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NCI CANCERLIT® Search: Hereditary Melanoma - October 2001
National Cancer Institute®
Last Modified: November 21, 2001
Table of Contents
1
UI - 21204715
AU - Ahmed NU; Shioda T; Coser KR; Ichihashi M; Ueda M
TI -
Aberrant expression of MSG1 transcriptional activator in human malignant
melanoma in vivo.
SO - Pigment Cell Res 2001 Apr;14(2):140-3
AD - Department of Dermatology, Kobe University School of Medicine, Japan.
MSG1 was originally isolated as a candidate pigmentation-related gene.
MSG1 mRNA transcripts were expressed strongly in cultured human and
mouse normal epidermal melanocytes, and in highly pigmented mouse
melanoma cells, while its expression was very weak in cultured
non-pigmented human melanoma cells. Thus, MSG1 was initially proposed to
be a melanocyte-specific gene, and its possible role in pigmentation has
been speculated. It was found recently that the MSG1 protein interacts
functionally with Smad4, which plays a pivotal role in signal
transduction of transforming growth factor-beta. In this study, we
analyzed MSG1 protein expression by immunohistochemistry using human
tumor samples from nevus and malignant melanoma to reveal its role in
pigmentation and melanoma development in vivo. A relatively strong but
heterogeneous expression of MSG1 protein was seen in melanomas compared
with weak expression in nevi. In nevi, MSG1 expression was mostly
confined to the pigmented region, while it was expressed in both
pigmented and non-pigmented regions in melanoma. Intracellularly, MSG1
protein was localized in the cytoplasm of nevus cells, but was seen in
both nuclei and cytoplasm of melanoma cells. These results support a
hypothesis that MSG1 plays a role in pigmentation. It is also suggested
that MSG1 may be involved in malignant transformation of pigment cells.
Alternatively, the aberrant expression of MSG1 in melanoma cells might
be due to the abnormal environment, including aberrant cytokine or
growth factor expression, associated with melanoma formation.
2
UI - 21204707
AU - Bar-Eli M
TI -
Gene regulation in melanoma progression by the AP-2 transcription
factor.
SO - Pigment Cell Res 2001 Apr;14(2):78-85
AD - Department of Cancer Biology, University of Texas M. D. Anderson Cancer
Center, Houston 77030, USA. mbareli@mail.mdanderson.org
The molecular changes associated with the transition of melanoma cells
from radial growth phase (RGP) to vertical growth phase [(VGP),
metastatic phenotype] are not very well defined. We previously
demonstrated that expression of the cell-surface adhesion molecule
MCAM/MUC18 correlates directly with the metastatic potential of human
melanoma cells. In addition, the progression of human melanoma towards
the metastatic phenotype is associated with loss of expression of the
tyrosine-kinase receptor c-KIT. In this review, I will summarize our
recent studies demonstrating that the expression of both genes is
regulated by the AP-2 transcription factor. Moreover, we have observed a
loss of AP-2 expression in metastatic melanoma cells. Re-expression of
AP-2 in the highly metastatic A375SM cells decreased their
tumorigenicity and inhibited their metastatic potential in nude mice.
MCAM/MUC18 mRNA and protein expression was significantly down-regulated
while c-KIT expression was up-regulated in the AP-2-transfected cells.
To further investigate the role of AP-2 in the progression of human
melanoma, we attempted to inactivate AP-2 in primary cutaneous melanoma
by using a dominant-negative AP-2, or the AP-2B gene. Expression of
AP-2B in SB-2 cells augmented their tumorigenicity in nude mice, and
upregulated MMP-2 expression and activity. As AP-2 also regulates other
genes that are involved in the progression of human melanoma such as
E-cadherin, p21/WAF-1, HER2/neu, Bcl-2, FAS/APO-1, IGF-R-1, VEGF and the
thrombin receptor (PAR-1), we therefore propose that loss of AP-2 is a
crucial event in the development of malignant melanoma. In addition, the
transition of melanoma cells from RGP to VGP is also associated with
over-expression of the transcription factors CREB and ATF-1. The notion
that the balance between AP-2 and CREB/ATF-1 expression determines the
progression of melanoma cells towards the metastatic phenotype will be
discussed.
3
UI - 21367959
AU - Obata T; Endo Y; Tanaka M; Uchida H; Matsuda A; Sasaki T
TI -
Deletion mutants of human deoxycytidine kinase mRNA in cells resistant
to antitumor cytosine nucleosides.
SO - Jpn J Cancer Res 2001 Jul;92(7):793-8
AD - Department of Experimental Therapeutics, Cancer Research Institute,
Kanazawa University, Kanazawa 920-0934, Japan.
takuma@kenroku.kanazawa-u.ac.jp
We studied mutational events in deoxycytidine (dCyd) kinase mRNA
expression, focusing on aberrant dCyd kinase mRNA, which has been
frequently observed in established cell lines resistant to antitumor
dCyd nucleoside analogues such as 1-beta-D-arabinofuranosyl cytosine
(Ara-C), gemcitabine (dFdC) and
2'-C-cyano-2'-deoxy-1-beta-D-arabinofuranosylcytosine (CNDAC). We
describe here the expression of aberrant dCyd kinase mRNAs identified as
splicing mutants. These mutants included deletions of the fifth exon in
CNDAC-resistant cells (originating from HT-1080 cells), of the third
exon in Ara-C-resistant cells (originating from SK-MEL-28 cells) and of
the fourth exon in 2'-deoxy-2'-methylidenecytidine (DMDC)-resistant
cells (originating from SK-MEL-28 cells). Various nucleoside-resistant
cells originating from the same parental HT-1080 cells were established.
