Ras signaling is important for the intracellular transduction of mitogenic stimuli from activated growth factor receptors. We have investigated 37 sporadic malignant melanomas (15 primary cutaneous melanomas and 22 melanoma metastases) and 6 melanoma cell lines for mutations in the 3 Ras genes NRAS, KRAS and HRAS. All tumors and cell lines were additionally analyzed for mutation and expression of BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties, as well as for expression of RASSF1A, which encodes a Ras-binding protein with tumor suppressor properties. Mutational analyses identified somatic NRAS mutations in 2 primary melanomas, 4 melanoma metastases and 2 cell lines. One melanoma metastasis showed a somatic KRAS mutation whereas HRAS mutations were not detected. Malignant melanoma is a highly aggressive form of skin cancer that may progress to a fatal metastatic disease. Unfortunately, both incidence and mortality of melanomas have markedly increased over the past decades. 1,2 Because metastatic melanomas are commonly resistant to available treatment regimens, long-term survival has not significantly improved since the 1970s. 3 To develop novel therapeutic strategies, it is important to elucidate the yet poorly characterized molecular mechanisms that lead to melanoma initiation and progression. Molecular genetic studies have identified several genes that are aberrant in variable fractions of sporadic or familial melanomas. These include the tumor suppressor genes CDKN2A and PTEN, as well as the proto-oncogenes CDK4, CTNNB1, NRAS and MYCC. 4 -6 Genetic alterations in these genes result in aberrations of different cellular pathways that are crucially involved in the regulation of signal transduction, cell cycle progression and apoptosis. 6 We have focussed on the molecular analysis of genetic and epigenetic changes in a set of genes that are important for the intracellular transduction of mitogenic signals from the cell membrane to the cell nucleus, namely the Ras genes NRAS, KRAS and HRAS, as well as the Ras-related genes BRAF and RASSF1A. Previous studies have demonstrated somatic NRAS mutations in between 10 -37% of sporadic melanomas and up to 95% of hereditary melanomas from patients carrying germline CDKN2A mutations. [7][8][9][10] In addition, BRAF mutations have been detected as a common somatic aberration in both melanomas and melanocytic nevi. [11][12][13] The Ras proteins are highly homologous small G-proteins with GTPase activity that mediate the cellular response to growth stimuli by signaling via different effector cascades. 14 -16 A major mechanism of Ras-induced oncogenic transformation is related to an enhanced mitogen-activated kinase (MAPK) pathway signaling caused by Ras-dependent activation of Raf serine/threonine-specific kinases. Effects on other pathways, however, such as the phosphatidylinositol 3-kinase (Pi3-kinase) and the Ral guanine nucleotide exchange factors (Ral-GEF) signaling cascades, are also important for Ras-induced tumorigenesis. 14 -16 ...
Key words: adenomatous polyposis coli; -catenin; loss of heterozygosity; ICAT; mutation; skin tumor Cutaneous malignant melanomas (CMMs) have shown a marked increase in both incidence and mortality over the past decades. 1 The genetic alterations associated with the development and progression of these tumors are still poorly understood. Cytogenetic and molecular genetic studies have implicated a number of chromosomal and genetic changes in melanoma pathogenesis. 2,3 The genes known to be aberrant in variable subsets of malignant melanomas include tumor-suppressor genes, such as CDKN2A and PTEN, as well as protooncogenes, such as CDK4, NRAS and MYCC. 2-4 A previous study showed that melanoma cell lines frequently carry mutations in the -catenin gene (CTNNB1). 5 The -catenin protein is a central component of the Wnt (wingless) signal-transduction pathway, which plays an important role in development and tumorigenesis. 6 -8 The Wnt signal is transduced through cell membrane-associated receptors of the frizzled family and stabilizes -catenin, which then enters the cell nucleus and forms a complex with members of the Tcf/Lef-1 family of transcription factors. 7,8 Activation of Tcf/Lef-1 by binding to -catenin induces the transcription of various target genes, including protooncogenes such as MYCC and CCND1. 9,10 Within the cell nucleus, the activity of the -catenin-Tcf/Lef-1 complex can be inhibited by the protein Icat (inhibitor of -catenin and Tcf-4), which blocks the interaction between -catenin and Tcf-4 and thereby antagonizes Wnt signaling. 11 In addition, the level of -catenin in the cell is tightly regulated by a multiprotein complex composed of the APC tumor-suppressor protein, axin and Gsk-3. 6 -8 In the absence of Wnt signal, this complex promotes the phosphorylation of serine and threonine residues in the aminoterminal region of -catenin by Gsk-3. Phosphorylated -catenin can be bound by the F-box and WD40 domain-containing protein Btrc, also known as -Trcp, 12 and is thereby targeted for degradation via the ubiquitin/proteasome pathway. [13][14][15] Oncogenic activation of -catenin by amino acid substitutions or deletions affecting its N-terminal degradation box has been demonstrated in various human tumors, including melanoma cell lines, 5 as well as a small fraction of primary melanomas. 16,17 Individual melanoma cell lines with APC mutations have also been reported. 5 The BTRC and ICAT gene loci map to the long arm of chromosome 10 (10q24.3) and the short arm of chromosome 1 (1p36.2), respectively. 11,18 Both regions are frequently affected by LOH in melanomas. 2,19 -22 Furthermore, a familial melanoma gene locus has been linked to 1p36. 23 Thus, in addition to CTNNB1 and APC, the BTRC and ICAT genes are interesting candidates for melanoma-associated tumor-suppressor genes. To better define the role of alterations in Wnt signaling pathway genes in the pathogenesis of melanomas, we determined the expression of -catenin in a panel of sporadic melanomas from 37 patients and analyzed the...
