National Cancer Institute®
Last Modified: February 1, 2002
UI - 11748642
AU - Meije CB; Hakvoort TB; Swart GW; Westerhof W; Lamers WH; Das PK
TI - Gene expression patterns in melanocytic cells: candidate markers for early stage and malignant transformation.
SO - J Pathol 2002 Jan;196(1):51-8
AD - Department of Pathology, Academic Medical Center, University of Amsterdam, The Netherlands.
Different stages of differentiation of human melanocytic cells, such as normal melanocytes, naevus and melanoma cells, reflect distinct gene expression patterns. A PCR-based subtractive hybridization and display method was applied to identify genes that are differentially expressed in melanocytic cells in relation to early stage and malignant transformation. This resulted in the identification of a number of candidate cDNAs differentially expressed among melanocytes, naevus cells, and (non)-metastatic melanoma cells. Out of this collection of cDNAs, 16 clones were screened that comprised 12 novel genes, one previously identified expressed sequence tag related to vesicular trafficking (Ras-related protein Rab5b). The other three were also known genes that were either related to cell motility (beta-tubulin), pre-mRNA splicing (small nuclear protein U1A), or of unknown function (the human TI227-H gene). The differential expression patterns of Rab5b and two novel gene fragments (pCMa1, pCMn2) were further assessed in melanocytic cells. pCMa1 was expressed more in metastatic melanoma than in primary melanoma cells. In contrast, pCMn2 was expressed in both non-metastatic and metastatic melanoma cells, but was not detectable in either normal melanocytes or naevus cells. The Ras-related protein Rab5b showed lower levels of expression in highly metastatic than in other melanoma cells. These three cDNAs may therefore be involved in the early stage and malignant transformation of melanocytes. Copyright 2001 John Wiley & Sons, Ltd.
UI - 11815963
AU - Lynch HT; Brand RE; Hogg D; Deters CA; Fusaro RM; Lynch JF; Liu L;
TI - Knezetic J; Lassam NJ; Goggins M; Kern S Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
SO - Cancer 2002 Jan 1;94(1):84-96
AD - Department of Preventive Medicine, Creighton University School of Medicine, Omaha, Nebraska 68178, USA. email@example.com
BACKGROUND: Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) germline mutations. METHODS: Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM-pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A germline mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS: Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A mutation. CONCLUSIONS: The authors suggest that these tumors may collectively, in concert with CDKN2A mutations, constitute a "new" putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required. Copyright 2002 American Cancer Society.
UI - 11506326
AU - Chana JS; Grover R; Wilson GD; Hudson DA; Forders M; Sanders R;
TI - Grobbelaar AO The prognostic importance of c-myc oncogene expression in head and neck melanoma.
SO - Ann Plast Surg 2001 Aug;47(2):172-7
AD - RAFT Institute of Plastic Surgery, Mt Vernon Hospital, Northwood, Middlesex, UK.
Melanomas of the head and neck have a poorer prognosis than melanomas arising at other cutaneous sites. To study the biology of this disease, the expression of the c-myc oncogene was studied in tumors from 97 patients with head and neck melanoma using the technique of flow cytometry. Survival analysis revealed that stratification of patients according to oncogene expression provided a prognostic marker with shorter overall survival in tumors with high nuclear c-myc oncoprotein positivity (log-rank test, chi2 = 8.77, p < 0.005). Multifactorial analysis using Cox's proportional hazards model revealed nuclear c-myc oncoprotein to be an independent prognostic marker (log-rank test, chi2 = 8.82, p = 0.005). These results support the authors' previous studies of the prognostic value of c-myc expression in melanoma and suggest that estimation of c-myc oncoprotein may be of clinical importance in identifying high-risk patients.
UI - 11807902
AU - Mantelli M; Barile M; Ciotti P; Ghiorzo P; Lantieri F; Pastorino L;
TI - Catricala C; Torre GD; Folco U; Grammatico P; Padovani L; Pasini B; Rovini D; Queirolo P; Rainero ML; Santi PL; Sertoli RM; Goldstein AM; Bianchi-Scarra G; Societa Italiana Dermatologia; Gruppo Italiano Studi Epidemiologici in Dermatologia High prevalence of the G101W germline mutation in the CDKN2A (P16(ink4a)) gene in 62 Italian malignant melanoma families.
SO - Am J Med Genet 2002 Jan 22;107(3):214-21
AD - Dipartimento di Oncologia, Biologia e Genetica, Universita degli Studi di Genova, Genova, Italy.