The resulting cells expressed the same mRNA with deletion of the fifth
exon, and the location of splicing was independent of the type of
nucleosides used for the establishment of resistant cells. The deletion
of the fifth exon in dCyd kinase seems to be a target for acquisition of
resistance to antitumor cytosine nucleosides. However, distinct
mutations in the dCyd kinase gene seem to be associated with acquisition
of resistance to different antitumor cytosine nucleosides.
4
UI - 21380011
AU - Bastiaens M; ter Huurne J; Gruis N; Bergman W; Westendorp R; Vermeer BJ;
TI -
Bouwes Bavinck JN
The melanocortin-1-receptor gene is the major freckle gene.
SO - Hum Mol Genet 2001 Aug 1;10(16):1701-8
AD - Department of Dermatology and Department of Clinical Epidemiology,
Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The
Netherlands.
Ephelides and solar lentigines are different types of pigmented skin
lesions. Ephelides appear early in childhood and are associated with
fair skin type and red hair. Solar lentigines appear with increasing age
and are a sign of photodamage. Both lesions are strong risk indicators
for melanoma and non-melanoma skin cancer. Melanocortin-1-receptor
(MC1R) gene variants are also associated with fair skin, red hair and
melanoma and non-melanoma skin cancer. The purpose of this study was to
investigate the relationship between MC1R gene variants, ephelides and
solar lentigines. In a large case-control study, patients with melanoma
and non-melanoma skin cancer and subjects without a history of skin
cancer were studied. In all participants, the presence of ephelides in
childhood and solar lentigines by physical examination was assessed
according to strict definitions. The entire coding sequence of the MC1R
gene was analyzed by single-strand conformation polymorphism analysis
followed by sequence analyses. Carriers of one or two MC1R gene variants
had a 3- and 11-fold increased risk of developing ephelides,
respectively (both P < 0.0001), whereas the risk of developing severe
solar lentigines was increased 1.5- and 2-fold (P = 0.035 and P <
0.0001), respectively. These associations were independent of skin type
and hair color, and were comparable in patients with and without a
history of skin cancer. The population attributable risk for ephelides
to MC1R gene variants was 60%, i.e. 60% of the ephelides in the
population was caused by MC1R gene variants. A dosage effect was found
between the degree of ephelides and the number of MC1R gene variants. As
nearly all individuals with ephelides were carriers of at least one MC1R
gene variant, our data suggest that MC1R gene variants are necessary to
develop ephelides. The results of the study also suggest that MC1R gene
variants play a role, although less important, in the development of
solar lentigines.
5
UI - 21385666
AU - Udart M; Utikal J; Krahn GM; Peter RU
TI -
Chromosome 7 aneusomy. A marker for metastatic melanoma? Expression of
the epidermal growth factor receptor gene and chromosome 7 aneusomy in
nevi, primary malignant melanomas and metastases.
SO - Neoplasia 2001 May-Jun;3(3):245-54
AD - Department of Dermatology, University of Ulm, Ulm, Germany.
martin.udart@medizin.uni-ulm.de
Receptor tyrosine kinases such as the epidermal growth factor receptor
(EGFR) play an important role in a variety of malignant neoplasias,
making the search for aberrations in the relevant chromosomes an
important issue. Differential expression of the EGFR gene was
investigated by reverse transcriptase (RT)-PCR on tissue samples of
normal skin, nevi, primary melanomas, and melanoma metastases. The EGFR
gene is located on chromosome 7p12.3-p12.1. To determine the number of
chromosomes 7 in cell nuclei of the mentioned tissue samples we
performed fluorescence in situ hybridization (FISH) on touch
preparations, using a DNA probe that hybridizes specifically to the
centromeric region of chromosome 7. Additionally, chromosome 7 number in
interphase nuclei was determined in short-term primary cell cultures of
nevi, primary melanomas, and metastases. The highest EGFR gene
expression frequency was found in melanoma metastases. By FISH we
detected the highest fraction of cell nuclei with more than two
chromosomes 7 in the group of metastases. Our results suggest that
overexpression of the EGFR gene might play an important role in
metastasis of malignant melanoma. This is well reflected by polysomy 7,
possibly accounting for an increased EGFR gene copy number.
6
UI - 21417734
AU - Coulie PG; Karanikas V; Colau D; Lurquin C; Landry C; Marchand M; Dorval
TI -
T; Brichard V; Boon T
A monoclonal cytolytic T-lymphocyte response observed in a melanoma
patient vaccinated with a tumor-specific antigenic peptide encoded by
gene MAGE-3.
SO - Proc Natl Acad Sci U S A 2001 Aug 28;98(18):10290-5
AD - Cellular Genetics Unit, Institute of Cellular Pathology, Cliniques
Universitaires Saint-Luc, Universite de Louvain, Brussels B1200,
Belgium. coulie@gece.ucl.ac.be
Vaccination of melanoma patients with tumor-specific antigens recognized
by cytolytic T lymphocytes (CTL) produces significant tumor regressions
in a minority of patients. These regressions appear to occur in the
absence of massive CTL responses. To detect low-level responses, we
resorted to antigenic stimulation of blood lymphocyte cultures in
limiting dilution conditions, followed by tetramer analysis, cloning of
the tetramer-positive cells, and T-cell receptor (TCR) sequence analysis
of the CTL clones that showed strict specificity for the tumor antigen.
A monoclonal CTL response against a MAGE-3 antigen was observed in a
melanoma patient, who showed partial rejection of a large metastasis
after treatment with a vaccine containing only the tumor-specific
antigenic peptide. Tetramer analysis after in vitro restimulation
indicated that about 1/40,000 postimmunization CD8(+) blood lymphocytes
were directed against the antigen. The same TCR was present in all of
the positive microcultures. TCR evaluation carried out directly on blood
lymphocytes by PCR amplification led to a similar frequency estimate
after immunization, whereas the TCR was not found among 2.5 x 10(6)
CD8(+) lymphocytes collected before immunization. Our results prove
unambiguously that vaccines containing only a tumor-specific antigenic
peptide can elicit a CTL response. Even though they provide no
information about the effector mechanisms responsible for the observed
reduction in tumor mass in this patient, they would suggest that
low-level CTL responses can initiate tumor rejection.
