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NCI CANCERLIT® Search: Hereditary Melanoma - January 2002
National Cancer Institute®
Last Modified: January 1, 2002
Table of Contents
1
UI - 11394498
AU - Riley JP; Rosenberg SA; Parkhurst MR
TI -
Identification of a new shared HLA-A2.1 restricted epitope from the
melanoma antigen tyrosinase.
SO - J Immunother 2001 May-Jun;24(3):212-20
AD - Surgery Branch, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland 20892-1502, USA.
Tyrosinase has many advantages as a target antigen for the immunotherapy
of patients with melanoma because it is expressed in nearly all melanoma
specimens with a high degree of cellular homogeneity, and its
distribution in normal tissues is limited to melanocytes. To broaden our
ability to direct cellular immune responses against this protein, we
pursued an investigation to identify new shared human leukocyte antigen
(HLA)-A2.1 restricted epitopes from tyrosinase. Peptides were
synthesized that fit a permissive HLA-A2.1 binding motif and did not
span common sites of polymorphism. The binding affinity of each peptide
to HLA-A2.1 relative to a standard peptide with intermediate binding
affinity was evaluated in a competitive inhibition assay. Twelve
peptides were selected that had binding affinities within 80% of that of
the standard peptide, and these were used to stimulate peripheral blood
mononuclear cells (PBMC) in vitro from three HLA-A2.1+ patients with
metastatic melanoma. Cytotoxic T lymphocytes that specifically
recognized peptide-pulsed target cells as well as HLA-A2.1+ tyrosinase+
melanoma cells were raised from one patient with tyrosinase:8-17
(CLLWSFQTSA). To evaluate further the immunogenicity of this peptide,
PBMC from 23 HLA-A2.1+ patients were stimulated in vitro with
tyrosinase:8-17. Eleven bulk T-cell cultures demonstrated specific
peptide recognition, and six of these also recognized HLA-A2.1+
tyrosinase+ melanoma cells. These data suggest that tyrosinase:8-17 may
be clinically useful for the treatment of patients with melanoma.
2
UI - 11411928
AU - Helsing P; Hoyheim B
TI -
The Asp84Glu variant of the MC1R gene in Norwegian melanoma patients.
SO - Acta Derm Venereol 2001 Jan-Feb;81(1):68-9
3
UI - 11434722
AU - Heinzerling LM; Feige K; Rieder S; Akens MK; Dummer R; Stranzinger G;
TI -
Moelling K
Tumor regression induced by intratumoral injection of DNA coding for
human interleukin 12 into melanoma metastases in gray horses.
SO - J Mol Med 2001;78(12):692-702
AD - Institute of Medical Virology, University of Zurich, Switzerland.
Preclinical studies investigating new therapeutic principles against
melanoma are presently being carried out in mouse models; however, these
are not optimal. Here we describe a novel animal model using gray
horses. These animals spontaneously develop metastatic melanoma that
resembles human disease and is thus highly relevant for preclinical
studies testing new immunotherapy protocols. We found that injection of
plasmid DNA coding for the human cytokine interleukin 12 into
established metastases induced significant regression in all 12 treated
lesions in a total of 7 horses. Complete disappearance was observed in
one treated lesion, with no recurrence after 6 months. No adverse events
have been observed in any of the animals during and after treatment.
These results demonstrate the effectiveness and safety of interleukin 12
encoding plasmid DNA therapy against established metastatic disease in a
large animal model and serve as a basis for a clinical trial.
4
UI - 11480587
AU - Gutgemann A; Golob M; Muller S; Buettner R; Bosserhoff AK
TI -
Isolation of invasion-associated cDNAs in melanoma.
SO - Arch Dermatol Res 2001 Jun;293(6):283-90
AD - University Hospital RWTH Aachen, Institute of Pathology, Germany.
Metastasis and invasion are key steps in the systemic spread of tumor
cells. To identify the genes involved in this process we recently
selected highly invasive and weakly invasive cell clones from a melanoma
cell line. Both cell clones showed a stable phenotype over more than 40
passages and previous analyses revealed a fivefold difference in their
invasive potential in vitro and in tumorigenesis in vivo. To compare
gene expression of the two cell clones a cDNA array system (Clontech
human cancer cDNA array) was used. Exact quantification of
differentially expressed genes in each cell clone was performed by
real-time RT-PCR. An evaluation of the array data revealed a total of 36
genes that were more than 1.5-fold differentially expressed, and 26
(72%) of these showed a differential expression pattern by quantitative
RT-PCR. Previously known differences in expression patterns, including
loss of p16 and HLA I, or equal expression of p73, and RAR alpha, beta
and gamma were confirmed by the array data. In addition, reduced
expression levels of several cytoskeletal proteins, such as vimentin,
gamma-actin, desmin and cytokeratins, in the highly invasive cell clone
were reproducibly identified. Other genes strongly upregulated in the
highly invasive cell clone included jagged 2, STAT1, tPA and c-myc,
whereas MDA-6 (p21), caspase 2 and semaphorin were found to be
downregulated. In conclusion, comparative hybridization of cDNA arrays
identified a series of novel invasion-associated changes in gene
expression and confirmed previously known expression patterns.