CDKN2A germline mutation frequency estimates are commonly based on families with several melanoma cases. When we started counseling in a research setting on gene susceptibility analysis in northern and central Italy, however, we mostly found small families with few cases. Here we briefly characterize those kindred, estimate CDKN2A/CDK4 mutation test yields, and provide indications on the possibility of implementing formal DNA testing for melanoma-prone families in Italy. In September 1995 we started genetic counseling in a research setting at our Medical Genetics Center. Screening for CDKN2A/CDK4 mutations was performed on families with two melanoma patients, one of whom was younger than 50 years at onset, the other complying with one of the following: 1) being a first-degree relative, 2) having an additional relative with pancreatic cancer, or 3) having multiple primary melanomas. Sixty-two of 67 (80%) melanoma cases met our criteria. Four previously described CDKN2A mutations (G101W, R24P, V126D, and N71S) were found in 21 of the 62 families (34%) with a high prevalence of G101W (18/21). The percentage of families with two melanoma cases/family harboring a mutation was low (7%, 2/27), but rose to 45% (9/20) if one of the melanoma patients carried multiple melanomas or if pancreatic cancer was present in that family. In the 15 families with three melanoma cases the presence of a mutation was higher (67%, 10/15) and reached 100% in the 4 families with four or more melanoma cases. Our results suggest that CDKN2A/CDK4 counseling-based mutational analysis may be reasonably efficient also for families with two melanoma cases, if one patient carries multiple melanomas or if pancreatic cancer is present in the family. Copyright 2002 Wiley-Liss, Inc.
UI - 11782382
AU - Sturm RA; Satyamoorthy K; Meier F; Gardiner BB; Smit DJ; Vaidya B;
TI - Herlyn M Osteonectin/SPARC induction by ectopic beta(3) integrin in human radial growth phase primary melanoma cells.
SO - Cancer Res 2002 Jan 1;62(1):226-32
AD - The Wistar Institute, Philadelphia, Pennsylvania 19104, USA. R.Sturm@imb.uq.edu.au
Expression of the beta(3) integrin subunit in melanoma in situ has been found to correlate with tumor thickness, the ability to invade and metastasize, and poor prognosis. Transition from the radial growth phase (RGP) to the vertical growth phase (VGP) is a critical step in melanoma progression and survival and is distinguished by the expression of beta(3) integrin. The molecular pathways that operate in melanoma cells associated with invasion and metastasis were examined by ectopic induction of the beta(3) integrin subunit in RGP SBcl2 and WM1552C melanoma cells, which converts these cells to a VGP phenotype. We used cDNA representational difference analysis subtractive hybridization between beta(3)-positive and -negative melanoma cells to assess gene expression profile changes accompanying RGP to VGP transition. Fourteen fragments from known genes including osteonectin (also known as SPARC and BM-40) were identified after three rounds of representational difference analysis. Induction of osteonectin was confirmed by Northern and Western blot analysis and immunohistochemistry and correlated in organotypic cultures with the beta(3)-induced progression from RGP to VGP melanoma. Expression of osteonectin was also associated with reduced adhesion to vitronectin, but not to fibronectin. Osteonectin expression was not blocked when melanoma cells were cultured with anti-alpha(v)beta(3) LM609 mAb, mitogen-activated protein kinase, or protein kinase C inhibitors, indicating that other signaling pathway(s) operate through alpha(v)beta(3) integrin during conversion from RGP to VGP.
UI - 11781663
AU - Narita M; Bahar R; Hatano M; Kang MM; Tokuhisa T; Goto S; Saisho H;
TI - Sakiyama S; Tagawa M Tissue-specific expression of a suicide gene for selective killing of neuroblastoma cells using a promoter region of the NCX gene.
SO - Cancer Gene Ther 2001 Dec;8(12):997-1002
AD - Division of Pathology, Chiba Cancer Center Research Institute, Chiba, Japan.