7
UI - 21369696
AU - Sargent LM; Nelson MA; Lowry DT; Senft JR; Jefferson AM; Ariza ME;
TI -
Reynolds SH
Detection of three novel translocations and specific common chromosomal
break sites in malignant melanoma by spectral karyotyping.
SO - Genes Chromosomes Cancer 2001 Sep;32(1):18-25
AD - Toxicology and Molecular Biology Branch, Health Effects Laboratory
Division, National Institute of Occupational Safety and Health,
Morgantown, West Virginia, USA. lqsl@cdc.gov
Chromosomal aberrations in malignant melanoma cells have been reported
using standard chromosome banding analysis and comparative genomic
hybridization. To identify marker chromosomes and translocations that
are difficult to characterize by standard banding analysis, 15 early
passage malignant melanoma cell lines were examined using spectral
karyotyping. All 15 tumor cell lines had lost all or part of 1p and 10q.
Losses of material on chromosome arms 4p (12/15), 6q (12/15), 9p
(15/15), 12p (13/15), 12q (13/15), 13q (11/15), and 19q (14/15) were the
next most frequent events. Gain of chromosome arms 1q (11/15), 6p
(13/15), and 20q11 (14/15) was also observed. Interestingly, we
identified translocations der(12)t(12;20)(q15;q11),
der(19)t(10;19)(q23;q13), and der(12)t(12;19)(q13;q13) in 4/15 tumors.
Three recurring translocations involving four of the most frequent break
points were detected. The identification of recurring translocations and
unique chromosome break points in melanoma will aid in the
identification of the genes that are important in the neoplastic
process. Copyright 2001 Wiley-Liss, Inc.
8
UI - 21369704
AU - Pollock PM; Stark MS; Palmer JM; Walters MK; Aitken JF; Martin NG;
TI -
Hayward NK
Mutation analysis of the CDKN2A promoter in Australian melanoma
families.
SO - Genes Chromosomes Cancer 2001 Sep;32(1):89-94
AD - Joint Experimental Oncology Program of the Queensland Institute of
Medical Research, University of Queensland, and the Queensland Cancer
Fund, P.O. Royal Brisbane Hospital, Brisbane, Australia.
Approximately 50% of all melanoma families worldwide show linkage to
9p21-22, but only about half of these have been shown to contain germ
line CDKN2A mutations. It has been hypothesized that a proportion of
these families carry mutations in the noncoding regions of CDKN2A.
Several Canadian families have been reported to carry a mutation in the
5' UTR, at position -34 relative to the start site, which gives rise to
a novel AUG translation initiation codon that markedly decreases
translation from the wild-type AUG (Liu et al., 1999). Haplotype sharing
in these Canadian families suggested that this mutation is of British
origin. We sequenced 1,327 base pairs (bp) of CDKN2A, making up 1,116 bp
of the 5' UTR and promoter, all of exon 1, and 61 bp of intron 1, in at
least one melanoma case from 110 Australian families with three or more
affected members known not to carry mutations within the p16 coding
region. In addition, 431 bp upstream of the start codon was sequenced in
an additional 253 affected probands from two-case melanoma families for
which the CDKN2A mutation status was unknown. Several known
polymorphisms at positions -33, -191, -493, and -735 were detected, in
addition to four novel variants at positions 120, -252, -347, and -981
relative to the start codon. One of the probands from a two-case family
was found to have the previously reported Q50R mutation. No family
member was found to carry the mutation at position -34 or any other
disease-associated mutation. For further investigation of noncoding
CDKN2A mutations that may affect transcription, allele-specific
expression analysis was carried out in 31 of the families with at least
three affected members who showed either complete or "indeterminate" 9p
haplotype sharing without CDKN2A exonic mutations. Reverse transcription
polymerase chain reaction and automated sequencing showed expression of
both CDKN2A alleles in all family members tested. The lack of CDKN2A
promoter mutations and the absence of transcriptional silencing in the
germ line of this cohort of families suggest that mutations in the
promoter and 5' UTR play a very limited role in melanoma predisposition.
Copyright 2001 Wiley-Liss, Inc.
9
UI - 21455680
AU - Rizos H; Puig S; Badenas C; Malvehy J; Darmanian AP; Jimenez L; Mila M;
TI -
Kefford RF
A melanoma-associated germline mutation in exon 1beta inactivates
p14ARF.
SO - Oncogene 2001 Sep 6;20(39):5543-7
AD - Westmead Institute for Cancer Research, University of Sydney, Westmead
Hospital, Westmead NSW 2145, Australia. helen_rizos@wmi.usyd.edu.au
The INK4a/ARF locus encodes the cyclin dependent kinase inhibitor,
p16(INK4a) and the p53 activator, p14ARF. These two proteins have an
independent first exon (exon 1alpha and exon 1beta, respectively) but
share exons 2 and 3 and are translated in different reading frames.
Germline mutations in this locus are associated with melanoma
susceptibility in 20-40% of multiple case melanoma families. Although
most of these mutations specifically inactivate p16(INK4a), more than
40% of the INK4a/ARF alterations located in exon 2, affect both
p16(INK4a) and p14ARF. We now report a 16 base pair exon 1beta germline
insertion specifically altering p14ARF, but not p16(INK4a), in an
individual with multiple primary melanomas. This mutant p14ARF, 60ins16,
was restricted to the cytoplasm, did not stabilize p53 and was unable to
arrest the growth of a p53 expressing melanoma cell line. This is the
first example of an exon 1beta mutation that inactivates p14ARF, and
thus implicates a role for this tumour suppressor in melanoma
predisposition.