5
UI - 11523115
AU - Okubo Y
TI -
[Overexpression of the human HOXD3-antisense in melanoma cells results
in decreased invasive activity]
SO - Hokkaido Igaku Zasshi 2001 Jul;76(4):239-50
AD - Department of Plastic and Reconstructive Surgery, Hokkaido University
Graduate School of Medicine, Sapporo 060-8638, Japan.
6
UI - 11529682
AU - Shiras A; Sengupta A; Shepal V
TI -
Cloning and tissue-specific gene expression studies with Dlxin-1, a
newly identified transcriptional activator.
SO - Mol Cell Biol Res Commun 2001 Sep;4(5):313-9
AD - National Centre for Cell Science (NCCS), NCCS Complex, Ganeshkhind,
Pune, 411007, India. Shiras99@hotmail.com
Dlxin-1, a unique member of the necdin/melanoma associated antigen gene
(MAGE) family, is a novel protein that binds Dlxin-5 and regulates its
transcriptional function. We have cloned the homology region between
Dlxin-1 and necdin from mouse melanoma cells. Here we report the
expression cloning, characterization, and detailed tissue-specific
expression studies of Dlxin-1. A unique expression pattern of Dlxin-1
emerged from the work wherein strong expression of a 3.2-Kb transcript
was observed in mouse brain and embryos. Amongst the representative
established cell lines of different tumor categories studied the
presence of transcript was detected only in sarcomas and neuroectodermal
tumors. Characteristically, lymphomas, leukaemias, adenocarcinomas, and
carcinomas did not express Dlxin-1. Also, we observed a growth
suppression on ectopic expression of this cDNA possibly due to the close
homology shared with necdin, a neuron-specific growth suppressor. The
extensive homology of our Dlxin-1 clone to necdin makes it an attractive
system to understand the importance of the necdin/MAGE family of
molecules in cell cycle regulation. Copyright 2001 Academic Press.
7
UI - 11556981
AU - Mendez R; Serrano A; Jager E; Maleno I; Ruiz-Cabello F; Knuth A; Garrido
TI -
F
Analysis of HLA class I expression in different metastases from two
melanoma patients undergoing peptide immunotherapy.
SO - Tissue Antigens 2001 Jun;57(6):508-19
AD - Departamento de Analisis Clinicos, Hospital Universitario Virgen de las
Nieves, Universidad de Granada, Spain.
We characterized the HLA class I alterations in five metastases obtained
from two patients with melanoma immunized with Melan A/MART-1,
tyrosinase and gp100 tumor peptides. All three metastases analyzed in
the first patient (NW145) showed a similar HLA class I alteration with a
dual population of melanoma cells. One population was HLA class I
antigen positive and the other had loss of heterozygosity (LOH) in the
short arm of chromosome 6 leading to an HLA haplotype loss (A02011,
B4007, Cw1). The absence of HLA-A2 antigen may explain why this patient
did not develop HLA-A2 restricted, Melan A/MART-1 specificity
immunization, since this HLA molecule is the restriction element for the
tumor peptides used. However, this HLA-deficient population was not
selected after peptide immunotherapy. The primary tumor in this patient
presented LOH in region 6q, but only in the vertical growth phase of the
lesion, whereas LOH at 6p was observed only in DNA from metastatic
material. The second patient (NW16) also presented two metastatic
lesions with an identical HLA molecular defect, i.e. HLA B locus
downregulation (HLA B51011: serological B51; B1503: serological B70).
One lesion expressed the tumor antigen (Melan A/ MART-1), but the other
did not. Interestingly, the antigen-positive metastasis regressed after
peptide immunotherapy, whereas the other progressed rapidly. These
findings provide the first indication that multiple metastases generated
in the same host can have identically altered HLA class I phenotypes.
8
UI - 11553709
AU - Voura EB; Ramjeesingh RA; Montgomery AM; Siu CH
TI -
Involvement of integrin alpha(v)beta(3) and cell adhesion molecule L1 in
transendothelial migration of melanoma cells.
SO - Mol Biol Cell 2001 Sep;12(9):2699-710
AD - Banting and Best Department of Medical Research, University of Toronto,
Toronto, Ontario, Canada M5G 1L6.
Tumor metastasis involves many stage-specific adhesive interactions. The
expression of several cell adhesion molecules, notably the integrin
alpha(v)beta(3), has been associated with the metastatic potential of
tumor cells. In this study, we used a novel in vitro assay to examine
the role of alpha(v)beta(3) in the transmigration of melanoma cells
through a monolayer of human lung microvascular endothelial cells.
Confocal microscopy revealed the presence of the integrin
alpha(v)beta(3) on melanoma membrane protrusions and pseudopods
penetrating the endothelial junction. alpha(v)beta(3) was also enriched
in heterotypic contacts between endothelial cells and melanoma cells.
