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NCI CANCERLIT^® Search: Hereditary Melanoma - July 2002

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National Cancer Institute^®
Ultima Vez Modificado: 1 de julio del 2002

Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours.
A cluster region of AP-1 responsive elements is required for transcriptional activity of mouse ODC gene by hepatocyte growth factor.
p16(Ink4a) in melanocyte senescence and differentiation.
[The use of gene gun in cancer gene therapy]
Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model.
Gene responsible for most malignant melanomas is discovered.
Expression, function and clinical relevance of MIA (melanoma inhibitory activity).
The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to
Cyclin D1 is a candidate oncogene in cutaneous melanoma.
Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells.
Lucky draw in the gene raffle.
Mutations of the BRAF gene in human cancer.
Mixture modelling of gene expression data from microarray experiments.
Genetic epidemiology of melanoma: of consortia and conundrums.
Geographical variation in the penetrance of CDKN2A mutations for melanoma.
High-frequency microsatellite instability is associated with defective DNA mismatch repair in human melanoma.
Re: DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.
Induction of melanoma in murine macrophage inflammatory protein 2 transgenic mice heterozygous for inhibitor of kinase/alternate reading
Characterization of the malignant melanoma of soft-parts cell line GG-62 by expression analysis using DNA microarrays.
Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma.
Frameshift mutations of RIZ, but no point mutations in RIZ1 exons in malignant melanomas with deletions in 1p36.
Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets.
Mutant laboratory mice with abnormalities in pigmentation: annotated tables.
A natural history of melanomas and dysplastic nevi: an atlas of lesions in melanoma-prone families.
Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.
Loss of heterozygosity, microsatellite instability, and mismatch repair protein alterations in the radial growth phase of cutaneous malignant

1
UI - 12015740
AU - van Dijk MC; Rombout PD; Mooi WJ; van de Molengraft FJ; van Krieken JH;
TI - Ruiter DJ; Ligtenberg MJ Allelic imbalance in the diagnosis of benign, atypical and malignant Spitz tumours.
SO - J Pathol 2002 Jun;197(2):170-8
AD - Department of Pathology, University Medical Centre Nijmegen, Nijmegen, The Netherlands. m.vandijk@pathol.azn.nl
To test the diagnostic usefulness of allelic imbalance (AI) analysis based on routinely paraffin-embedded tissue, a series of 55 benign Spitz naevi, Spitz tumours with uncertain malignant potential, and malignant Spitzoid melanomas was investigated. Laser microdissection was used to ensure representative sampling of lesional cells and to investigate AI in separate tumour areas of four melanomas. AI was found in 2/12 (17%) typical Spitz naevi, 3/9 (33%) atypical Spitz tumours, 12/17 (65%) atypical Spitz tumours suspicious for melanoma and 15/17 (88%) Spitzoid melanomas. Additional immunohistochemical staining for Ki-67 using the MIB-1 antibody revealed positive deeply situated lesional cells in 0/6 (0%) Spitz naevi, 1/8 (13%) atypical Spitz tumours, 5/14 (35%) atypical Spitz tumours suspicious for melanoma, and 7/14 (50%) Spitzoid melanomas, respectively. Two of the melanomas examined for AI in separate tumour areas showed intratumoural genetic heterogeneity. In view of the finding of AI and deeply situated Ki-67 positive cells not only in melanomas but also in Spitz tumours with uncertain malignant potential, these approaches appear to have no direct diagnostic applicability for the distinction between benign and malignant Spitz tumours. Further molecular studies will be required to determine whether Spitz tumours and Spitzoid melanomas are unrelated entities, or whether there is a true spectrum of tumour progression. Copyright 2002 John Wiley & Sons, Ltd.

2
UI - 12054494
AU - Bianchi L; Tacchini L; Matteucci E; Desiderio MA
TI - A cluster region of AP-1 responsive elements is required for transcriptional activity of mouse ODC gene by hepatocyte growth factor.
SO - Arch Biochem Biophys 2002 May 1;401(1):115-23
AD - Institute of General Pathology and C.N.R. Center for Research on Cell Pathology, University of Milano, School of Medicine, via L. Mangiagalli, 31-20133 Milan, Italy.
Ornithine decarboxylase (ODC) activity is regulated by a variety of mechanisms including transcription, translation, and RNA and protein half-life. Since in mouse B16-F1 melanoma cells an early and remarkable (about 6-fold) increase in steady state mRNA levels was observed after hepatocyte growth factor (HGF) treatment, we investigated the transcriptional regulation of mouse ODC promoter. Transient transfection of various ODC-luciferase promoter constructs into the B16-Fl cells in combination with electrophoretic mobility shift assays identified the HGF-responsive element as a cluster of three AP-1 binding sites (-1660 to -1572). Even if each site differs from the canonical TPA responsive element for one nucleotide, only the first two AP-1 consensus sequences seemed to be functional since allowed DNA-binding activity of nuclear proteins after HGF treatment. Comparison of the results of transfection assays with the pOD2.5-luc (2.5 kb gene fragment) and with the construct deprived of the AP-1 cluster pOD-B-luc showed that this 50 bp region was required for ODC transactivating activity in response to HGF. Since in B16-F1 cells HGF increased AP-1 activity and the mRNA expression of various AP-1 subunits, we may conclude that HGF-induced transcription of mouse ODC was largely due to triggering of AP-1 pathway. (c) 2002 Elsevier Science (USA).