10
UI - 21448758
AU - Sarangarajan R; Budev A; Zhao Y; Gahl WA; Boissy RE
TI -
Abnormal translocation of tyrosinase and tyrosinase-related protein 1 in
cutaneous melanocytes of Hermansky-Pudlak Syndrome and in melanoma cells
transfected with anti-sense HPS1 cDNA.
SO - J Invest Dermatol 2001 Sep;117(3):641-6
AD - Department of Dermatology, University of Cincinnati, Cincinnati, Ohio
45267, USA.
Hermansky-Pudlak syndrome is an autosomal recessive disorder
characterized by oculocutaneous albinism, a bleeding disorder, and, in
some patients, ceroid storage and progressive lung disease. Although
Hermansky-Pudlak syndrome exhibits locus heterogeneity, most patients
have mutations in the HPS1 gene. Melanocytes in the basal epithelial
layer of skin from patients with different mutations in the HPS1 gene
exhibited occasional large complexes containing
dihydroxyphenylalanine-positive cisterna and 50 nm vesicles. To
characterize the role of the HPS1 protein in cells, human HPS1 cDNA was
transfected into pigmented SK-MEL-188 melanoma cells (M-188) in either
the sense (S-188) or the antisense (A-188) orientation. Expression of
the 79 kDa HPS1 protein (in M-188 and S-188 cells) or lack of expression
(in A-188 cells) was confirmed by Western blotting using two
HPS1-protein-specific polyclonal antibodies. Significant reduction in
expression of HPS1 protein in A-188 cells resulted in a significant
decrease in tyrosinase activity and melanin content compared with M-188
and S-188 cells using an intact cell assay for tyrosinase. In contrast,
tyrosinase activities in cell lysates of M-188, S-188, and A-188 cells
were not significantly different. Knockout of HPS1 protein expression in
A-188 cells caused both tyrosinase and tyrosinase-related protein 1 to
be localized to large granular complexes in the cell cytosol and
dendrites. Electron microscope analysis of the A-188 cells revealed that
absence of HPS1 protein resulted in the deposition of
dihydroxyphenylalanine reaction products (i.e., tyrosinase) confined to
large membrane-bound structures with limiting membranes. We conclude
that lack of HPS1 protein expression results in mistranslocation of
tyrosinase and tyrosinase-related protein 1 to large granular complexes
rather than melanosomes, compromising melanin synthesis.
11
UI - 21448766
AU - Dai Y; Kato M; Takeda K; Kawamoto Y; Akhand AA; Hossain K; Suzuki H;
TI -
Nakashima I
T-cell-immunity-based inhibitory effects of orally administered herbal
medicine juzen-taiho-to on the growth of primarily developed melanocytic
tumors in RET-transgenic mice.
SO - J Invest Dermatol 2001 Sep;117(3):694-701
AD - Department of Immunology, Nagoya University Graduate School of Medicine,
Showa-ku, Nagoya, Japan.
We examined the effect of oral administration of juzen-taiho-to, one of
the most popular herbal medicines in Japan, on primary melanocytic tumor
growth in RET-transgenic mice. There was virtually no difference between
the lengths of tumor-free stages in the juzen-taiho-to-treated mice and
the untreated littermate control mice. The rate of tumor growth in the
juzen-taiho-to-treated mice, however, was greatly suppressed during the
entire period after the initial tumor development. Correspondingly, the
life span of juzen-taiho-to-treated transgenic mice was longer (over 6
mo in mean value) than that of control mice. We partially elucidated the
mechanism of the antitumor effect of juzen-taiho-to. The addition of
juzen-taiho-to at any of a wide range (50-1600 microg per ml) of
concentrations to in vitro cultures of Mel-Ret cells, a malignant
melanoma cell line derived from a RET-transgenic mouse, caused neither
cell death nor cell cycle arrest directly. The addition of 50-400 microg
per ml of juzen-taiho-to to cultures of murine spleen cells, however,
promoted their DNA synthesis. More importantly, peritoneal exudate cells
from the juzen-taiho-to-treated transgenic mice, in which the ratio and
number of T cells were increased, displayed an antitumor immunity
against Mel-Ret cells in vitro. Interestingly, the
peritoneal-exudate-cell-associated antitumor immunity was further
augmented by the addition of 200-400 microg per ml of juzen-taiho-to in
vitro. This immunity, which was primarily conveyed by Thy-1+ T cells,
was antigen (RET/melanoma) specific and cytotoxic. Amongst various
chemical ingredients of juzen-taiho-to examined in this study,
glycirrhizin displayed an action, partially replacing that of
juzen-taiho-to, in promoting anti-Mel-Ret immunity when supplementarily
added in vitro. These results suggest that juzen-taiho-to suppresses
once-developed primary melanocytic tumors through potentiation of
T-cell-mediated antitumor cytotoxic immunity in vivo.
12
UI - 21298909
AU - Fusaro RM
TI -
Multiple interpretations of cancer risks from body mole counts in
preventive care.
SO - Arch Dermatol 2001 Jun;137(6):823
13
UI - 21429434
AU - Krimpenfort P; Quon KC; Mooi WJ; Loonstra A; Berns A
TI -
Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice.
SO - Nature 2001 Sep 6;413(6851):83-6
AD - Division of Molecular Genetics and Centre for Biomedical Genetics, The
Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
CDKN2A (INK4a/ARF) is frequently disrupted in various types of human
cancer, and germline mutations of this locus can confer susceptibility
to melanoma and other tumours. However, because CDKN2A encodes two
distinct cell cycle inhibitory proteins, p16INK4a and p14ARF (p19Arf in
mice), the mechanism of tumour suppression by CDKN2A has remained
controversial. Genetic disruption of Cdkn2a(p19Arf) (hereafter Arf)
alone predisposes mice to tumorigenesis, demonstrating that Arf is a
tumour-suppressor gene in mice. We mutated mice specifically in
Cdkn2a(p16Ink4a) (hereafter Ink4a). Here we demonstrate that these mice,
designated Ink4a*/*, do not show a significant predisposition to
spontaneous tumour formation within 17 months. Embryo fibroblasts
derived from them proliferate normally, are mortal, and are not
mice implies that the very strong phenotypes of the original
Ink4a/ArfDelta2,3 mice were primarily or solely due to loss of Arf.