The human NCX gene, a homologue of the murine neural crest homeobox (Ncx/Hox11L.1) gene whose expression is restricted to a subset of neural crest-derived tissues, was expressed in human neuroblastoma cells but not in other tumors or fibroblasts. A 4.5-kb genomic fragment in the 5'-flanking region of the NCX gene efficiently transcribed the fused luciferase reporter gene in human neuroblastoma cells but not in non-neuroblastoma cells. Sequential deletion of this regulatory region from the 5' side demonstrated that a 1.7-kb fragment upstream from the start codon retained the preferential promoter activity in neuroblastoma cells. The transcriptional activation by the NCX promoter was stronger than that by the SV40 T antigen promoter in human neuroblastoma cells. Transfection of neuroblastoma cells with the NCX promoter-linked herpes simplex virus-thymidine kinase (HSV-TK) gene increased their sensitivity to ganciclovir. The regulatory region of the NCX gene is thus useful for neuroblastoma-specific suicide gene therapy.
UI - 11809177
AU - Walker GJ; Hayward NK
TI - p16INK4A and p14ARF tumour suppressors in melanoma: lessons from the mouse.
SO - Lancet 2002 Jan 5;359(9300):7-8
AD - Human Genetics Laboratory, Queensland Institute of Medical Research, Royal Brisbane Hospital, Queensland, 4029, Brisbane, Australia.
UI - 11809676
AU - Deng J; Kloosterbooer F; Xia W; Hung MC
TI - The NH(2)-terminal and conserved region 2 domains of adenovirus E1A mediate two distinct mechanisms of tumor suppression.
SO - Cancer Res 2002 Jan 15;62(2):346-50
AD - Department of Molecular and Cellular Oncology, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Adenovirus E1A has been shown to suppress tumor growth and induce apoptosis in response to stress. To determine the mechanisms and regions of E1A that mediate these functions, we characterized stable transfectants of various E1A mutants in murine melanoma cells both in vitro and in vivo. Three E1A-mutant constructs were used in this study, those having a single deletion at either the NH(2)-terminal (dl1101) or conserved region 2 (CR2) domain (dl1108), or double deletions at both domains (dl0108). The in vitro study showed that the CR2 domain is required for E1A-mediated apoptosis, whereas the NH(2)-terminal domain is dispensable. The in vivo study showed that dl1101 and dl1108 were still able to suppress tumor growth, whereas dl0108 lost tumor-suppressive activity. By in situ immunohistostaining, we found that factor VIII, a marker for angiogenesis, was greatly suppressed in dl1108 transfectants that are resistant to apoptosis. Thus, inhibition of angiogenesis is involved in the NH(2)-terminal domain of E1A. In conclusion, we suggest that the NH(2)-terminal and CR2 domain of E1A mediate two distinct mechanisms of tumor suppression.
UI - 11556532
AU - Llewellyn K; Barnhill RL
TI - Distinguishing Spitz tumors from malignant melanoma: potential role of comparative genomic hybridization and fluorescence in situ hybridization in diagnosis and prognosis.
SO - Adv Anat Pathol 2001 Sep;8(5):249-54
AD - Department of Dermatology, George Washington University, Washington, DC, USA.
UI - 11742542
AU - Jean D; Guillaume N; Frade R
TI - Characterization of human cathepsin L promoter and identification of binding sites for NF-Y, Sp1 and Sp3 that are essential for its activity.
SO - Biochem J 2002 Jan 1;361(Pt 1):173-84
AD - Immunochimie des Regulations Cellulaires et des Interactions Virales, INSERM U.354, Centre INSERM, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, 75012 Paris, France.
Cathepsin L is a cysteine protease whose overexpression in human melanoma cells increases their tumorigenicity and switches their phenotype from non-metastatic to highly metastatic. Regulation of the transcription of the gene encoding human cathepsin L has not been yet studied and only preliminary data exist on the promoter regulation of the gene encoding rodent cathepsin L. In the present study we identified molecular elements involved in the transcriptional regulation of human cathepsin L in melanoma cells. The sequence of the 5'-flanking region of the gene encoding human cathepsin L was determined up to 3263 bp upstream of the translation start site. The major transcription intiation site was located. Three mRNA splice variants, differing in their 5' untranslated ends, were identified. Regulatory regions crucial for cathepsin L promoter activity were characterized between -1489 and -1646 bp. In this region, two GC boxes (-1590/-1595 and -1545/-1550) and a CCAAT motif (-1571/-1575) were involved in specific DNA-protein interactions. An electrophoretic mobility-shift assay demonstrated that Sp1 and Sp3 transcription factors bound to these GC boxes, and only the transcription factor nuclear factor Y (NF-Y) bound to the CCAAT motif. Mutagenesis studies demonstrated that these binding sites contributed at least 85% of cathepsin L promoter activity. Thus structural and functional analysis demonstrated that binding sites for NF-Y, Sp1 and Sp3 are essential for transcription of the gene encoding human cathepsin L in melanoma cells.