3
UI - 11904317
AU - Sviderskaya EV; Hill SP; Evans-Whipp TJ; Chin L; Orlow SJ; Easty DJ;
TI - Cheong SC; Beach D; DePinho RA; Bennett DC p16(Ink4a) in melanocyte senescence and differentiation.
SO - J Natl Cancer Inst 2002 Mar 20;94(6):446-54
AD - Department of Anatomy and Developmental Biology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, U.K.
BACKGROUND: The Ink4a-Arf tumor suppressor locus encodes two growth inhibitors, p16 and Arf, both of which are also implicated as effectors in cellular senescence. Because human germline defects in the INK4A-ARF locus are associated with familial melanoma, melanocytes may have unusual INK4A-ARF functions or controls of cell senescence. Because senescence is believed to be an anticancer mechanism, we investigated the role of Ink4a-Arf and its individual components in melanocyte senescence. METHODS: Melanocytes were cultured from littermate mice with zero, one, or two functional copies of the Ink4a-Arf locus. Senescence was evaluated by cumulative population doubling curves and by the assessment of acidic beta-galactosidase (an indicator of senescence) expression. Pigmentation and cell size were evaluated by spectrophotometry and microscopy. p16 and Arf expression in primary and spontaneously immortalized melanocyte or melanocyte precursor cell lines were evaluated by immunoblotting. Retroviral vectors containing normal p16 and Arf complementary DNAs were used to restore expression of these genes in Ink4a-Arf(-/-) melanocytes. RESULTS: Wild-type melanocytes (i.e., Ink4a-Arf(+/+)) senesced within 4-5 weeks of culture. Ink4a-Arf(-/-) melanocytes did not senesce and readily became immortal. Ink4a-Arf(+/-) melanocytes showed defective senescence. Senescent Ink4a-Arf(+/+) melanocytes were heavily pigmented, but Ink4a-Arf(+/-) and Ink4a-Arf(-/-) melanocytes were less pigmented. All of six spontaneously immortalized melanocyte or melanocyte precursor lines from Ink4a-Arf(+/+) mice lacked p16 protein expression, although most retained Arf protein expression. After restoration of p16 but not Arf expression, Ink4a-Arf(-/-) melanocytes stopped growing, became highly melanized, and expressed acidic beta-galactosidase. By contrast, restoration of Arf but not p16 expression led to cell death without evidence of senescence. CONCLUSION: Normal mouse melanocyte senescence and associated pigmentation require both copies of Ink4a-Arf and appear to depend more on p16 than on Arf function. Mutations of the INK4A-ARF locus may favor tumorigenesis from melanocytes by impairing senescence, cell differentiation, and (where ARF is disrupted) cell death.

4
UI - 11798811
AU - Zha Y; Lin C; Liang X
TI - [The use of gene gun in cancer gene therapy]
SO - Zhonghua Yi Xue Za Zhi 2000 Jul;80(7):522-5
AD - National Lab of Molecule Oncology, Cancer Institute, PUMC & CAMS, Beijing, 100021 China.
OBJECTIVE: With Helios gene gun, the report genes EGFP and Lac-Z were transfected to several cultured mammalian tumor cell lines in vitro and mice skin in vivo, respectively. A stable long time exogene's expression were got. Then, the pWRG3142, which carried mGM-CSF gene was delivered to the abdominal skin of C57BL/6 mice using gene gun. Pathological sections showed the local transproteins' expression companying with a profound inflammation reaction characterized by neutrophilic infiltration. ELISA assay of transfected mouse's serum sample indicated a high improvement of transgenic proteins level, which demonstrated that transgenic GM-CSF secreted from treated skin into the bloodstream effectively. In B16 melanoma tumor model, mice immunized with mGM-CSF expression plasmids could be partially protected from 1 x 10(5) B16 cells challenge and exhibited a drastically reduced tumor growth rate. Finally, we conclucled that exogenes could be transfected into cultured cell lines and mice skin effectively by gene gun technology, and gene gun mediated in vivo delivery of GM-CSF cDNA should be further developed for potential clinical testing as an approach for human cancer gene therapy.

