G2Cdb::Human Disease report

Disease id
D00000035
Name
Malignant melanoma
Nervous system disease
no

Genes (3)

Gene Name/Description Mutations Found Literature Mutations Type Genetic association?
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (12124804) Single nucleotide polymorphism (SNP) Y
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (12124804) Deletion (D) Y
G00002235 CTNNB1
catenin (cadherin-associated protein), beta 1, 88kDa
Y (15133491) Single nucleotide polymorphism (SNP) Y
G00000036 NF1
neurofibromin 1
Y (8499944) Deletion (D) Y
G00000031 HRAS
v-Ha-ras Harvey rat sarcoma viral oncogene homolog
Y (2894003) TaqI polymorphism (TaP) Y

References

  • Genetic and epigenetic alterations of the APC gene in malignant melanoma.

    Worm J, Christensen C, Grønbaek K, Tulchinsky E and Guldberg P

    Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.

    High levels of beta-catenin and activating mutations in the beta-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic beta-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on beta-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity.

    Oncogene 2004;23;30;5215-26

  • Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC.

    Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, Ruzicka T and Reifenberger G

    Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany. reifenbergerj@med.uni-duesseldorf.de

    Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e., CTNNB1 (beta-catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (beta-transducin repeat-containing protein gene, 10q24.3) and ICAT (inhibitor of beta-catenin and Tcf-4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N-terminal degradation box of beta-catenin, which is important for the regulation of beta-catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real-time RT-PCR showed markedly reduced ICAT transcript levels (<or=20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts.

    International journal of cancer 2002;100;5;549-56

  • Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines.

    Andersen LB, Fountain JW, Gutmann DH, Tarlé SA, Glover TW, Dracopoli NC, Housman DE and Collins FS

    Howard Hughes Medical Institute, University of Michigan, Ann Arbor 48109.

    Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by progressive and variable involvement of tissues predominantly derived from the neural crest and a predisposition toward malignancies. The NF1 gene encodes neurofibromin, a GTPase-activating protein containing a GAP-related domain (NF1-GRD) that is capable of down-regulating ras by stimulating its intrinsic GTPase activity. We report a homozygous deletion of most of NF1 in one of eight malignant melanoma cell lines leading to loss of detectable mRNA and protein, as well as the apparent absence of protein and mRNA in another melanoma. This data suggests that NF1 can function as a tumour suppressor gene in the development or progression of malignant melanoma.

    Funded by: NCI NIH HHS: 1-F32-CA08985-01; NINDS NIH HHS: NS01590, NS23410; ...

    Nature genetics 1993;3;2;118-21

  • HRAS1 proto-oncogene polymorphisms in human malignant melanoma: TaqI defined alleles significantly associated with the disease.

    Radice P, Pierotti MA, Borrello MG, Illeni MT, Rovini D and Della Porta G

    Division of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.

    We have analysed the DNA of peripheral blood leukocytes (PBL) from 55 melanoma patients and 53 healthy individuals and failed to find any significant association between melanoma and rare HRAS1 alleles defined by MspI/HpaII digestion. However, the analysis of the same DNAs for a different polymorphism based on the presence of additional TaqI sites in the variable tandem repeat region of HRAS1 showed that the total frequency of a group of allelic variants, named Tp, was significantly higher in melanoma patients than in normal donors.

    Oncogene 1987;2;1;91-5

Literature (4)

Pubmed - human_disease

  • Genetic and epigenetic alterations of the APC gene in malignant melanoma.

    Worm J, Christensen C, Grønbaek K, Tulchinsky E and Guldberg P

    Institute of Cancer Biology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark.

    High levels of beta-catenin and activating mutations in the beta-catenin gene (CTNNB1) have been demonstrated in malignant melanomas, implicating dysregulated Wnt signalling in the pathogenesis of this malignancy. We systematically examined melanoma cell lines for activating CTNNB1 mutations as well as genetic and epigenetic alterations of the adenomatous polyposis coli gene (APC), another key component of the Wnt signalling transduction pathway. Of 40 cell lines tested, one carried a truncating APC mutation and loss of the corresponding wild-type allele, and one carried a CTNNB1 missense mutation. Hypermethylation of APC promoter 1A was present in five of the cell lines (13%) and in nine of 54 melanoma biopsies (17%). Cells with truncating APC or activating CTNNB1 mutations showed increased transcription from endogenous and ectopic beta-catenin/T-cell factor (Tcf)-responsive target genes, consistent with the known effects of these alterations on beta-catenin stability and Tcf transactivation. In contrast, cell lines with APC promoter 1A hypermethylation did not show increased Wnt signalling, probably due to residual APC activity expressed from promoter 1B. Suppression of APC transcripts in melanoma cells by stable expression of short hairpin RNAs led to a Wnt signalling-independent increase in cell proliferation, but also reduced the invasive growth in collagen type I. Collectively, our data suggest that the tumour-suppressive function of APC in melanocytic cells is dose dependent. We propose that epigenetic silencing of promoter 1A may contribute to the development of malignant melanoma by reducing the expression of APC to a level that promotes cell proliferation without compromising the invasive capacity.