UI - 11821057
AU - Slominski A; Semak I; Pisarchik A; Sweatman T; Szczesniewski A; Wortsman
TI - J Conversion of L-tryptophan to serotonin and melatonin in human melanoma cells.
SO - FEBS Lett 2002 Jan 30;511(1-3):102-6
AD - Department of Pathology, University of Tennessee Health Science Center, Memphis, TN 38163, USA. firstname.lastname@example.org
We showed in human melanoma cells tryptophan hydroxylase (TPH) and hydroxyindole methyltransferase genes expression with the sequential enzymatic activities of TPH, serotonin (Ser) N-acetyltransferase and hydroxyindole methyltransferase. The presence of the products Ser, 5OH-tryptophan, N-acetylserotonin, melatonin (Mel), 5-methoxytryptamine and 5-methoxytryptophol was documented by liquid chromatography-mass spectrometry. Thus, human melanoma cells can synthesize and metabolize Ser and Mel.
UI - 11550811
AU - Waldmann V; Wacker J; Deichmann M
TI - Mutations of the activation-associated phosphorylation sites at codons 308 and 473 of protein kinase B are absent in human melanoma.
SO - Arch Dermatol Res 2001 Jul;293(7):368-72
AD - Department of Dermatology, University of Heidelberg, Germany.
UI - 11472999
AU - von Heydebreck A; Huber W; Poustka A; Vingron M
TI - Identifying splits with clear separation: a new class discovery method for gene expression data.
SO - Bioinformatics 2001;17 Suppl 1():S107-14
AD - Division of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, Ihnestr. 73, D-14195 Berlin, Germany. email@example.com
We present a new class discovery method for microarray gene expression data. Based on a collection of gene expression profiles from different tissue samples, the method searches for binary class distinctions in the set of samples that show clear separation in the expression levels of specific subsets of genes. Several mutually independent class distinctions may be found, which is difficult to obtain from most commonly used clustering algorithms. Each class distinction can be biologically interpreted in terms of its supporting genes. The mathematical characterization of the favored class distinctions is based on statistical concepts. By analyzing three data sets from cancer gene expression studies, we demonstrate that our method is able to detect biologically relevant structures, for example cancer subtypes, in an unsupervised fashion.
UI - 10922411
AU - Borg A; Sandberg T; Nilsson K; Johannsson O; Klinker M; Masback A;
TI - Westerdahl J; Olsson H; Ingvar C High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families.
SO - J Natl Cancer Inst 2000 Aug 2;92(15):1260-6
AD - Department of Oncology, University Hospital, Lund, Sweden.
BACKGROUND:: Inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16(INK4a) protein, and in the cyclin-dependent kinase 4 (CDK4) gene confer susceptibility to cutaneous malignant melanoma. We analyzed families with two or more cases of melanoma for germline mutations in CDKN2A and CDK4 to elucidate the contribution of these gene defects to familial malignant melanoma and to the occurrence of other cancer types. METHODS:: The entire CDKN2A coding region and exon 2 of the CDK4 gene of an affected member of each of 52 families from southern Sweden with at least two cases of melanoma in first- or second-degree relatives were screened for mutations by use of polymerase chain reaction-single-strand conformation polymorphism analysis. Statistical tests were two-sided. RESULTS:: CDKN2A mutations were found in 10 (19%) of the 52 families. Nine families carried an identical alteration consisting of the insertion of arginine at position 113 of p16(INK4a), and one carried a missense mutation, in which the valine at position 115 was replaced with a glycine. The 113insArg mutant p16(INK4a) was unable to bind cdk4 and cdk6 in an in vitro binding assay. Six of the 113insArg families had at least one member with multiple primary melanomas; the 113insArg families also had a high frequency of other malignancies-in particular, breast cancer (a total of eight cases compared with the expected 2.1; P =.0014) and pancreatic cancer (a total of six cases compared with the expected 0.16; P<.0001). Families with breast cancer also had a propensity for multiple melanomas in females, suggesting that a sex-dependent factor may modify the phenotypic expression of CDKN2A alterations. CONCLUSIONS:: Our findings confirm that the majority of CDKN2A-associated melanoma families in Sweden are due to a single founder mutation. They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer.