Transendothelial migration of melanoma cells was inhibited by either a
cyclic Arg-Gly-Asp peptide or the anti-alpha(v)beta(3) monoclonal
antibody LM609. Although both platelet endothelial cell adhesion
molecule-1 and L1 are known to bind integrin alpha(v)beta(3), only L1
serves as a potential ligand for alpha(v)beta(3) during melanoma
transendothelial migration. Also, polyclonal antibodies against L1
partially inhibited the transendothelial migration of melanoma cells.
However, addition of both L1 and alpha(v)beta(3) antibodies did not show
additive effects, suggesting that they are components of the same
adhesion system. Together, the data suggest that interactions between
the integrin alpha(v)beta(3) on melanoma cells and L1 on endothelial
cells play an important role in the transendothelial migration of
melanoma cells.
9
UI - 11555786
AU - Issing WJ
TI -
[Expression of retinoic acid receptors in head and neck squamous cell
carcinomas and their possible implication for chemoprevention]
SO - Laryngorhinootologie 2001 Sep;80(9):530-4
AD - Klinik und Poliklinik fur Hals, Nasen und Ohrenkranke der
Ludwig-Maximilians, Universitat Munchen, Klinikum Grosshadern, Germany.
BACKGROUND: Retinoic acid and its natural and synthetic analogs
(retinoids) affect a wide array of biological processes. Retinoids are
used in the treatment of many skin diseases and are promising drugs for
several cancers. Most of their actions are thought to result from
changes in gene expression which is done through nuclear retinoic acid
receptors and retinoid X receptors. We conducted a study to determine
whether the expression of these receptors is different in malignant
tumors and tumor cell lines versus normal tissue. METHODS: We performed
reverse transcription PCR from 29 tissue specimens of squamous cell
carcinomas and one melanoma and of the head and neck as well as from 13
cell lines established from head and neck cancer. We were looking for
the expression pattern of RARalpha, beta, gamma and RXRalpha. RESULTS:
Only RARgamma was expressed 100 % in cell lines and tissue specimens.
RARbeta showed a 100 % expression only in tissue specimens whereas a 54
% expression in cell lines was seen. All other receptors were diminished
in their expression. In the positive controls all receptors were
expressed 100 %. CONCLUSION: The expression of RARalpha and RARbeta was
partially lost in cell lines established from squamous cell carcinoma of
the head and neck. The 100 % expression of RARbeta in tissue samples
versus 54 % in cell lines can be explained by clonal growth of malignant
cells in cell lines and also possible "contamination" by normal cells in
the tissue specimen. In concordance with the literature it seems that
RARalpha and beta play a pivotal role in mediating the response to
retinoids.
10
UI - 11574157
AU - Chakraborty AK; de Freitas Sousa J; Espreafico EM; Pawelek JM
TI -
Human monocyte x mouse melanoma fusion hybrids express human gene.
SO - Gene 2001 Sep 5;275(1):103-6
AD - Department of Dermatology, Yale University School of Medicine, New
Haven, CT 06520, USA. ashok.chakraborty@yale.edu
Artificial fusion of human monocyte with Cloudman S91 mouse melanoma
cells resulted in hybrids that showed increased motility in vitro,
enhanced metastatic potential in vivo, and also tended to be super
melanotic (Rachkovsky et al., Clin. Exp. Metastasis 16 (1998) 299).
However, no gene derived from monocytes has been shown to be expressed
in these hybrids until now. Similar observations have also been noted in
hybrids originating from mouse macrophage and mouse melanoma cells.
Having the advantage of species differences in mouse x human hybrids, we
are able, this time, to show by RT-PCR that some genes specific to the
human genome are expressed in these hybrids, indicating that not only is
the genomic DNA from parental monocytes integrated in the hybrids but
also some genes are being expressed. This observation may lead us to
find contributory genes from monocyte and/or macrophage that are
responsible for modulating the genotypes and hence the phenotypes in the
hybrids.
11
UI - 11581522
AU - Walter RB; Kazianis S
TI -
Xiphophorus interspecies hybrids as genetic models of induced neoplasia.
SO - ILAR J 2001;42(4):299-321
AD - Department of Chemistry and Biochemistry, Southwest Texas State
University (SWTSU), San Marcos, Texas, USA.
Fishes of the genus Xiphophorus (platyfishes and swordtails) are small,
internally fertilizing, livebearing, and derived from freshwater
habitats in Mexico, Guatemala, Belize, and Honduras. Scientists have
used these fishes in cancer research studies for more than 70 yr. The
genus is presently composed of 22 species that are quite divergent in
their external morphology. Most cancer studies using Xiphophorus use
hybrids, which can be easily produced by artificial insemination.
Phenotypic traits, such as macromelanophore pigment patterns, are often
drastically altered as a result of lack of gene regulation within hybrid
fishes. These fish can develop large exophytic melanomas as a result of
upregulated expression of these pigment patterns. Because backcross
hybrid fish are susceptible to the development of melanoma and other
neoplasms, they can be subjected to potentially deleterious chemical and
physical agents. It is thus possible to use gene mapping and cloning
methodologies to identify and characterize oncogenes and tumor
suppressors implicated in spontaneous or induced neoplasia. This article
reviews the history of cancer research using Xiphophorus and recent
developments regarding DNA repair capabilities, mapping, and cloning of
candidate genes involved in neoplastic phenotypes. The particular
genetic complexity of melanoma in these fishes is analyzed and reviewed.