    Oncogene 2004;23;30;5215-26

  • Mutations in the neurofibromatosis 1 gene in sporadic malignant melanoma cell lines.

    Andersen LB, Fountain JW, Gutmann DH, Tarlé SA, Glover TW, Dracopoli NC, Housman DE and Collins FS

    Howard Hughes Medical Institute, University of Michigan, Ann Arbor 48109.

    Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by progressive and variable involvement of tissues predominantly derived from the neural crest and a predisposition toward malignancies. The NF1 gene encodes neurofibromin, a GTPase-activating protein containing a GAP-related domain (NF1-GRD) that is capable of down-regulating ras by stimulating its intrinsic GTPase activity. We report a homozygous deletion of most of NF1 in one of eight malignant melanoma cell lines leading to loss of detectable mRNA and protein, as well as the apparent absence of protein and mRNA in another melanoma. This data suggests that NF1 can function as a tumour suppressor gene in the development or progression of malignant melanoma.

    Funded by: NCI NIH HHS: 1-F32-CA08985-01; NINDS NIH HHS: NS01590, NS23410; ...

    Nature genetics 1993;3;2;118-21

  • HRAS1 proto-oncogene polymorphisms in human malignant melanoma: TaqI defined alleles significantly associated with the disease.

    Radice P, Pierotti MA, Borrello MG, Illeni MT, Rovini D and Della Porta G

    Division of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy.

    We have analysed the DNA of peripheral blood leukocytes (PBL) from 55 melanoma patients and 53 healthy individuals and failed to find any significant association between melanoma and rare HRAS1 alleles defined by MspI/HpaII digestion. However, the analysis of the same DNAs for a different polymorphism based on the presence of additional TaqI sites in the variable tandem repeat region of HRAS1 showed that the total frequency of a group of allelic variants, named Tp, was significantly higher in melanoma patients than in normal donors.

    Oncogene 1987;2;1;91-5

Pubmed - other

  • Molecular genetic analysis of malignant melanomas for aberrations of the WNT signaling pathway genes CTNNB1, APC, ICAT and BTRC.

    Reifenberger J, Knobbe CB, Wolter M, Blaschke B, Schulte KW, Pietsch T, Ruzicka T and Reifenberger G

    Department of Dermatology, Heinrich-Heine-University, Düsseldorf, Germany. reifenbergerj@med.uni-duesseldorf.de

    Aberrant activation of the Wnt signaling pathway has been reported in different human tumor types, including malignant melanomas. We investigated 37 malignant melanomas (15 primary tumors and 22 metastases) for alterations of 4 genes encoding members of this pathway, i.e., CTNNB1 (beta-catenin gene, 3p22.1), APC (adenomatous polyposis coli gene, 5q22.2), BTRC (beta-transducin repeat-containing protein gene, 10q24.3) and ICAT (inhibitor of beta-catenin and Tcf-4, 1p36.2). Mutational analysis of CTNNB1 identified somatic mutations in 1 primary melanoma and 1 melanoma metastasis from 2 different patients (5%). Both mutations affected the N-terminal degradation box of beta-catenin, which is important for the regulation of beta-catenin homeostasis. Another primary melanoma carried a somatic APC missense mutation within the known mutation cluster region in exon 15. Fourteen tumors (40%) showed LOH at microsatellite markers on 1p36. None of the tumors had lost both copies of the ICAT gene, but 1 melanoma metastasis carried a somatic point mutation altering the translation start codon of ICAT. Real-time RT-PCR showed markedly reduced ICAT transcript levels (<or=20% relative to normal skin and benign melanocytic nevi) in 28/36 malignant melanomas (78%), including 13/14 tumors with LOH on 1p36. Allelic loss on 10q was detected in 15 tumors (44%). We found neither mutations nor complete loss of expression of the BTRC gene in our melanoma series. Taken together, our results indicate that the Wnt pathway may be altered in malignant melanomas by different mechanisms, including rare somatic mutations in CTNNB1, APC or ICAT, as well as low or absent expression of ICAT transcripts.

    International journal of cancer 2002;100;5;549-56

© G2C 2014. The Genes to Cognition Programme received funding from The Wellcome Trust and the EU FP7 Framework Programmes:
EUROSPIN (FP7-HEALTH-241498), SynSys (FP7-HEALTH-242167) and GENCODYS (FP7-HEALTH-241995).

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