5
UI - 12019177
AU - Yu Y; Merlino G
TI - Constitutive c-Met signaling through a nonautocrine mechanism promotes metastasis in a transgenic transplantation model.
SO - Cancer Res 2002 May 15;62(10):2951-6
AD - Molecular Genetics Section, Laboratory of Molecular Biology, National Cancer Institute/NIH, Bethesda, MD 20892-4264, USA.
Normal cells are dependent on exogenous, receptor-mediated growth stimulation for cell cycle entry and progression, providing a critical homeostatic mechanism regulating cellular proliferation. In contrast, tumor cells acquire some degree of growth signal autonomy, often through their ability to produce growth factors as well as their receptors (autocrine signaling). Recently, data have begun to emerge implicating heterotypic signaling between diverse cell types within a tumor in the genesis and progression of cancer; however, current experimental approaches in vivo have not adequately addressed this critical relationship. Here we used transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF), or its growth antagonist NK2, as genetically modified hosts for transplantation of tumor cells expressing their receptor, c-Met, to directly assess the contribution of heterotypic signaling to metastatic colonization. We demonstrate that metastatic potential under nonautocrine signaling conditions (i.e., where tumor cells expressing c-Met are transplanted into transgenic hosts producing HGF/SF) rivaled that observed under conditions of autocrine signaling (i.e., where tumor cells expressing both HGF/SF and c-Met are transplanted into wild-type hosts). HGF/SF and NK2 were not functionally equivalent in vivo. Attenuation of NK2-associated growth inhibition by the presence of an HGF/SF-Met autocrine loop uncovered a shift in metastatic site preference from lung to liver only in NK2-transgenic hosts, a qualitative behavioral alteration likely detectable only through the genetic approach used here. Our data demonstrate that growth factors not intrinsic to malignant cells can have profound effects on metastatic efficiency in vivo and provide experimental support of a role for heterotypic signaling in tumor progression.

6
UI - 12065256
AU - Gould M
TI - Gene responsible for most malignant melanomas is discovered.
SO - BMJ 2002 Jun 15;324(7351):1412
AD - London.

7
UI - 11813878
AU - Bosserhoff AK; Buettner R
TI - Expression, function and clinical relevance of MIA (melanoma inhibitory activity).
SO - Histol Histopathol 2002 Jan;17(1):289-300
AD - Institute of Pathology, Medical School RWTH Aachen, Germany. bosserhoff@pat.rwth-aachen.de
Despite its ambiguous name the protein melanoma-inhibitory-activity (MIA) was identified as a key molecule involved in progression and metastasis of malignant melanomas. Therefore, in this review we intend to update the current knowledge on expression patterns, transcriptional regulation, function and clinical relevance of MIA. Furthermore, we will cover the recently discovered MIA homologous proteins OTOR/MIAL, MIA 2 and TANGO. In order to identify autocrine growth-regulatory factors secreted by melanoma cells, MIA was purified and cloned. Subsequent analyses of non-neoplastic tissues revealed specific MIA expression patterns in cartilage. In neoplastic tissues MIA expression was detected in malignant melanomas, in chondrosarcomas and less frequently in a variety of different adenocarcinomas including breast and colon cancers. For melanoma cells and chondrocytes it was shown that regulation of expression pattern was controlled on the level of mRNA transcription by defined transcription factors. Evidence obtained from in vitro and in vivo experiments indicated that MIA plays an important functional role in melanoma metastasis and invasion. A number of studies from different laboratories evaluated MIA as a highly specific and sensitive marker, clinically useful for follow-up and therapy-monitoring of patients with malignant melanomas. In addition, preliminary data suggests a further potential application as a surrogate marker for measuring cartilage damage in rheumatoid arthritis. Recently, it has become evident that MIA belongs to a gene family of four homologous proteins, MIA, OTOR (FDP, MIAL), MIA 2 and TANGO. Determination of the three-dimensional structure in solution identified MIA as the first member of this novel family of secreted, extracellular proteins adopting an SH3 domain-like fold. The data suggest specific protein-protein interactions with components of the extracellular matrix and possibly epitopes on cellular surfaces and will certainly attract further interest and investigations.

8
UI - 12036907
AU - Khong HT; Rosenberg SA
TI - The Waardenburg syndrome type 4 gene, SOX10, is a novel tumor-associated antigen identified in a patient with a dramatic response to immunotherapy.
SO - Cancer Res 2002 Jun 1;62(11):3020-3
AD - Affiliation Surgery Branch, National Cancer Institute, National Institutes of Health, Building 10 Room 2B42, 10 Center Drive, Bethesda, MD 20892, USA.
In this study, we have identified, for the first time, the presence of de novo cellular immune reactivity against the transcription factor SOX10, using tumor-infiltrating lymphocytes obtained from a patient who experienced a dramatic clinical response to immunotherapy. SOX10 acts as a critical transactivator of tyrosinase-related protein-2 during melanoblast development and a potent transactivator of micropthalmia-associated transcription factor, which is considered to be a master gene that controls the development and postnatal survival of melanocytes. Mutations in SOX10 result in Waardenburg syndrome type 4. The overlapping epitopes AWISKPPGV and SAWISKPPGV, designated SOX10: 332-340 and SOX10: 331-340, respectively, were recognized by tumor-infiltrating lymphocyte clone M37 in an HLA-A2-restricted fashion.