However, Ink4a*/Delta2,3 mice that are deficient for Ink4a and
heterozygous for Arf spontaneously develop a wide spectrum of tumours,
including melanoma. Treatment of these mice with the carcinogen
7,12-dimethylbenzanthracene (DMBA) results in an increased incidence of
melanoma, with frequent metastases. Our results show that, in the mouse,
Ink4a is a tumour-suppressor gene that, when lost, can recapitulate the
tumour predisposition seen in humans.
14
UI - 99139514
AU - Nelson MA; Ariza ME; Yang JM; Thompson FH; Taetle R; Trent JM; Wymer J;
TI -
Massey-Brown K; Broome-Powell M; Easton J; Lahti JM; Kidd VJ
Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex
(CDC2L) on chromosome band 1p36 in melanoma.
SO - Cancer Genet Cytogenet 1999 Jan 15;108(2):91-9
AD - Arizona Cancer Center, Tucson 85724, USA.
The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and
CDC2L2, are localized to human chromosome band 1p36. The PITSLRE protein
kinases are a part of the p34cdc2 supergene family. Several protein
products of the CDC2L locus may be effector(s) in apoptotic signaling.
The larger PITSLRE p110 isoforms appear to regulate some aspect of RNA
splicing/transcription during the cell cycle. One or more of these genes
may function as tumor suppressor genes in melanoma. Using fluorescence
in situ hybridization, one allele of the CDC2L gene complex on
chromosome 1 was either deleted or translocated in 8 of 14 different
melanoma cell lines. We also observed mutations in the 5' promoter
region of the CDC2L1 gene in four different cell lines relative to
normal melanocytes using PCR-SSCP analysis and direct DNA sequencing.
Western blot analysis revealed decreased level of PITSLRE protein
expression in several cell lines, as well as in four surgical malignant
melanoma specimens relative to normal melanocytes. Thus, the decreased
PITSLRE protein expression appears to result from deletion of the CDC2L
alleles and possibly by mutations within the 5' promoter region. We
propose that aberrations in the CDC2L genes may contribute to the
pathogenesis or progression of melanoma.
15
UI - 21370568
AU - Poetsch M; Dittberner T; Woenckhaus C
TI -
Does the PITSLRE gene complex contribute to the pathogenesis of
malignant melanoma of the skin? A study of patient-derived tumor
samples?
SO - Cancer Genet Cytogenet 2001 Jul 15;128(2):181-2
16
UI - 21369396
AU - Goidin D; Mamessier A; Staquet MJ; Schmitt D; Berthier-Vergnes O
TI -
Ribosomal 18S RNA prevails over glyceraldehyde-3-phosphate dehydrogenase
and beta-actin genes as internal standard for quantitative comparison of
mRNA levels in invasive and noninvasive human melanoma cell
subpopulations.
SO - Anal Biochem 2001 Aug 1;295(1):17-21
AD - INSERM U 346, affiliee CNRS, Edouard Herriot Hospital, Lyon, F-69437,
France.
The comparison of the gene expression profiles between two
subpopulations of melanoma cells (1C8 and T1C3) derived from the tumor
of one patient by cDNA array revealed differences in GAPDH and
beta-actin gene levels. These two housekeeping genes were up-regulated
in invasive T1C3 melanoma cells compared to noninvasive 1C8 cells. Since
cDNA array results were not confirmed by conventional RT-PCR throughout
the exponential phase of amplification, we performed duplex relative
RT-PCR using ribosomal 18S RNA as internal standard including competimer
technology. Statistical analyses provided significant evidence that
invasive T1C3 melanoma cells exhibited a twofold higher mRNA level of
both GAPDH and beta-actin than noninvasive 1C8 cells. This study
demonstrates that the duplex relative RT-PCR procedure including
ribosomal 18S RNA as internal standard and competimer technology is
precise for RNA quantification and is tailored for cDNA array
validation. Our data provide molecular evidence that cellular
subpopulations of the same pathological origin are highly heterogeneous
and extend the concept that the selection of an appropriate internal
control for comparative mRNA analysis should be adapted to each model of
human cancers. Copyright 2001 Academic Press.
17
UI - 21372381
AU - Kageshita T; Mizuno M; Ono T; Matsumoto K; Saida T; Yoshida J
TI -
Growth inhibition of human malignant melanoma transfected with the human
interferon-beta gene by means of cationic liposomes.
SO - Melanoma Res 2001 Aug;11(4):337-42
AD - Department of Dermatology, Kumamoto University School of Medicine,
Japan.
Among the various types of human interferons, human interferon-beta
(HuIFNbeta) has the strongest anti-proliferative activity against human
melanoma cell lines. Therefore, we investigated the growth inhibitory
effect of a cationic liposome containing the HuIFNbeta gene on human
melanoma cell lines in vitro and in vivo. After transfection with
liposomes containing the HuIFN-beta gene, human melanoma cell lines
produced HuIFNbeta in the culture medium at levels ranging from 67 to
3.8 IU/ml on day 6, and growth of the cells was inhibited by 71-92%.
Moreover, six injections of liposomes containing the HuIFNbeta gene
completely eradicated human melanoma nodules transplanted onto the backs
of nude mice 40 days after the first injection. Histological analysis of
the injected nodules revealed that the HuIFNbeta gene transfection
induced apoptosis of the human melanoma cells. These data suggest that
transfection of the HuIFNbeta gene using cationic liposomes is a
promising candidate for gene therapy of human melanoma.