12
UI - 11579459
AU - Auroy S; Avril MF; Chompret A; Pham D; Goldstein AM; Bianchi-Scarra G;
TI -
Frebourg T; Joly P; Spatz A; Rubino C; Demenais F; Bressac-de Paillerets
B; French Hereditary Melanoma Study Group
Sporadic multiple primary melanoma cases: CDKN2A germline mutations with
a founder effect.
SO - Genes Chromosomes Cancer 2001 Nov;32(3):195-202
AD - Service de Genetique, Institut Gustave Roussy, Villejuif, France.
Multiple primary cancers are one of the hallmarks of inherited
predisposition. Outside the familial context, multiple primary tumors
could be related either to germline de novo mutations or to
low-penetrance mutations, in predisposing genes. We selected 100
patients who displayed multiple primary melanoma (MPM) without any known
melanoma cases recorded within their families and looked for germline
mutations in the two melanoma-predisposing genes identified to date,
CDKN2A and CDK4 exon 2. Nine patients (9%) had germline mutations in
CDKN2A, whereas none carried germline mutations in exon 2 of CDK4. Seven
cases displayed a recurrent missense mutation, G101W, already described
in more than 20 melanoma-prone families; one case carried a missense
mutation never reported to date (P114S), and the last case was a carrier
of a 6 bp insertion at nucleotide 57 resulting in a duplication of
codons 18 and 19. To ascertain whether the G101W was a mutational hot
spot for de novo mutations or a common founder mutation, we genotyped
eight microsatellite markers flanking the CDKN2A gene. After allowing
for recombination over time, haplotype sharing provided evidence for an
original G101W mutation common to 6 out of 7 sporadic MPM cases.
Therefore, it can be concluded that de novo germline CDKN2A mutations
associated with MPM are rare. Copyright 2001 Wiley-Liss, Inc.
13
UI - 11583964
AU - Nakamoto K; Ito A; Watabe K; Koma Y; Asada H; Yoshikawa K; Shinomura Y;
TI -
Matsuzawa Y; Nojima H; Kitamura Y
Increased expression of a nucleolar Nop5/Sik family member in metastatic
melanoma cells: evidence for its role in nucleolar sizing and function.
SO - Am J Pathol 2001 Oct;159(4):1363-74
AD - Department of Molecular Genetics, Research Institute for Microbial
Diseases, Osaka University, Suita, Osaka, Japan.
F10 and BL6 cells of B16 mouse melanoma cells are metastatic after
intravenous injection, but only BL6 cells can metastasize to lungs after
subcutaneous injection. Differences in gene expression between the two
cell lines were examined, and a greater expression of the Sik-similar
protein (Sik-SP) gene was found in BL6 cells. Structurally, Sik-SP
belongs to the nucleolar Nop5/Sik family whose members play central
roles in ribosome biogenesis; however, the function of Sik-SP has not
been examined. Cytology with green fluorescent protein-fused proteins
showed that Sik-SP was localized to the nucleolus. To examine whether
Sik-SP is involved in ribosome biogenesis, two parameters were measured:
magnitude of ribosomal RNA synthesis per nucleus and magnitude of
protein production from the same amount of mRNA of an exogenous
luciferase gene. Both values and, in addition, nucleolar size were
larger in COS-7 monkey kidney cells overexpressing Sik-SP and BL6 cells
than in mock-transfected COS-7 and F10 cells, respectively. Sik-SP
seemed to promote ribosome biogenesis in the nucleolus. Furthermore, the
expression of Sik-SP seemed to confer a greater cell growth response to
serum, because such a response was greater in BL6 cells and F10 cells
overexpressing Sik-SP than in untreated and mock-transfected F10 cells.
Sik-SP may render melanoma cells more competent to survive through
augmenting the activity of nucleolus.
14
UI - 11584064
AU - Lynch HT; Sanger WG; Pirruccello S; Quinn-Laquer B; Weisenburger DD
TI -
Familial multiple myeloma: a family study and review of the literature.
SO - J Natl Cancer Inst 2001 Oct 3;93(19):1479-83
AD - Department of Preventive Medicine, Creighton University School of
Medicine, Omaha, NE 68178, USA. htlynch@creighton.edu
BACKGROUND: The etiology of multiple myeloma (MM) remains obscure,
although reports of familial clustering have implicated both a host
susceptibility factor and environmental effects. Here we describe the
medical histories of members of a family prone to MM. METHODS: We
developed a pedigree for an MM-prone family by using information
obtained from a questionnaire. Protein immunoelectrophoresis of serum
and urine from the proband and from 19 family members was performed to
detect monoclonal immunoproteins. Peripheral blood obtained from the
proband and from five relatives was subjected to standard cytogenetic
studies to detect constitutional chromosomal abnormalities.
