels in normal lung and in lung tumors, representing a candidate ethnically specific genetic factor underlying the association between the MYCL1 locus and lung cancer patients' survival.

Xiong F, Wu C, Chang J, et al.
Genetic variation in an miRNA-1827 binding site in MYCL1 alters susceptibility to small-cell lung cancer.
Cancer Res. 2011; 71(15):5175-81 [PubMed] Related Publications
Genetic variations in microRNAs (miRNA) that affect control of their target genes may alter individual susceptibilities to cancer. In this study, we took an in silico approach to identify single-nucleotide polymorphisms (SNP) within the 3'-untranslated region (UTR) of miRNA genes deregulated in human small-cell lung cancer (SCLC), and then investigated their associations with SCLC susceptibility in 666 SCLC patients and 758 controls. Odds ratios (OR) were estimated by multivariate logistic regression, and biochemical assays were conducted to investigate SNP functions. We identified 2 SNPs, rs3134615 and rs2291854, which were located in the 3'-UTR of the L-MYC gene MYCL1 and the neuronal development Achaete-Scute Complex homolog ASCL1. Case-control analyses showed that the rs3134615T allele was associated with a significantly increased risk of SCLC, with the OR for carrying the GT or TT genotype being 2.08 (95% confidence interval, 1.39-3.21; P = 0.0004) compared with the GG genotype. In support of the likelihood that these 3'-UTR SNPs may directly affect miRNA-binding sites, reporter gene assays indicated MYCL1 as the target of hsa-miR-1827 and the rs3134615 G>T change resulted in altered regulation of MYCL1 expression. Our findings define a 3'-UTR SNP in the human L-MYC oncogene that may increase susceptibility to SCLC, possibly resulting from attenuated interaction with the miRNA hsa-miR-1827.

Wasylishen AR, Stojanova A, Oliveri S, et al.
New model systems provide insights into Myc-induced transformation.
Oncogene. 2011; 30(34):3727-34 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
The ability of Myc to promote cellular transformation is well established; however, a better understanding of the mechanisms through which Myc mediates tumorigenesis is essential for the development of therapeutic approaches to target this potent oncoprotein. Structure-function studies in rodent fibroblast cells have provided the basis for much of our current understanding of these mechanisms. To build on these approaches, we have characterized three novel human cell line models of Myc-dependent transformation: MCF10A, SH-EP Tet21/N-Myc, and LF1/TERT/LT/ST cells. We have also evaluated Myc family proteins (c-Myc and L-Myc), a naturally occurring isoform of Myc (MycS), and a set of N-terminal domain mutants (ΔMBII, W135E, T58A) for their ability to promote anchorage-independent growth in these models. Taken together, these results provide the field with three new human cell-based models to study Myc activity, highlight the importance of cellular context, and challenge the paradigm that the ability of Myc to promote tumorigenesis is exclusively MBII-dependent.

Chen SQ, Lin XD, Zhu JW, et al.
Association of a MYCL1 single nucleotide polymorphism, rs3134613, with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer in a southeast Chinese population.
DNA Cell Biol. 2010; 29(12):739-43 [PubMed] Related Publications
A MYCL1 single nucleotide polymorphism, rs3134613, has been reported to play an important role in many cancers. However, its involvement in gastric cancer is controversial. The aim of the study was to investigate the influence of rs3134613 on the development and progression of gastric cancer in a southeast Chinese population. Genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism in 317 gastric cancer patients and 200 cancer-free controls. Data show that the risk of diffuse-type gastric cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted odds ratio [OR] = 2.601, 95% confidence interval [CI] = 1.431-4.895, p = 0.003). The risk of diffuse-type gastric cancer in T allele carriers was higher than that in G allele carriers (adjusted OR = 1.594, 95% CI = 1.157-2.286, p = 0.009). The risk of poorly differentiated cancer in carriers with the T allele (T/T or G/T genotype) was higher than that in carriers with the G/G genotype (adjusted OR = 1.963, 95% CI = 1.156-3.325, p = 0.015). The results demonstrate that rs3134613 is associated with susceptibility to diffuse-type gastric cancer and with differentiation of gastric cancer. rs3134613 may be used as a potential marker to identify individuals who are at high risk of diffuse-type gastric cancer.