18
UI - 21372382
AU - Walker G; Hayward N
TI -
No evidence of a role for activating CDK2 mutations in melanoma.
SO - Melanoma Res 2001 Aug;11(4):343-8
AD - Queensland Cancer Fund Research Unit, Joint Experimental Oncology
Program, Queensland Institute of Medical Research, Post Office Royal
Brisbane Hospital, QLD 4029, Australia. graemeW@qimr.edu.au
Inactivation of p16INK4a and/or activation of cyclin-dependent kinase-4
(CDK4) are strongly associated with both susceptibility and progression
in melanoma. Activating CDK4 mutations prevent the binding and
inhibition of CDK4 by p16INK4a. A second, more indirect role for CDK4 is
in late G1, where it may sequester the inhibitors p27KIP1 or p21CIP1
away from CDK2, and in doing so upregulate the CDK2 activity necessary
for cells to proceed completely through G1 into S phase. As the pivotal
residues around the most predominant R24C activating CDK4 mutation are
invariant between CDK2 and CDK4, we speculated that the pivotal arginine
(position 22 in CDK2), or a nearby residue, may be mutated in some
melanomas, resulting in the diminution of its binding and inhibition by
p27KIP1 or p21CIP1. However, except for a silent polymorphism, we
detected no variants within this region of the CDK2 gene in 60 melanoma
cell lines. Thus, if CDK2 activity is dysregulated in melanoma it is
likely to occur by a means other than mutations causing loss of direct
inhibition. We also examined the expression of the CDK2 gene in melanoma
cell lines, to assess its possible co-regulation with the gene for the
melanocyte-lineage antigen pmel17, which maps less than 1 kb away in
head to head orientation with CDK2 and may be transcribed off the same
bidirectional promoter. However, expression of the genes is not
co-regulated.
19
UI - 21372383
AU - Bogdan I; Xin H; Burg G; Boni R
TI -
Heterogeneity of allelic deletions within melanoma metastases.
SO - Melanoma Res 2001 Aug;11(4):349-54
AD - Department of Dermatology, University Hospital Zurich, Gloriastreet 31,
8091 Zurich, Switzerland. bogdan@derm.unizh.ch
During the initiation and progression of malignant melanoma, a series of
different genetic events accumulate on several different chromosomes.
The biological heterogeneity of tumour cells presents a major problem,
preventing effective treatment of melanoma. To examine the degree of
genetic heterogeneity, we searched for allelic losses (loss of
heterozygosity; LOH) on chromosomes 9p, 9q, 1p and 17p, examining
different areas within human melanoma metastases. All of the examined
metastases were informative within at least one dissected area for at
least one marker. Out of 29 areas in 11 melanoma metastases, 58% showed
LOH with at least one marker. On chromosome 9p21-22, eight out of 26
informative loci (31%) showed LOH at D9S171 (three not informative), two
out of 18 (11%) at IFNA (11 not informative) and seven out of 24 (29%)
at D9S169 (five not informative). LOH on chromosome 9q22.3 was examined
by the microsatellite marker D9S12; three out of 24 areas (12.5%) showed
LOH, and five were not informative. Deletions on chromosome 1p were
assessed using D1S450. Four out of 25 (16%) showed LOH; four were not
informative. Deletions on chromosome 17p13 were examined with TP53; two
out of 21 cases (9%) showed LOH, and eight were not informative. Our
data demonstrate an impressive heterogeneity of allelic losses in the
investigated chromosomal areas within the same metastatic lesion. This
suggests that there is not one specific genetic alteration that accounts
for melanoma progression to metastases. Rather there seem to be multiple
genetic alterations accumulating even on the same chromosome, and
progression from melanoma to metastases is paralleled by the
accumulation of clones harbouring multiple genetic abnormalities.
20
UI - 21372384
AU - Gilhooly EM; Morse-Gaudio M; Bianchi L; Reinhart L; Rose DP; Connolly
TI -
JM; Reed JA; Albino AP
Loss of expression of protein kinase C beta is a common phenomenon in
human malignant melanoma: a result of transformation or differentiation?
SO - Melanoma Res 2001 Aug;11(4):355-69
AD - American Health Foundation, Valhalla, NY 10595, USA.
As with most cancers, the aetiology of human cutaneous melanoma is
likely to be multifactorial and to include the accumulation of
irreversible alterations in an unknown number of genes. Elucidating this
molecular progression necessitates both the identification of genetic
perturbations at each clinically relevant stage, and the assessment of
their impact on the normal melanocyte. The observation that the
epidermal melanocyte, in contrast to metastatic melanoma cells, requires
activation of the protein kinase C (PKC) pathway to facilitate growth in
vitro indicates that one or more isoforms (or substrates) of this large
and complex family of proteins are among those that undergo alteration
during the development of malignant melanoma. Consequently, a number of
studies have investigated the expression of various PKC family members
in both melanocyte and melanoma cell lines, without a consensus of
opinion as to which isoforms are of biological significance in melanoma
development and progression. The present study involved a comprehensive
evaluation of the PKC profile in normal melanocytes and in 16 metastatic
melanoma cell lines. The results show that the major difference in
isoform expression between epidermal melanocytes and melanoma cells is
the loss of PKCbeta protein expression in 90% of melanoma cell lines.
Examination of PKCbeta in benign and malignant melanocytic lesions
revealed that this protein is either downregulated or absent in both
naevi and metastatic melanomas. We conjecture that, although the loss of
PKCbeta expression is a common phenomenon in malignant melanocytes, it
may be related more to a normal process of melanocytic differentiation
than to malignant transformation.