Malignant melanomas frequently show loss of alleles on the long arm of chromosome 10. The PTEN (MMAC1) gene has been identified as a tumour suppressor gene at 10q23.3 that is mutated in various types of advanced human cancers. We have investigated a series of 40 sporadic melanomas from 37 patients (15 primary cutaneous melanomas and 25 melanoma metastases) for allelic losses on chromosome 10, as well as for deletion and mutation of the PTEN gene. Microsatellite analysis revealed loss of heterozygosity at loci located on 10q in tumours from 15 of 34 patients investigated (44%). Somatic PTEN mutations were identified in melanomas from 4 of 37 patients (11%), all of whom had metastatic disease. In two of these patients, the tumours had additionally lost one PTEN allele, indicating complete loss of wild-type PTEN in the tumour cells. Our findings corroborate that loss of heterozygosity on chromosome 10 is a frequent aberration in malignant melanomas and implicate PTEN as a tumour suppressor gene inactivated by somatic mutation in a fraction of these tumours.
Photodynamic therapy with topically applied δ-aminolaevulinic acid is used to treat skin tumours by employing endogenously formed porphyrins as photosensitizers. This study examines the time course of porphyrin metabolite formation after topical application of δ-aminolaevulinic acid. Porphyrin biosynthesis in human skin tumours (basal cell carcinoma, squamous cell carcinoma), in psoriatic lesions, and in normal skin was investigated. Skin areas were treated with δ-aminolaevulinic acid, and levels of total porphyrins, porphyrin metabolites and proteins were measured in samples excised after 1, 2, 4, 6, 9, 12 and 24 h. There was an increase in porphyrin biosynthesis in all tissues with maximum porphyrin levels in tumours between 2 and 6 h and in psoriatic lesions 6 h after treatment. The pattern of porphyrins showed no significant difference between normal and neoplastic skin, protoporphyrin being the predominant metabolite. The results suggest that optimum irradiation time for superficial epithelial skin tumours may be as soon as 2 h after application of δ-aminolaevulinic acid, whereas for treatment of psoriatic lesions an application time of 6 h is more suitable. © 1999 Cancer Research Campaign
The incidence of malignant melanoma has been continuously increasing over the last few decades. Non-plantar melanomas are nowadays usually diagnosed and treated surgically at an early stage. In contrast, melanoma in a plantar location is usually diagnosed at an advanced tumour stage, conferring a poor prognosis. To discover the reasons for this remarkable difference in recognition and prognosis, we analysed our cases of plantar malignant melanoma in a retrospective study. From 1990 to 1997, we treated 925 melanoma patients. Of these, 68 cases (7%) were classified as plantar melanoma. For non-plantar melanoma patients the mean age was 52.6 years, the mean Clark level was 2.8 and the mean tumour depth was 1.22 mm. In contrast, the mean age of patients with plantar melanoma was 63.3 years, the mean Clark level was 3.61 and the mean tumour depth was 2.55 mm. The mean time between the first observation of the plantar skin lesion and the first consultation with a physician (patients' delay) was 4.8 years and, on average, it took an additional 7 months before adequate surgical treatment was performed (physicians' delay). The prognosis of our patients was poor. In 98.5% (n = 67) further metastases were observed on follow-up. Since there is still no cure for advanced plantar malignant melanoma, the early detection and subsequent surgical treatment of plantar melanoma is decisive for the prognosis. Based on our results, the poor survival can be improved by a significant reduction in the time period between the first observation of a plantar skin lesion and surgical treatment. Therefore there is an urgent need for special preventive health care campaigns to reduce significantly both the patients' and the physicians' delay.
Extramammary Paget's disease (EPD) is a rare malignancy occurring mainly in apocrine gland-bearing regions. Surgical excision is the treatment of choice. This may be very difficult or even impossible if the disease is widespread or located in a critical anatomical site. We report on the successful treatment of a 71-year-old man with EPD in the suprapubic region with CO2 laser guided by photodynamic diagnosis.
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