UI - 11181786
AU - Plna K; Hemminki K
TI - Re: High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families.
SO - J Natl Cancer Inst 2001 Feb 21;93(4):323-5
UI - 11844511
AU - Shahbazi M; Pravica V; Nasreen N; Fakhoury H; Fryer AA; Strange RC;
TI - Hutchinson PE; Osborne JE; Lear JT; Smith AG; Hutchinson IV Association between functional polymorphism in EGF gene and malignant melanoma.
SO - Lancet 2002 Feb 2;359(9304):397-401
AD - Immunology Research Group, School of Biological Sciences, Stopford Building, University of Manchester, Manchester M13 9PT, UK.
BACKGROUND: Malignant melanoma, the most serious cutaneous malignancy, has attracted substantial attention because of its rapidly increasing incidence and the poor prognosis of some tumours. Little is known of the genetic factors that mediate susceptibility to, and outcome of, sporadic malignant melanoma. Because of its role in mitogenesis, which is especially relevant to wound healing, tumorigenesis, and proliferation of epidermal tissues, epidermal growth factor (EGF) is an attractive candidate in which to look for genetic polymorphisms. METHODS: We enrolled 135 white European patients with malignant melanoma and 99 healthy white European controls, and screened a selection of DNA samples for polymorphisms in the promoter and 5' untranslated region of the EGF gene by analysis. We then screened DNA samples from all participants for the identified polymorphism by restriction-fragment-length polymorphism (RFLP) analysis. In-vitro EGF production was measured in peripheral-blood mononuclear cells from 34 controls, and the results were compared with the individuals' EGF genotypes. FINDINGS: We identified a single nucleotide substitution (G to A) at position 61 of the EGF gene. Allele frequencies in the controls were 56% EGF 61*A and 44% EGF 61*G. Cells from individuals homozygous for the 61*A allele produced significantly less EGF than cells from 61*G homozygotes (p=0.0004) or heterozygous A/G individuals (p=0.001). Compared with the A/A genotype, G/G was significantly associated with Breslow thickness (p=0.045) and with risk of malignant melanoma (odds ratio 4.9 [95% CI 2.3-10.2], p<0.0001). INTERPRETATION: This study suggests that high EGF production might be important in the development of malignant melanoma.
UI - 11850817
AU - Recio JA; Merlino G
TI - Hepatocyte growth factor/scatter factor activates proliferation in melanoma cells through p38 MAPK, ATF-2 and cyclin D1.
SO - Oncogene 2002 Feb 7;21(7):1000-8
AD - Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
Members of the mitogen-activated protein kinase (MAPK) superfamily, including p38 kinase and SAPK/JNK, play a central role in mediating cellular response to environmental stress, growth factors and cytokines. Hepatocyte growth factor/scatter factor (HGF/SF) is a multifunctional cytokine capable of eliciting mitogenic, motogenic and morphogenetic activities in responsive cells, and has been implicated in tumor development and metastasis. Binding of HGF/SF to its tyrosine kinase receptor c-Met stimulates multiple signal transduction pathways, leading to the activation of numerous transcription factors. We here report that HGF/SF can induce cyclin D1 expression in mouse melanoma cells, and that this up-regulation is mediated in part by the activating transcription factor-2 (ATF-2). HGF/SF-mediated phosphorylation of ATF-2 was reduced in the presence of either the p38 kinase-specific inhibitor SB203580, a dominant negative p38 mutant, the SAPK/JNK inhibitor JNK-interacting protein-1 (JIP-1), or the phosphatidylinositol 3-kinase (PI3K)-specific inhibitor LY294002. Activation of p38 kinase by HGF/SF was partially blocked by the PI3K-specific inhibitor as well. The upstream kinases for p38, MKK3/6, did not become activated following HGF/SF exposure, and ATF-2 activation was undiminished by transient transfection of a dominant negative MKK6 mutant. However, transcriptional up-regulation of cyclin D1 by HGF/SF was partially inhibited by the p38 kinase-specific inhibitor, and cyclin D1 protein induction was partially blocked by a dominant negative ATF-2 mutant. Notably, the p38 kinase-specific inhibitor was able to block melanoma cell proliferation but not motility. We conclude that the ATF-2 transcription factor becomes activated by HGF/SF through p38 MAPK and SAPK/JNK. Moreover, the p38-ATF-2 pathway can help mediate proliferation signals in tumor cells through transcriptional activation of key cell cycle regulators.
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