21
UI - 21372385
AU - Max N; Willhauck M; Wolf K; Thilo F; Reinhold U; Pawlita M; Thiel E;
TI -
Keilholz U
Reliability of PCR-based detection of occult tumour cells: lessons from
real-time RT-PCR.
SO - Melanoma Res 2001 Aug;11(4):371-8
AD - Department of Medicine III, University Hospital Benjamin Franklin, Free
University Berlin, Hindenburgdamm 30, 12200 Berlin, Germany.
max@ukbf.fu-berlin.de
For the molecular detection of rare tumour cells in clinical samples,
real-time reverse transcription-polymerase chain reaction (RT-PCR)
offers two important advantages over conventional RT-PCR assays: the
results are quantitative and, perhaps more importantly, it facilitates
exact sensitivity controls on a per sample basis as well as exact
comparison of different assay protocols. We report here on quantitative
results obtained with different protocols for RNA isolation and cDNA
synthesis for amplification of beta2-microglobulin transcripts using the
light cycler system. Furthermore, housekeeping gene-specific PCRs were
compared with PCRs specific for an artificial transcript (internal
standard) detected simultaneously at a level comparable to the wild-type
sequence. Artificial tyrosinase transcripts derived from a vector
construct stably transfected into a human lymphoma cell line were used
as a model to test the usefulness of artificial internal standards as an
alternative to housekeeping genes. The highest RNA yields were obtained
using a combination of phenol-chloroform extraction and the High Pure
RNA Isolation Kit. Analysing beta2-microglobulin transcript-specific
RT-PCRs, the highest sensitivity was obtained for cDNAs generated with
Omniscript reverse transcriptase and oligo-p(dT)15 primer. Regarding
patient blood samples, RT-PCRs specific for beta2-microglobulin,
porphobilinogen deaminase and artificial tyrosinase transcripts provided
quantitative data for all, for 18 out of 21, and for 10 out of 21
samples, respectively. Quantification of beta2-microglobulin transcripts
by the light cycler system defined the protocol revealing the highest
cDNA quality. Comparisons of quantitative data from RT-PCRs specific for
beta2-microglobulin, porphobilinogen deaminase and artificial tyrosinase
transcripts enabled us to determine a close range for crossing points
within which sufficient cDNA quality can be guaranteed, even for the
detection of rare transcripts. PCRs specific for the artificial internal
standard are ideally suited for cDNA quality assessment on a per sample
basis.
22
UI - 21372386
AU - Lucas T; Pratscher B; Krishnan S; Fink D; Gunsberg P; Wolschek M;
TI -
Wacheck V; Muster T; Romirer I; Wolff K; Pehamberger H; Eichler HG;
Rangnekar VM; Jansen B
Differential expression levels of Par-4 in melanoma.
SO - Melanoma Res 2001 Aug;11(4):379-83
AD - Department of Clinical Pharmacology, Section of Experimental
Oncology/Molecular Pharmacology, University of Vienna, Wahringer Gurtel
18-20, A-1090 Vienna, Austria.
The pro-apoptotic prostate apoptosis response-4 gene product Par-4
sensitizes prostate cells to the induction of programmed cell death. In
this study we examined Par-4 expression in human melanoma cell lines and
melanoma metastases. The heterogeneous expression detected prompted us
to investigate the biological relevance of Par-4 in a human melanoma
xenotransplantation model. Overexpression of Par-4 by transfection
decreased tumour development in xenotransplanted A375-C6 melanoma cells
in SCID mice and correlated to an increase in tumour cell apoptosis.
These data suggest that high expression of the pro-apoptotic protein
Par-4 could qualify as a prognostic marker in human melanoma.
23
UI - 21372391
AU - Bosserhoff AK; Echtenacher B; Hein R; Buettner R
TI -
Functional role of melanoma inhibitory activity in regulating invasion
and metastasis of malignant melanoma cells in vivo.
SO - Melanoma Res 2001 Aug;11(4):417-21
AD - Institute of Pathology, RWTH Aachen, D-52074 Aachen, Germany.
bosserhoff@pat.rwth-aachen.de
MIA (melanoma inhibitory activity) has been previously isolated from the
tissue culture supernatant of melanoma cell lines as an autoregulatory
activity, inhibiting thymidine incorporation. However, subsequent
analyses of melanocytic tumours in vivo have correlated enhanced MIA
expression with progression of melanocytic tumours, conflicting with the
idea that MIA acts as a tumour suppressor. To investigate the role of
MIA in vivo, we have therefore generated a panel of stably transfected
B16 cell clones secreting different amounts of MIA. The capacity of
these cell clones to form lung metastases in syngeneic C57Bl6 mice was
strictly correlated to the level of MIA secretion, but the clones did
not differ with respect to their proliferation in vitro. In summary, we
suggest that MIA plays a causal role in promoting the metastasis of
malignant melanomas, involving inhibition of tumour cell attachment to
extracellular matrix molecules within their local milieu.
24
UI - 21426325
AU - Box NF; Duffy DL; Chen W; Stark M; Martin NG; Sturm RA; Hayward NK
TI -
MC1R genotype modifies risk of melanoma in families segregating CDKN2A
mutations.
SO - Am J Hum Genet 2001 Oct;69(4):765-73
AD - Centre for Functional and Applied Genomics, Institute for Molecular
Bioscience, University of Queensland, Brisbane, QLD 4029, Australia.