Lee SY, Chung H, Devaraj B, et al.
Microsatellite alterations at selected tetranucleotide repeats are associated with morphologies of colorectal neoplasias.
Gastroenterology. 2010; 139(5):1519-25 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
BACKGROUND & AIMS: Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) occurs during microsatellite instability (MSI) that is not associated with major defects in DNA mismatch repair (MMR) but rather the reduced (heterogenous) expression of the MMR protein hMSH3; it occurs in sporadic colorectal tumors. We examined the timing of development of EMAST during progression of colorectal neoplasias and looked for correlations between EMAST and clinical and pathology features of tumors.
METHODS: We evaluated tumor samples from a cohort of patients that had 24 adenomas and 84 colorectal cancers. EMAST were analyzed after DNA microdissection of matched normal and tumor samples using the polymorphic tetranucleotide microsatellite markers MYCL1, D9S242, D20S85, D8S321, and D20S82; data were compared with clinical and pathology findings. Traditional MSI analysis was performed and hMSH3 expression was measured.
RESULTS: Moderately differentiated adenocarcinomas and poorly differentiated adenocarcinomas had higher frequencies of EMAST (56.9% and 40.0%, respectively) than well-differentiated adenocarcinomas (12.5%) or adenomas (33.3%) (P = .040). In endoscopic analysis, ulcerated tumors had a higher frequency of EMAST (52.3%) than flat (44.0%) or protruded tumors (20.0%) (P = .049). In quantification, all tumors with >3 tetranucleotide defects lost MSH3 (>75% of cells); nuclear heterogeneity of hMSH3 occurred more frequently in EMAST-positive (40.0%) than in EMAST-negative tumors (13.2%) (P = .010).
CONCLUSIONS: EMAST is acquired during progression of adenoma and well-differentiated carcinomas to moderately and poorly differentiated carcinomas; it correlates with nuclear heterogeneity for hMSH3. Loss of hMSH3 corresponds with multiple tetranucleotide frameshifts. The association between EMAST and ulcerated tumors might result from increased inflammation.

Albihn A, Johnsen JI, Henriksson MA
MYC in oncogenesis and as a target for cancer therapies.
Adv Cancer Res. 2010; 107:163-224 [PubMed] Related Publications
MYC proteins (c-MYC, MYCN, and MYCL) regulate processes involved in many if not all aspects of cell fate. Therefore, it is not surprising that the MYC genes are deregulated in several human neoplasias as a result from genetic and epigenetic alterations. The near "omnipotency" together with the many levels of regulation makes MYC an attractive target for tumor intervention therapy. Here, we summarize some of the current understanding of MYC function and provide an overview of different cancer forms with MYC deregulation. We also describe available treatments and highlight novel approaches in the pursuit for MYC-targeting therapies. These efforts, at different stages of development, constitute a promising platform for novel, more specific treatments with fewer side effects. If successful a MYC-targeting therapy has the potential for tailored treatment of a large number of different tumors.

Hishida A, Terazawa T, Mamiya T, et al.
Efficacy of genotype notification to Japanese smokers on smoking cessation--an intervention study at workplace.
Cancer Epidemiol. 2010; 34(1):96-100 [PubMed] Related Publications
OBJECTIVES: It is well-known that smoking causes many diseases including cancers. Informing smokers of their genotypes associated with the vulnerability to the harms of smoking may be effective measures for smoking cessation. The present study examined the effects of genotype notification of an oncogene (L-myc) genotype to smokers on their behavior to quit smoking.
METHODS: Subjects were 562 employees of a bank who answered to be a smoker for a questionnaire used at annual health checkup at workplace from July to December 2002. Those enrolled on August, October, and December were allocated into the genotype notification group (intervention group), and the rest into the controls. Among 286 smokers allocated into the intervention group, 257 participants (89.9%) agreed to genotype testing. One year after the enrollment, a follow-up questionnaire survey was conducted for all smokers including controls.
RESULTS: Those who stated to have quitted smoking were 22 (8.0%) among the 276 controls and 15 (5.8%) among the 257 genotype notified participants, providing that the odds ratio (OR) of cessation for the intervention was 0.64 (95% confidence interval, 0.32-1.28). No psychological problems associated with genotype notification were observed.
CONCLUSION: The present study did not show positive effects of genotype notification on smoking cessation rate. To elevate the cessation rate, methods to explain and notify genotypes should be improved.