Multifluor-fluorescence in situ hybridization (M-FISH) and standard FISH
studies were performed on peripheral blood from the proband and from two
other affected living relatives to determine their karyotypes and to
detect clonal chromosomal abnormalities frequently seen in patients with
MM. RESULTS: Within this family, a sibship of seven included three
individuals (including the proband) with histologically verified MM and
two individuals with a monoclonal gammopathy of unknown significance
(MGUS), as determined by immunoelectrophoresis of serum and urine. This
family also had members with acute lymphocytic leukemia, malignant
melanoma, and prostate cancer. In the family members tested, we detected
no constitutional chromosomal abnormality. None of the three individuals
analyzed by FISH had a deletion of the retinoblastoma (Rb-1) locus,
which is frequently deleted in patients with MM, and only one (the
proband) had a translocation involving chromosomes 11 and 14, a clonal
abnormality commonly seen in MM. CONCLUSION: The study of familial MM
may provide insights into the pathogenesis and, ultimately, the control
and prevention of MM and related disorders.
15
UI - 11592838
AU - Rudginsky S; Siders W; Ingram L; Marshall J; Scheule R; Kaplan J
TI -
Antitumor activity of cationic lipid complexed with immunostimulatory
DNA.
SO - Mol Ther 2001 Oct;4(4):347-55
AD - Genzyme Corporation, Framingham, Massachusetts 01701, USA.
We previously reported that treatment of intraperitoneal tumors with
complexes of cationic lipid and noncoding plasmid DNA leads to the
development of a specific, cytotoxic T-cell response correlating with
the rejection of established tumor cells as well as subsequent tumor
re-challenge. Here, focusing on an intraperitoneal AB12 mesothelioma
model, we show that the anticancer effects of the lipid:DNA complex are
associated with DNA containing immunostimulatory CpG motifs. Complexes
prepared with cationic lipid and bacterial plasmid DNA, Escherichia coli
genomic DNA fragments, or synthetic immunostimulatory CpG
oligodeoxynucleotides provided a substantial survival benefit, whereas
eukaryotic DNA and methylated bacterial DNA had little or no therapeutic
activity. Alternative inflammatory stimuli such as thioglycolate,
poly(I:C), and incomplete or complete Freund's adjuvant failed to
reproduce the antitumor activity obtained with the lipid:DNA complex.
The innate immune response triggered by lipid:DNA complexes led to the
development of a systemic immune response against tumor cells that
allowed animals to reject tumors not only at the intraperitoneal
treatment site, but also at a distal subcutaneous site. These data
demonstrate that immunostimulatory DNA complexed with cationic lipid is
a potent inducer of innate and adaptive immune responses against tumor
cells and represents a potentially useful tool in the immunotherapy of
cancers for which tumor-associated antigens have not been identified.
16
UI - 11594745
AU - Murakami T; Toda S; Fujimoto M; Ohtsuki M; Byers HR; Etoh T; Nakagawa H
TI -
Constitutive activation of Wnt/beta-catenin signaling pathway in
migration-active melanoma cells: role of LEF-1 in melanoma with
increased metastatic potential.
SO - Biochem Biophys Res Commun 2001 Oct 19;288(1):8-15
AD - Department of Dermatology, Jichi Medical School, 3311-1 Yakushiji,
Minamikawachi-machi, Kawachi-gun, Tochigi 329-0498, Japan.
takmu@jichi.ac.jp
A constitutive complex of beta-catenin and LEF-1 has been detected in
melanoma cell lines expressing either mutant beta-catenin or mutant APC
(Rubinfeld et al., Science, 275, 1790-1792, 1997). However, it has been
recently reported that beta-catenin mutations are rare in primary
malignant melanoma, but its nuclear and/or cytoplasmic localization, a
potential indicator of Wnt/beta-catenin pathway activation, is
frequently observed in melanoma (Rimm et al., Am. J. Pathol., 154,
325-329, 1999). In human malignant melanoma, the appearance of the
tumorigenic phase represents a capacity for metastasis and is the
significant phenotypic step in disease progression. Cell motility in
invasive melanoma is thought to play a crucial role in metastatic
behavior. In this work, we sought to determine which transcription
factor of the LEF/TCF family was preferentially involved in human
melanoma from different stages of tumor progression. We show that LEF-1
mRNA expression is predominant in highly migrating cells from metastatic
melanomas. These actively migrating melanoma cells showed nuclear and
cytoplasmic accumulation of beta-catenin and active transcription from a
reporter plasmid of the LEF/TCF binding site. These results may provide
a new insight into the role of the Wnt/beta-catenin signaling pathway in
the tumor progression of malignant melanoma. Copyright 2001 Academic
Press.
17
UI - 11595726
AU - Becker TM; Rizos H; Kefford RF; Mann GJ
TI -
Functional impairment of melanoma-associated p16(INK4a) mutants in
melanoma cells despite retention of cyclin-dependent kinase 4 binding.