9
UI - 12036934
AU - Sauter ER; Yeo UC; von Stemm A; Zhu W; Litwin S; Tichansky DS; Pistritto
TI - G; Nesbit M; Pinkel D; Herlyn M; Bastian BC Cyclin D1 is a candidate oncogene in cutaneous melanoma.
SO - Cancer Res 2002 Jun 1;62(11):3200-6
AD - Department of Dermatology, University of California-San Francisco, San Francisco, CA 94143, USA.
The retinoblastoma pathway has been implicated in melanoma; however, previous studies of one of the key components of this pathway, cyclin D1 (CD1), failed to find amplification of this gene in a large series of melanomas. We have recently shown that a particular subtype of melanoma, acral melanoma (AM), has frequent amplification of the CD1 locus. This suggested that CD1 might be important in AM and that it may also be important in other melanoma types, even though its copy number may not be altered. We compared CD1 gene copy number and protein expression in 137 invasive primary cutaneous melanomas (71 superficial spreading melanomas, 17 nodular melanomas, 19 lentigo maligna melanomas, 18 AMs, and 12 unclassifiable melanomas) using fluorescence in situ hybridization and immunohistochemistry. We found frequent amplification of CD1 in AM (44.4%) and occasional amplification in lentigo maligna melanoma (10.5%) and superficial spreading melanoma (5.6%). CD1 protein was overexpressed in all cases with amplifications and in an additional 20% of cases without amplification. We tested the importance of CD1 in cell growth in melanoma by using adenovirus-mediated antisense treatment targeted to CD1 in two melanoma cell lines, one with and the other without CD1 amplification and overexpression. Antisense mediated down-regulation of CD1 induced apoptosis in vitro and led to significant tumor shrinkage of melanoma xenografts in severe combined immunodeficient mice. However, it did not alter the growth of normal melanocytes. Together, these results suggest that CD1 may be an oncogene in melanoma and that targeting its expression may be therapeutically beneficial.

10
UI - 12067988
AU - Padovan E; Terracciano L; Certa U; Jacobs B; Reschner A; Bolli M;
TI - Spagnoli GC; Borden EC; Heberer M Interferon stimulated gene 15 constitutively produced by melanoma cells induces e-cadherin expression on human dendritic cells.
SO - Cancer Res 2002 Jun 15;62(12):3453-8
AD - Department of Surgical Research, University of Basel, 4031, Switzerland. epadovan@uhbs.ch
The immunobiology of tumor-infiltrating dendritic cells (DCs) can be strongly influenced by the cytokine environment present in the malignant tissue. We have previously identified discrete melanoma lines, inducing E-cadherin expression on monocyte-derived DCs in vitro. We demonstrate here that this effect, independent of cell contact, is not inducible in the presence of tumor lysates and requires the constitutive expression of IFN stimulated gene 15 (ISG15) by malignant cells. High-density oligonucleotide arrays were used to investigate the expression pattern of 7000 genes in RNA from two melanoma cell clones competent for E-cadherin induction and two clones devoid of DC-modulating capacity. A total of 13 genes encoding soluble proteins were expressed at higher magnitude in melanomas able to induce E-cadherin expression on DCs. Combining those data with quantitative protein assays, we could narrow our investigation down to three factors: the chemokine CCL5 and the cytokines ISG15 and type I IFNs. Strikingly, >7 ng/ml of ISG15 could be detected in the corresponding melanoma-conditioned medium and induction of E-cadherin on DCs failed in the presence of antibodies neutralizing ISG15 protein. Most importantly, strong cytoplasmic expression of ISG15 was detected by immunohistochemistry in the original tumor specimen from which the melanoma cell lines under investigation were derived. These data describe a novel property of ISG15 targeting induction of E-cadherin on DCs and possibly influencing their migratory behavior.

11
UI - 12087387
AU - Pollock PM; Meltzer PS
TI - Lucky draw in the gene raffle.
SO - Nature 2002 Jun 27;417(6892):906-7

12
UI - 12068308
AU - Davies H; Bignell GR; Cox C; Stephens P; Edkins S; Clegg S; Teague J;
TI - Woffendin H; Garnett MJ; Bottomley W; Davis N; Dicks E; Ewing R; Floyd Y; Gray K; Hall S; Hawes R; Hughes J; Kosmidou V; Menzies A; Mould C; Parker A; Stevens C; Watt S; Hooper S; Wilson R; Jayatilake H; Gusterson BA; Cooper C; Shipley J; Hargrave D; Pritchard-Jones K; Maitland N; Chenevix-Trench G; Riggins GJ; Bigner DD; Palmieri G; Cossu A; Flanagan A; Nicholson A; Ho JW; Leung SY; Yuen ST; Weber BL; Seigler HF; Darrow TL; Paterson H; Marais R; Marshall CJ; Wooster R; Stratton MR; Futreal PA Mutations of the BRAF gene in human cancer.
SO - Nature 2002 Jun 27;417(6892):949-54
AD - Cancer Genome Project, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
Cancers arise owing to the accumulation of mutations in critical genes that alter normal programmes of cell proliferation, differentiation and death. As the first stage of a systematic genome-wide screen for these genes, we have prioritized for analysis signalling pathways in which at least one gene is mutated in human cancer. The RAS RAF MEK ERK MAP kinase pathway mediates cellular responses to growth signals. RAS is mutated to an oncogenic form in about 15% of human cancer. The three RAF genes code for cytoplasmic serine/threonine kinases that are regulated by binding RAS. Here we report BRAF somatic missense mutations in 66% of malignant melanomas and at lower frequency in a wide range of human cancers. All mutations are within the kinase domain, with a single substitution (V599E) accounting for 80%. Mutated BRAF proteins have elevated kinase activity and are transforming in NIH3T3 cells. Furthermore, RAS function is not required for the growth of cancer cell lines with the V599E mutation. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation in human cancer, it may provide new therapeutic opportunities in malignant melanoma.