Bektas-Kayhan K, Unür M, Yaylim-Eraltan I, et al.
Role of L-MYC polymorphism in oral squamous cell carcinoma in Turkey.
Anticancer Res. 2009; 29(7):2519-24 [PubMed] Related Publications
BACKGROUND: An association between restriction fragment length polymorphism (RFLP) of known oncogenes and a predisposition to develop cancer has been postulated. Our aim was to test the hypothesis that there was an association between the L-MYC S allele in oral squamous cell carcinoma (OSCC) and a predisposition for the disease.
PATIENTS AND METHODS: The distribution of L-MYC polymorphism in 80 patients with OSCC was determined by polymerase chain reaction-based RFLP and compared with that of 60 healthy controls.
RESULTS: There was no significant difference between patients with OSCC and healthy controls. Patients with the L-MYC S allele and a positive family history of cancer were found to be 1.74 times more at risk for OSCC than those with any other genotype (95% confidence interval=0.88-3.45). Moreover, tumor recurrence was higher among individuals carrying a L-MYC S allele than those with any other allele type.
CONCLUSION: L-MYC polymorphism was not a significant marker for predicting susceptibility to OSCC in this population but may be a useful marker for identifying patient susceptibility to tumor recurrence and to developing OSCC, especially in individuals having a family history of cancer.

Gao L, Nieters A, Brenner H
Cell proliferation-related genetic polymorphisms and gastric cancer risk: systematic review and meta-analysis.
Eur J Hum Genet. 2009; 17(12):1658-67 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Apart from Helicobacter pylori infection and lifestyle factors, host genetic susceptibility has been suggested to contribute to individual variation in gastric cancer risk as well. Aiming to evaluate the associations between host cell proliferation-related genetic polymorphisms and gastric cancer susceptibility, we reviewed the related studies published until 15 September 2008 and quantitatively summarized the associations of the most widely studied polymorphisms (TP53 Arg72Pro, L-myc EcoRI) using meta-analysis. Fifty-five eligible studies were included in this review. Twenty-three polymorphisms significantly related to gastric cancer risk in at least one study were identified. Polymorphisms determining higher levels of growth factors, which are important for tissue repair, were recently observed to be associated with reduced risk of gastric cancer. In the meta-analysis, TP53 72Pro was associated with increased risk of diffuse gastric cancer among Asians (OR, 1.44; 95% CI, 1.04-1.99), but decreased risk of intestinal gastric cancer among Caucasians (OR, 0.56; 95% CI, 0.36-0.89). This review suggests that cell proliferation-related genetic polymorphisms could be candidate biomarkers of gastric cancer risk, but current evidence for the use for risk stratification is still very limited. Modestly significant associations in meta-analyses stratified by population or type of gastric cancer may be observed by chance because of the limited number of studies and small sample size. Larger studies are warranted to clarify the effect of cell proliferation-related genetic polymorphisms on gastric carcinogenesis.

Paulson KG, Lemos BD, Feng B, et al.
Array-CGH reveals recurrent genomic changes in Merkel cell carcinoma including amplification of L-Myc.
J Invest Dermatol. 2009; 129(6):1547-55 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer with poorly characterized genetics. We performed high resolution comparative genomic hybridization on 25 MCC specimens using a high-density oligonucleotide microarray. Tumors frequently carried extra copies of chromosomes 1, 3q, 5p, and 6 and lost chromosomes 3p, 4, 5q, 7, 10, and 13. MCC tumors with less genomic aberration were associated with improved survival (P=0.04). Tumors from 13 of 22 MCC patients had detectable Merkel cell polyomavirus DNA, and these tumors had fewer genomic deletions. Three regions of genomic alteration were of particular interest: a deletion of 5q12-21 occurred in 26% of tumors, a deletion of 13q14-21 was recurrent in 26% of tumors and contains the well-characterized tumor suppressor RB1, and a previously unreported focal amplification at 1p34 was present in 39% of tumors and centers on L-Myc (MYCL1). L-Myc is related to the c-Myc proto-oncogene, has transforming activity, and is amplified in the closely related small cell lung cancer. Normal skin showed no L-Myc expression, whereas 4/4 MCC specimens tested expressed L-Myc RNA in relative proportion to the DNA copy number gain. These findings suggest several genes that may contribute to MCC pathogenesis, most notably L-Myc.