SO - Clin Cancer Res 2001 Oct;7(10):3282-8
AD - Westmead Institute for Cancer Research, University of Sydney at Westmead
Millennium Institute, Westmead Hospital, NSW 2145, Australia.
therese_becker@mail.wmi.usyd.edu.au
PURPOSE: Melanoma-associated germ-line mutations affecting the tumor
suppressor and cyclin-dependent kinase (CDK) inhibitor,
CDKN2A/p16(INK4a) have been identified in >100 melanoma-prone families.
To predict the melanoma risk for carriers of specific mutations, it is
useful to test the function of the mutant proteins in biochemical
assays; however, it is unclear how well these results correlate with
their cellular effects. We examined the relationship between loss of CDK
binding by mutant proteins and various measures of cellular growth in
melanoma cells. EXPERIMENTAL DESIGN: The cellular activities of four
melanoma-associated p16(INK4a) mutations (Arg24Pro, Ala36Pro, Met53Ile,
and Val126Asp) were compared by use of inducible expression in stably
transfected melanoma cells, deficient in expression of the endogenous
protein, and compared with their ability to bind CDK4. RESULTS: The cell
cycle-inhibitory activity of all of the mutants was profoundly reduced,
and partially retained capacity for CDK4 binding in functional assays
did not correlate with significant preservation of cell cycle-regulatory
function. CONCLUSION: Testing of p16(INK4a) interactions with CDKs in
protein-binding assays is an unreliable predictor of mutant p16(INK4a)
function in cells. In addition to exhibiting reduced stability, these
mutant proteins may also be defective in interaction with cellular
targets other than CDKs.
18
UI - 11597184
AU - Radmacher MD; Simon R; Desper R; Taetle R; Schaffer AA; Nelson MA
TI -
Graph models of oncogenesis with an application to melanoma.
SO - J Theor Biol 2001 Oct 21;212(4):535-48
AD - Biometric Research Branch, National Cancer Institute, National
Institutes of Health, Bethesda, MD, USA. mdradmac@helix.nih.gov
We describe several analytical techniques for use in developing genetic
models of oncogenesis including: methods for the selection of important
genetic events, construction of graph models (including distance-based
trees, branching trees, contingency trees and directed acyclic graph
models) from these events and methods for interpretation of the
resulting models. The models can be used to make predictions about:
which genetic events tend to occur early, which events tend to occur
together and the likely order of events. Unlike simple path models of
oncogenesis, our models allow dependencies to exist between specific
genetic changes and allow for multiple, divergent paths in tumor
progression. A variety of genetic events can be used with the graph
models including chromosome breaks, losses or gains of large DNA
regions, small mutations and changes in methylation. As an application
of the techniques, we use a recently published cytogenetic analysis of
206 melanoma cases [Nelson et al. (2000), Cancer Genet. Cytogenet.122,
101-109] to derive graph models for chromosome breaks in melanoma. Among
our predictions are: (1) breaks in 6q1 and 1q1 are early events, with
6q1 preferentially occurring first and increasing the probability of a
break in 1q1 and (2) breaks in the two sets [1p1, 1p2, 9q1] and [1q1,
7p2, 9p2] tend to occur together. This study illustrates that the
application of graph models to genetic data from tumor sets provide new
information on the interrelationships among genetic changes during tumor
progression. Copyright 2001 Academic Press.
19
UI - 11606374
AU - Shirasaki F; Takata M; Hatta N; Takehara K
TI -
Loss of expression of the metastasis suppressor gene KiSS1 during
melanoma progression and its association with LOH of chromosome
6q16.3-q23.
SO - Cancer Res 2001 Oct 15;61(20):7422-5
AD - Department of Dermatology, Graduate School of Medical Science, School of
Medicine, Kanazawa University, Kanazawa 920-8641, Japan.
KiSS1 is a putative melanoma metastasis suppressor gene, the expression
of which may be regulated by another gene(s) mapping to chromosome
6q16.3-q23. To additionally elucidate the role of KiSS1 in the
progression of human melanoma in vivo, we examined KiSS1 mRNA expression
in 51 melanocytic tumors with various stages of progression by in situ
hybridization. We also examined a correlation between loss of KiSS1 mRNA
expression and loss of heterozygosity (LOH) of 6q16.3-q23 in 27 melanoma
metastases. All of the four nevocellular nevi and eight primary
melanomas <4 mm in thickness showed KiSS1 mRNA expression, whereas only
50% (6 of 12) of primary melanomas >4 mm in thickness expressed KiSS1.
Loss of KiSS1 mRNA was equally frequent in metastases; 44% (12 of 27) of
tumors lost KiSS1 expression. LOH of 6q16.3-q23 was observed in 52% (14
of 27) of metastases. There was a strong association between LOH and
loss of KiSS1 expression (P = 0.03); nine metastases with LOH of
6q16.3-q23 lost KiSS1 expression, whereas 10 tumors with no LOH showed
positive KiSS1 mRNA expression. The findings in this study show, for the
first time, KiSS1 down-regulation during the progression of melanoma in
vivo and strongly suggest that inactivation of a tumor suppressor
gene(s) mapping to 6q16.3-q23 by deletion or mutation coupled with LOH
may lead to the down-regulation of KiSS1.