13
UI - 11847075
AU - Ghosh D; Chinnaiyan AM
TI - Mixture modelling of gene expression data from microarray experiments.
SO - Bioinformatics 2002 Feb;18(2):275-86
AD - Department of Biostatistics, School of Public Health, University of Michigan, 1420 Washington Heights, Room M4057, Ann Arbor, MI 48109-2029, USA. ghoshd@umich.edu
MOTIVATION: Hierarchical clustering is one of the major analytical tools for gene expression data from microarray experiments. A major problem in the interpretation of the output from these procedures is assessing the reliability of the clustering results. We address this issue by developing a mixture model-based approach for the analysis of microarray data. Within this framework, we present novel algorithms for clustering genes and samples. One of the byproducts of our method is a probabilistic measure for the number of true clusters in the data. RESULTS: The proposed methods are illustrated by application to microarray datasets from two cancer studies; one in which malignant melanoma is profiled (Bittner et al., Nature, 406, 536-540, 2000), and the other in which prostate cancer is profiled (Dhanasekaran et al., 2001, submitted).

14
UI - 12072536
AU - Petersen GM; Vachon CM
TI - Genetic epidemiology of melanoma: of consortia and conundrums.
SO - J Natl Cancer Inst 2002 Jun 19;94(12):872-3

15
UI - 12072543
AU - Bishop DT; Demenais F; Goldstein AM; Bergman W; Bishop JN; Bressac-de
TI - Paillerets B; Chompret A; Ghiorzo P; Gruis N; Hansson J; Harland M; Hayward N; Holland EA; Mann GJ; Mantelli M; Nancarrow D; Platz A; Tucker MA; The Melanoma Genetics Consortium Geographical variation in the penetrance of CDKN2A mutations for melanoma.
SO - J Natl Cancer Inst 2002 Jun 19;94(12):894-903
AD - Genetic Epidemiology Division, Cancer Research UK Clinical Centre, St. James's University Hospital, Leeds, UK. tim.bishop@cancer.org.uk
BACKGROUND: Germline mutations in the CDKN2A gene, which encodes two proteins (p16INK4A and p14ARF), are the most common cause of inherited susceptibility to melanoma. We examined the penetrance of such mutations using data from eight groups from Europe, Australia and the United States that are part of The Melanoma Genetics Consortium. METHODS: We analyzed 80 families with documented CDKN2A mutations and multiple cases of cutaneous melanoma. We modeled penetrance for melanoma using a logistic regression model incorporating survival analysis. Hypothesis testing was based on likelihood ratio tests. Covariates included gender, alterations in p14ARF protein, and population melanoma incidence rates. All statistical tests were two-sided. RESULTS: The 80 analyzed families contained 402 melanoma patients, 320 of whom were tested for mutations and 291 were mutation carriers. We also tested 713 unaffected family members for mutations and 194 were carriers. Overall, CDKN2A mutation penetrance was estimated to be 0.30 (95% confidence interval (CI) = 0.12 to 0.62) by age 50 years and 0.67 (95% CI = 0.31 to 0.96) by age 80 years. Penetrance was not statistically significantly modified by gender or by whether the CDKN2A mutation altered p14ARF protein. However, there was a statistically significant effect of residing in a location with a high population incidence rate of melanoma (P =.003). By age 50 years CDKN2A mutation penetrance reached 0.13 in Europe, 0.50 in the United States, and 0.32 in Australia; by age 80 years it was 0.58 in Europe, 0.76 in the United States, and 0.91 in Australia. CONCLUSIONS: This study, which gives the most informed estimates of CDKN2A mutation penetrance available, indicates that the penetrance varies with melanoma population incidence rates. Thus, the same factors that affect population incidence of melanoma may also mediate CDKN2A penetrance.

17
UI - 12011229
AU - Pedeux R; Boniol M; Autier P; Dore JF
TI - Re: DNA repair, dysplastic nevi, and sunlight sensitivity in the development of cutaneous malignant melanoma.
SO - J Natl Cancer Inst 2002 May 15;94(10):772-3; discussion 773-4