Mutations in the exons of the cyclin-dependent kinase inhibitor gene
CDKN2A are melanoma-predisposition alleles which have high penetrance,
although they have low population frequencies. In contrast, variants of
the melanocortin-1 receptor gene, MC1R, confer much lower melanoma risk
but are common in European populations. Fifteen Australian CDKN2A
mutation-carrying melanoma pedigrees were assessed for MC1R genotype, to
test for possible modifier effects on melanoma risk. A CDKN2A mutation
in the presence of a homozygous consensus MC1R genotype had a raw
penetrance of 50%, with a mean age at onset of 58.1 years. When an MC1R
variant allele was also present, the raw penetrance of the CDKN2A
mutation increased to 84%, with a mean age at onset of 37.8 years
(P=.01). The presence of a CDKN2A mutation gave a hazard ratio of 13.35,
and the hazard ratio of 3.72 for MC1R variant alleles was also
significant. The impact of MC1R variants on risk of melanoma was
mediated largely through the action of three common alleles, Arg151Cys,
Arg160Trp, and Asp294His, that have previously been associated with red
hair, fair skin, and skin sensitivity to ultraviolet light.
25
UI - 21426326
AU - van der Velden PA; Sandkuijl LA; Bergman W; Pavel S; van Mourik L;
TI -
Frants RR; Gruis NA
Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch
families with melanoma.
SO - Am J Hum Genet 2001 Oct;69(4):774-9
AD - Department of Human Genetics, Leiden University Medical Center, 2333 AL
Leiden, The Netherlands.
Germline mutations of the cell-cycle regulator p16 (also called
"CDKN2A") in kindreds with melanoma implicate this gene in
susceptibility to malignant melanoma. Most families with familial
atypical multiple-mole melanoma (FAMMM) who are registered at the Leiden
dermatology clinic share the same p16-inactivating deletion
(p16-Leiden). Incomplete penetrance and variable clinical expression
suggest risk modification by other genetic and/or environmental factors.
Variants of the melanocortin-1 receptor (MC1R) gene have been shown to
be associated with red hair, fair skin, and melanoma in humans. Carriers
of the p16-Leiden deletion in Dutch families with FAMMM show an
increased risk of melanoma when they also carry MC1R variant alleles.
The R151C variant is overrepresented in patients with melanoma who are
from families with the p16-Leiden mutation. Although some of the effect
of the R151C variant on melanoma risk may be attributable to its effect
on skin type, our analyses indicate that the R151C variant contributes
an increased melanoma risk even after statistical correction for its
effect on skin type. These findings suggest that the R151C variant may
be involved in melanoma tumorigenesis in a dual manner, both as a
determinant of fair skin and as a component in an independent additional
pathway.
26
UI - 21471441
AU - Richards B; Karpilow J; Dunn C; Zharkikh L; Maxfield A; Kamb A; Teng DH
TI -
Creation of a stable human reporter cell line suitable for FACS-based,
transdominant genetic selection.
SO - Somat Cell Mol Genet 1999 Jul;25(4):191-205
AD - Arcaris, Inc, 615 Arapeen Drive, Suite 300, Salt Lake City, Utah 84108,
USA.
Quality bioassays are central to all approaches directed at
understanding or perturbing the function of proteins. One type of
cell-based bioassay involves an engineered reporter whose
transcriptional activity serves as a readout for upstream signals of a
biochemical pathway(s) that feeds into the reporter. We describe a
general strategy for creating a mammalian reporter line with attributes
suitable for a high complexity, en masse transdominant genetic screen.
The basic criteria required of the mammalian cells engineered with the
reporter include ease of maintenance, ease of sorting by FACS, ability
to be transduced by retroviruses, and high expression of transduced
peptides or cDNAs. For maximal enrichment during selection, the reporter
line should have a relatively homogeneous response and a high
signal-to-background ratio. We use a melanoma cell line transduced with
a retinoic-acid-responsive promoter coupled to a GFP reporter as a case
study to demonstrate the strategy. We characterize an optimized
retinoic-acid-responsive reporter clone to determine the kinetics of
reporter induction and decay in the presence and absence of retinoids.
Dose-response studies reveal that the reporter responds to all-trans
retinoic acid with an EC50 of approximately 1 nM. The strategy described
is general and may be applied to create other reporter lines that
respond to a specific stimulus.
27
UI - 21464710
AU - Scholes AG; Liloglou T; Maloney P; Hagan S; Nunn J; Hiscott P; Damato
TI -
BE; Grierson I; Field JK
Loss of heterozygosity on chromosomes 3, 9, 13, and 17, including the
retinoblastoma locus, in uveal melanoma.
SO - Invest Ophthalmol Vis Sci 2001 Oct;42(11):2472-7
AD - Unit of Ophthalmology, Department of Medicine, The University of
Liverpool, United Kingdom. agms@liv.ac.uk
PURPOSE: To identify tumor-suppressor loci that may contribute to the
pathogenesis of uveal melanoma. METHODS: Multiplex fluorescence
microsatellite assays were performed on 27 uveal melanomas using markers
at 3p25-p26, 3p14.2, 9p21-p23, 13q14, 13q12.3-q13, and 17p13, close to
or within the von Hippel Lindau (VHL), fragile histidine triad (FHIT),
p16/cyclin-dependent kinase inhibitor 2 (CDKN2A), retinoblastoma (RB1),
breast cancer 2 (BRCA2), and p53 tumor suppressor loci, respectively.
Further markers on chromosomes 3 and 9 were analyzed individually.
RESULTS: Loss of heterozygosity (LOH) was identified in 63% of tumors,
most frequently on chromosome 3 (52%), in association with epithelioid
cells (P = 0.0002) and microvascular loops (P = 0.0008). In the majority
of cases, LOH on chromosome 3 was detected at all informative markers.
The second most common alteration was LOH at an RB1 intragenic marker
(21% tumors), with retention of a more centromeric 13q marker (near
BRCA2). The pattern of LOH on chromosome 9p was consistent with the
involvement of a region telomeric to CDKN2A. LOH at TP53 was infrequent.
CONCLUSIONS: In the majority of cases, chromosome 3 LOH involves an
entire chromosome homologue, which hampers identification of the
relevant suppressor lo
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