Eilers M, Eisenman RN
Myc's broad reach.
Genes Dev. 2008; 22(20):2755-66 [PubMed] Article available free on PMC after 25/09/2015 Related Publications
The role of the myc gene family in the biology of normal and cancer cells has been intensively studied since the early 1980s. myc genes, responding to diverse external and internal signals, express transcription factors (c-, N-, and L-Myc) that heterodimerize with Max, bind DNA, and modulate expression of a specific set of target genes. Over the last few years, expression profiling, genomic binding studies, and genetic analyses in mammals and Drosophila have led to an expanded view of Myc function. This review is focused on two major aspects of Myc: the nature of the genes and pathways that are targeted by Myc, and the role of Myc in stem cell and cancer biology.

Gözü A, Ergen A, Dayicioglu D, et al.
L-myc polymorphism in head and neck nonmelanoma skin and lower lip cancers.
Arch Otolaryngol Head Neck Surg. 2008; 134(7):725-8 [PubMed] Related Publications
OBJECTIVE: To evaluate the presence of L-myc gene variations as a genetic predisposition to head and neck nonmelanoma skin cancer (HNNMSC) and lower lip cancer (LLC).
DESIGN: A case-control study.
SETTING: An academic institute laboratory.
PARTICIPANTS: Twenty-four patients with HNNMSC and 27 with LLC were compared with 51 age- and sex-matched control subjects.
MAIN OUTCOME MEASURES: Polymerase chain reaction restriction fragment length polymorphism and agarose gel electrophoresis were used to determine the L-myc oncogene genotypes.
RESULTS: The presence of the LS genotype was found to be significantly increased in the study group, whereas the LL genotype was not detected. The S allele was also more frequent in the study group. The SS genotype was found to correlate with aggressive tumor behavior in patients with HNNMSC and a family history of cancer. Patients with LLC displayed significantly less of the SS genotype.
CONCLUSIONS: The L-myc gene polymorphism may help detect and prevent HNNMSC and LLC in susceptible individuals. It may also contribute to estimation of tumor behavior in patients with HNNMSC.

Yaylim-Eraltan I, Bozkurt N, Ergen A, et al.
L-myc gene polymorphism and risk of thyroid cancer.
Exp Oncol. 2008; 30(2):117-20 [PubMed] Related Publications
UNLABELLED: L-myc gene polymorphism is a representative genetic trait responsible for an individual's susceptibility to several cancers. However, there have been no reports concerning the association between thyroid cancer and L-myc gene polymorphism.
AIM: To analyze the distribution of L-myc gene polymorphism in Turkish patients with thyroid disorders and thyroid cancers.
METHODS: We used a molecular genotyping method, polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). We studied 138 patients of whom 47 had multinodular goiter, 13 had follicular cancer and 69 had papillar cancer, in comparison with control group of 109 healthy individuals.
RESULTS: No significant difference in the distribution of genotypes was observed between thyroid patients and controls. Carrying SS or LS genotype revealed a 1.96-fold (95% CI 0.573-6.706) risk for the occurrence of follicular cancer when compared with controls, and 3.11-fold (95% CI 0.952-10.216), when compared with multinodular goiter patients (p=0.04).
CONCLUSION: We suggest that L-myc genotype profiling together with other susceptibility factors, may be useful in the screening for thyroid nodular malignancy.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. MYCL1 gene, Cancer Genetics Web: http://www.cancer-genetics.org/MYCL1.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 06 August, 2015     Cancer Genetics Web, Established 1999