18
UI - 11719444
AU - Yang J; Luan J; Yu Y; Li C; DePinho RA; Chin L; Richmond A
TI - Induction of melanoma in murine macrophage inflammatory protein 2 transgenic mice heterozygous for inhibitor of kinase/alternate reading frame.
SO - Cancer Res 2001 Nov 15;61(22):8150-7
AD - Veterans Affairs Medical Center and Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
The molecular and genetic events that contribute to the genesis and progression of cutaneous malignant melanoma are poorly understood, attributable in large part to the different genetic alterations accompanying tumorigenesis. Inhibitor of kinase 4a (INK4a) is often inactivated in families with hereditary melanoma. Loss of INK4a/alternate reading frame (ARF) in mice is associated with increased incidence of other tumors such as lymphoma and fibrosarcoma. However, the incidence of melanoma in INK4a/ARF-deficient mice is very low. Our previous studies have revealed that the CXC chemokine, CXCL1, is overexpressed in human malignant melanoma cells and is linked to transformation of immortalized murine melanocytes. To study the direct role of CXCL1 on the genesis of primary melanoma lesions, transgenic mouse lines were established that express the murine homologue of CXCL1, murine macrophage inflammatory protein 2 (MIP-2), under the transcriptional control of the tyrosinase promoter/enhancer (Tyr-MIP-2) in the mice that were deficient or not deficient for INK4a/ARF. Strong MIP-2 immunoreactivity was associated with pigmented melanocytes in the hyperproliferative hair follicles in the Tyr-MIP-2 transgenic mice, and the level of MIP-2 expression was similar in both INK4a/ARF heterozygous or wild-type mice. After treatment of mice with 7,12-dimethylbenz(a)anthracene, cutaneous melanomas formed in 12% (17/145) of the Tyr-MIP-2 transgene-positive mice, whereas only 2% (3/146) of the Tyr-MIP-2 transgene-negative mice developed melanoma. When melanocytes cultured from MIP-2 transgenic mice null for INK4a/ARF were transplanted into nude mice, melanoma formation occurred in 83% (10/12) of the cases with a latency period of 3 months. However, no melanoma lesions arose in nude mice injected with INK4a/ARF -/- melanocytes, which did not express the MIP-2 transgene. Our results demonstrate that constitutive expression of MIP-2 in INK4a/ARF-deficient melanocytes facilitates formation of malignant melanoma.

19
UI - 12021921
AU - Schaefer KL; Wai DH; Poremba C; Korsching E; van Valen F; Ozaki T;
TI - Boecker W; Dockhorn-Dworniczak B Characterization of the malignant melanoma of soft-parts cell line GG-62 by expression analysis using DNA microarrays.
SO - Virchows Arch 2002 May;440(5):476-84
AD - Gerhard-Domagk-Institute of Pathology, University of Munster, Domagkstrasse 17, 48149 Munster, Germany.
GG-62 is a cell line previously thought to be derived from an atypical Ewing tumor (ET). Reverse-transcriptase polymerase chain reaction revealed an in-frame fusion between the Ewing sarcoma gene ( EWS) codon 325 and the activating transcription factor 1 gene ( ATF1) codon 65 which permits the production of chimeric EWS-ATF1 oncoproteins. We also identified the genomic breakpoint resulting from a reciprocal t(12;22)(q13;q12), which is the hallmark of malignant melanoma of soft parts (MMSP). We applied Affymetrix human cancer G110 arrays to compare the gene expression patterns of GG-62 and other cell lines derived from small blue round cell tumors of childhood. Hierarchical clustering of 463 differentially expressed genes distinguished GG-62 from the ETs, as well as the neuroblastomas, and revealed a cluster of 36 upregulated genes. Several of these genes are involved in signal transduction pathways that may be critical for maintaining cell transformation; some examples are avian erythroblastic leukemia viral oncogene homolog 3 ( ERBB3), neuregulin 1 ( NRG1), fibroblast growth factor 9 ( FGF9), and fibroblast growth factor receptor-1 ( FGFR1). Furthermore, genes near the chromosome-12q13 breakpoint exhibited increased expression of GG-62 including ERBB3, NR4A1 (nuclear receptor subfamily 4, group A, member 1), cyclin-dependent kinase 2 ( CDK2), and alpha 5 integrin ( ITGA5). Altogether our findings demonstrate the MMSP derivation of GG-62 and may shed light on the mechanisms of tumorigenesis in this rare disease.

20
UI - 11259086
AU - Fang W; Piao Z; Buyse IM; Simon D; Sheu JC; Perucho M; Huang S
TI - Preferential loss of a polymorphic RIZ allele in human hepatocellular carcinoma.
SO - Br J Cancer 2001 Mar 23;84(6):743-7
AD - Program in Oncogenes and Tumor Suppressor Genes, The Burnham Institute, La Jolla, CA 92037, USA.
The RIZ (PRDM2) locus commonly undergoes loss of heterozygosity (LOH) and maps within the minimal deleted region on 1p36 in hepatocellular carcinoma (HCC). Although peptide-altering mutations of RIZ are rare in HCC, the RIZ1 product is commonly lost in HCC and has tumour suppressive activities. Here, we analysed RIZ gene mutations and LOH in HCC, breast cancer, familial melanoma, colon cancer, and stomach cancer. We found 7 polymorphisms but no mutations. By analysing the Pro704-deletion polymorphism, we detected LOH of RIZ in 31 of 79 (39%) informative HCC cases, 11 of 47 (23%) colon cancer cases, 8 of 43 (19%) breast cancer cases, 8 of 66 (12%) stomach cancer cases. Importantly, loss of the Pro704(+)allele was found in 74% of the 31 LOH positive HCC cases (P< 0.01), indicating a preferential loss and hence a stronger tumour suppressor role for this allele compared to the P704(-)allele. In addition, the Pro704(+)allele was found to be more common in Asians (0.61) than Caucasians (0.42) (P = 0.0000), suggesting an interesting link between gene polymorphisms and potential differences in tumour incidence between racial groups. Copyright 2001 Cancer Research Campaign.