20
UI - 11606406
AU - Polsky D; Bastian BC; Hazan C; Melzer K; Pack J; Houghton A; Busam K;
TI -
Cordon-Cardo C; Osman I
HDM2 protein overexpression, but not gene amplification, is related to
tumorigenesis of cutaneous melanoma.
SO - Cancer Res 2001 Oct 15;61(20):7642-6
AD - Ronald O. Perelman Department of Dermatology, New York University School
of Medicine/Veterans Affairs Medical Center, New York, New York 10016,
USA.
We investigated the role of alterations of HDM2, the human homologue of
murine mdm2, in the tumorigenesis and progression of cutaneous melanoma.
A well-characterized cohort of 172 cases representing different points
in the spectrum of melanocyte transformation (16 dysplastic nevi, 11
melanomas in situ, 107 invasive primaries, and 38 metastatic lesions),
as well as 11 human melanoma cell lines were examined by
immunohistochemistry and Western blotting for HDM2 protein expression,
and by either Southern blotting (SB) or fluorescence in situ
hybridization for HDM2 gene amplification. HDM2 overexpression, defined
as >20% tumor cells showing nuclear immunoreactivity, was observed in 1
of 16 (6%) dysplastic nevi, 3 of 11 (27%) melanomas in situ, and 81 of
145 (56%) invasive primary and metastatic melanomas. Comparable
frequencies of HDM2 overexpression were observed among invasive primary
cases with differing tumor thicknesses as well as among the metastatic
cases: 21 of 40 (53%) at < or =1.5 mm; 31 of 50 (62%) at 1.6-3.9 mm; 10
of 17 (58%) at >4 mm; and 19 of 38 (50%) metastases. HDM2 amplification
was observed in 1 of 88 (1%) primary cases using fluorescence in situ
hybridization, and in 0 of 12 (0%) metastatic cases that overexpressed
HDM2 using SB. Melanoma cell lines expressed HDM2 protein, but there was
no evidence of amplification by SB. Our data suggest that HDM2 protein
overexpression is common in invasive and metastatic melanoma. Observing
HDM2 overexpression in noninvasive melanoma suggests that expression of
this oncogene may play an early role in melanocyte transformation. HDM2
amplification occurs infrequently, and other mechanisms that up-regulate
HDM2 expression are under investigation.
21
UI - 11668523
AU - Kumar R; Smeds J; Berggren P; Straume O; Rozell BL; Akslen LA; Hemminki
TI -
K
A single nucleotide polymorphism in the 3'untranslated region of the
CDKN2A gene is common in sporadic primary melanomas but mutations in the
CDKN2B, CDKN2C, CDK4 and p53 genes are rare.
SO - Int J Cancer 2001 Nov 20;95(6):388-93
AD - Department of Biosciences, Center for Nutrition and Toxicology,
Karolinska Institute, Novum, Huddinge, Sweden. rajiv.kumar@cnt.ki.se
In this report we present the results of mutational analysis of the
CDKN2B, CDKN2C, CDK4, p53 genes and 5'UTR of the CDKN2A gene in a set of
44 sporadic primary melanomas, which had been earlier analysed for
mutations in the CDKN2A (p16/p14(ARF)) gene. No tumour-associated
mutations were detected except in 1 melanoma where we found a CC>T*
deletion-mutation in the codon 151-152 (exon 5) of the p53 gene. On the
basis of our preliminary results, we did extended genotyping of the 500
C>G and 540 C>T polymorphisms in the 3'UTR of the CDKN2A gene in 229
melanoma cases and 235 controls. The T-allele frequency (for 540 C>T
polymorphism) in melanomas was significantly higher than in controls
(0.14 vs. 0.08; chi(2) = 5.95, p = 0.01; OR = 1.71, 95%CI = 1.11-2.66).
The heterozygote frequency for this polymorphism was 0.26 (59/229) in
melanomas compared to 0.13 (30/235) in healthy controls (chi(2) = 11.4;
p = 0.0007; OR = 2.34, 95% CI = 1.40-3.92). The frequency of the 500 C>G
polymorphism in the 3'UTR in the CDKN2A gene was not significantly
higher in melanomas compared to healthy controls. The 500 C>G
polymorphism, however, was in linkage disequilibrium with approximately
50 kb apart the C>A intronic polymorphism in the CDKN2B gene (determined
in 44 melanomas and 90 controls; Fisher exact test, p<0.0001). Finally,
the sequence analysis of genomic DNA isolated from T cell lymphocytes of
healthy individuals exhibited that the codon reported as last of exon 2
of the CDKN2C gene is rather the first codon of exon 3. Copyright 2001
Wiley-Liss, Inc.
22
UI - 11673691
AU - Flaherty KT; Stevenson JP; O'Dwyer PJ
TI -
Antisense therapeutics: lessons from early clinical trials.
SO - Curr Opin Oncol 2001 Nov;13(6):499-505
AD - University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania
19104, USA. ktflaherty@aol.com
The authors review the early clinical experience with antisense
oligodeoxynucleotides, documenting their limited toxicity profile and
initial reports of efficacy. Several oncogene products, most notably
bcl-2, c-raf-1, protein kinase C-alpha, and H-ras, have been evaluated
as targets for therapeutic downregulation, and oligodeoxynucleotides
designed to inhibit the expression of these products specifically have
been studied extensively in phase I and II trials in cancer patients.
Inhibition of target expression in tumor (non-Hodgkin lymphoma) and
surrogate tissues has been demonstrated in several of these trials.
Continuous infusion over 2 to 3 weeks appears preferable to weekly
administration for toxicity and downregulation of target mRNA. The
efficacy data available suggest that antisense therapy alone appears
capable of limiting disease progression in some patients, but major
tumor responses are uncommon. The specificity and tolerability of these
oligodeoxynucleotides support the investigation of combinations of
antisense oligodeoxynucleotides with cytotoxic chemotherapy, and early
combination studies have yielded results of interest. Antisense
oligodeoxynucleotides against bcl-2, c-raf-1, and protein kinase C-alpha
continue to be the focus of ongoing trials.
23
UI - 11518711
AU - Rizos H; Darmanian AP; Holland EA; Mann GJ; Kefford RF
TI -
Mutations in the INK4a/ARF melanoma susceptibility locus functionally
impair p14ARF.
SO - J Biol Chem 2001 Nov 2;276(44):41424-34
AD - Westmead Institute for Cancer Research, University of Sydney at Westmead
Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145,
Australia. helen_rizos@wmi.usyd.edu.au
The INK4a/ARF locus encodes two cell cycle regulatory proteins, the
cyclin-dependent kinase inhibitor, p16(INK4a), and the p53 activator,
p14(ARF). Germline mutations in this locus are associated with melanoma
susceptibility in 20-40% of multiple case melanoma families. Many of
these mutations specifically impair p16(INK4a), whereas mutations
uniquely targeting p14(ARF) are rare. Nevertheless, the importance of
p14(ARF) has not been excluded because more than 40% of INK4a/ARF
alterations affect p16(INK4a) and p14(ARF). We now report that p14(ARF)
is functionally impaired in melanoma kindreds carrying INK4a/ARF
mutations. Of the seven INK4a/ARF mutations tested, three altered the
subcellular distribution of p14(ARF) and diminished the ability of
p14(ARF) to activate the p53 pathway. This work establishes the
importance of p14(ARF) in melanoma predisposition.
24
UI - 11684128
AU - Fonteneau JF; Larsson M; Somersan S; Sanders C; Munz C; Kwok WW;
TI -
Bhardwaj N; Jotereau F
Generation of high quantities of viral and tumor-specific human CD4+ and
CD8+ T-cell clones using peptide pulsed mature dendritic cells.
SO - J Immunol Methods 2001 Dec 1;258(1-2):111-26
AD - Laboratory of Cellular Physiology and Immunology, The Rockefeller
University, 1230 York Avenue, New York, NY, USA.
fontenj@rockvax.rockefeller.edu
CD4+ and CD8+ T cells are key components of immune response against
tumors and viruses. Many techniques have been used to clone and expand
these cells in vitro for purposes of immunotherapy. Here, we describe an
improved method to obtain large quantities of tumor and virus-specific
human CD4+ and CD8+ T-cell clones. T cells derived from peripheral blood
mononuclear cells (PBMCs) of healthy donors were stimulated several
times by peptide pulsed monocyte-derived mature dendritic cells (DCs) in
the presence of exogenous cytokines. T cells specific for influenza or
melanoma antigens were detected by IFN-gamma intracellular staining and
were cloned by limiting dilution. Specific polyclonal T-cell populations
were derived for all epitopes presented by mature DCs. Nine different
populations were cloned and clones were raised from eight of them.
Clonality was verified by HLA/peptide tetramer staining. With additional
rounds of stimulation after the cloning procedure, it was possible to
obtain from 10(9) to 10(12) of each clone. Furthermore, clones could be
maintained in culture in the presence of IL-2 for at least 1 month
without losing their antigen-specific reactivity (e.g. cytokine
secretion, cytolytic activity and proliferation). Importantly, a
majority of the CD8+ T-cell clones recognized endogenously processed
antigens. This method is of value for the purposes of adoptive
anti-virus or anti-tumor immunotherapy.
25
UI - 11704829
AU - Huang EY; Madireddi MT; Gopalkrishnan RV; Leszczyniecka M; Su Z;
TI -
Lebedeva IV; Kang D; Jiang H; Lin JJ; Alexandre D; Chen Y; Vozhilla N;
Mei MX; Christiansen KA; Sivo F; Goldstein NI; Mhashilkar AB; Chada S;
Huberman E; Pestka S; Fisher PB
Genomic structure, chromosomal localization and expression profile of a
novel melanoma differentiation associated (mda-7) gene with cancer
specific growth suppressing and apoptosis inducing properties.
SO - Oncogene 2001 Oct 25;20(48):7051-63<
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