21
UI - 12082534
AU - Poetsch M; Dittberner T; Woenckhaus C
TI - Frameshift mutations of RIZ, but no point mutations in RIZ1 exons in malignant melanomas with deletions in 1p36.
SO - Oncogene 2002 May 2;21(19):3038-42
AD - Institute of Forensic Medicine, Ernst Moritz Arndt-University of Greifswald, Kuhstrasse 30, D-17489 Greifswald, Germany. poetsch@mail.uni-greifswald.de
Recently, the retinoblastoma protein interacting zinc finger gene RIZ has been proposed as a candidate for the tumor suppressor locus on 1p36, because of the common loss of RIZ1 RNA in human tumors. In addition, frameshift mutations of this gene have been demonstrated in a variety of tumors with microsatellite instability. Since alterations in this region have been described in malignant melanomas, we investigated DNA of paraffin-embedded sections from 16 typical naevi, 19 atypical naevi, 33 primary melanoma lesions and 25 metastases and DNA from four melanoma cell lines by PCR and direct sequencing analysis of RIZ. Frameshift mutations in the RIZ gene were found in 17% of melanoma samples and 8.6% of naevi, but we could not demonstrate any missense mutations in the exons of RIZ1. No LOH of the RIZ gene nor any microsatellite instability in six dinucleotide markers or in the mononucleotide repeats IGRIIR, hMSH3, and hMSH6 could be demonstrated in the samples with RIZ frameshift mutations. Although our results do not explain the high rate of deletions in 1p36 found in this tumor, they assign RIZ a potential role in the multi-step tumor forming process of malignant melanoma of the skin.

22
UI - 11831644
AU - Grossman D; Altieri DC
TI - Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets.
SO - Cancer Metastasis Rev 2001;20(1-2):3-11
AD - Department of Dermatology and the Huntsman Cancer Institute, University of Utah, Salt Lake City, USA.
Melanoma is the most aggressive form of skin cancer. Patients with advanced disease, such as lymph node involvement and distant metastases, have 5-year survival rates of 50% and 10-20%, respectively. This poor prognosis largely results from resistance to conventional chemotherapy, namely cytotoxic drugs. The basis for drug resistance in melanoma is most likely dysregulation of apoptosis, although other mechanisms including drug transport, detoxification, and enhanced DNA repair may also play a role. Defects at multiple levels and in both major apoptotic pathways have been described in melanoma. Our laboratory has identified an inhibitor of apoptosis, termed survivin, that is expressed in melanoma and required for maintenance of melanoma cell viability. Targeting of survivin and other apoptotic regulators increases the sensitivity of melanoma cells to cytotoxic drugs, and may provide a promising new therapeutic approach to cancer.

23
UI - 11916127
AU - Nakamura M; Tobin DJ; Richards-Smith B; Sundberg JP; Paus R
TI - Mutant laboratory mice with abnormalities in pigmentation: annotated tables.
SO - J Dermatol Sci 2002 Jan;28(1):1-33
AD - Department of Dermatology, University Hospital Eppendorf, University of Hamburg, Germany.
Mammalian pigment cell research has recently entered a phase of significantly increased activity due largely to the exploitation of the many mutant mouse stocks that are coming on stream. Numerous transgenic, targeted mutagenesis (so-called 'knockouts'), conditional (so-called 'gene switch') and spontaneous mutant mice develop abnormal coat color phenotypes. The number of mice that exhibit such abnormalities is increasing exponentially as genetic engineering methods become routine. Since defined abnormalities in such mutant mice provide important clues to the as yet often poorly understood functional roles of many gene products, this overview includes a corresponding, annotated table of mutant mice with pigmentation alterations. These range from early developmental defects via a large array of coat color abnormalities to a melanoma metastasis model. This overview should provide helpful pointers to investigators who are looking for mouse models to explore or to compare functional activities of genes of interest and for comparing coat color phenotypes of spontaneous or genetically engineered mouse mutants with novel ones. Secondly, this review includes a table of mouse models of specific human diseases with genetically defined pigmentation abnormalities. In summary, this annotated table should serve as a useful reference for anyone interested in the molecular controls of pigmentation.

24
UI - 12115352
AU - Tucker MA; Fraser MC; Goldstein AM; Struewing JP; King MA; Crawford JT;
TI - Chiazze EA; Zametkin DP; Fontaine LS; Clark WH Jr A natural history of melanomas and dysplastic nevi: an atlas of lesions in melanoma-prone families.
SO - Cancer 2002 Jun 15;94(12):3192-209
AD - Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland 20892-7236, USA. tuckerp@exchange.nih.gov
BACKGROUND: Few long-term clinical and histologic data for melanocytic lesions have been available based on the mutation status of families at an increased risk of melanoma. In the current study, the authors describe the clinical and histologic features of dysplastic nevi and melanoma over time in families at an increased risk of melanoma with differing germline mutations in CDKN2A, CDK4, or not yet identified genes. METHODS: Thirty-three families with > 2 living members with invasive melanoma were evaluated clinically and followed prospectively for up to 25 years. All the participants were evaluated by the same study team at the Clinical Center of the National Institutes of Health or in local clinics. After informed consent was obtained, family members (n = 844) were examined and photographed. Blood was obtained for genetic studies; genotyping for CDKN2A and CDK4 was performed. Sequential photographs of melanocytic lesions were taken as part of the clinical evaluations. When melanocytic lesions were removed, the histology was reviewed. Representative photographs and photomicrographs were selected for six classes of lesions and three mutation groups. RESULTS: All the families were found to have members with dysplastic nevi and melanoma; 17 had mutations in CDKN2A, 2 had mutations in CDK4, and 14 had no mutations in either gene identified. The majority of dysplastic nevi either remain stable or regress; few change in a manner that should cause concern for melanoma. With careful surveillance, melanomas can be found early. CONCLUSIONS: The melanomas and dysplastic nevi that were found to occur in the study families did not appear to vary by the type of mutation identified in the families. Copyright 2002 American Cancer Society.

25
UI - 12086864
AU - Weeraratna AT; Jiang Y; Hostetter G; Rosenblatt K; Duray P; Bittner M;
TI - Trent JM Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma.
SO - Cancer Cell 2002 Apr;1(3):279-88
AD - National Human Genome Research Institute, Cancer Genetics Branch, National Institutes of Health, Bethesda, MD 20892, USA.
Gene expression profiling identified human melanoma cells demonstrating increased cell motility and invasiveness. The gene WNT5A best determined in vitro invasive behavior. Melanoma cells were transfected with vectors constitutively overexpressing Wnt5a. Consistent changes included actin reorganization and increased cell adhesion. No increase in beta-catenin expression or nuclear translocation was observed. There was, however, a dramatic increase in activated PKC. In direct correlation with Wnt5a expression and PKC activation, there was an increase in melanoma cell invasion. Blocking this pathway using antibodies to Frizzled-5, the receptor for Wnt5a, inhibited PKC activity and cellular invasion. Furthermore, Wnt5a expression in human melanoma biopsies directly correlated to increasing tumor grade. These observations support a role for Wnt5a in human melanoma progression.

26
UI - 12112321
AU - Hussein MR; Sun M; Roggero E; Sudilovsky EC; Tuthill RJ; Wood GS;
TI - Sudilovsky O Loss of heterozygosity, microsatellite instability, and mismatch repair protein alterations in the radial growth phase of cutaneous malignant melanomas.
SO - Mol Carcinog 2002 May;34(1):35-44
AD - Department of Medicine (Dermatology), University of Wisconsin and William S. Middleton Memorial Veteran Hospital, Madison, Wisconsin 53715, USA.
Little is known about genomic alterations during development of the radial growth phase (RGP) of cutaneous malignant melanomas (CMMs). In this investigation polymerase chain reaction-based microsatellite assays were applied to analyze 13 RGP-CMMs with 18 microsatellite markers at six chromosomal regions: 1p, 3p, 4q, 6q, 9p, and 10q. Loss of heterozygosity (LOH) was found in eight cases (62%), at 9p22, 1p36, and 10q11, suggesting the presence of tumor-suppressor genes at these regions. LOH was encountered frequently at the interferon-alpha (31%) and D10S249 loci (15%). Low-level microsatellite instability (MSI) (11-16% of investigated loci unstable) was noted in three cases (23%). Two MSI banding patterns were seen: band shift and the presence of additional bands. To investigate the underlying mechanisms of the low-level MSI pattern, we analyzed the lesions for expression of mismatch repair (MMR) proteins with immunoperoxidase methods and mouse monoclonal antibodies. The average percentages of positively stained cells for human MutL homolog 1 (hMLH1), human MutS homolog 2 (hMSH2), and human MutS homolog 6 (hMSH6) in RGP-CMM (75.6 +/- 3.4%, 67.20 +/- 7.71%, and 76.6 +/- 2.1%, respectively) were reduced compared with benign nevi. No statistically significant differences in MMR protein expression were found between microsatellite-stable and low-level MSI lesions (P = 0.173, P = 0.458, and P = 0.385 for hMLH1, hMSH2, and hMSH6, respectively). There was a direct correlation between values for percentages of positively stained cells for hMSH2 and hMSH6 (r = +0.9, P = 0.03), suggesting that common mechanisms regulate their expression. In conclusion, LOH, MSI, and reduced MMR protein expression appear to be present in at least some RGP-CMMs and may play a role in their pathogenesis. Further studies are necessary to support these finding and to determine their diagnostic and prognostic significance. Copyright 2002 Wiley-Liss, Inc.

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