Background Cyclin D1 is a key cell cycle regulator of the G1–S transition. A common single nucleotide polymorphism A870G in exon 4 of CCND1 (encoding cyclin D1) has been associated with carcinogenesis and tumor progression. Alternate splicing of CCND1 which produces two major transcripts is modulated by the A870G polymorphism. Both A and G alleles are capable of yielding both transcripts, but the A allele is associated with preferential production of an aberrant splicing product termed cyclin D1b which lacks the PEST domain. It has been hypothesized that since cyclin D1b lacks the PEST domain which destabilises cyclin D1 it might be more stable than the full-length cyclin D1a. Our aim was to investigate whether there is an association between the CCND1 A870G polymorphism and age of onset of melanoma.

Purpose: Both the retinoblastoma and p53 pathways are often genetically altered in human cancers and their complex regulation is in part mediated by the three gene products p16, p14ARF, and p15 of the INK4 locus on chromosome 9p21. Partial or complete biallelic deletions of the INK4 locus have been recognized in a variety of malignant tumors, including malignant melanoma. We have in the present study measured the frequency of INK4 deletions in a large number of melanoma metastases and determined their association with clinicopathologic variables and survival data. Experimental Design: Quantitative real-time PCR, as well as fluorescence-based fragment analysis, has been used to perform measurements of the relative allelic concentrations of the INK4 genes in 112 human melanoma tumor samples from 86 patients. Results: Thirty-eight of 86 melanoma patients (44%) had metastases with biallelic losses in INK4. Ten of 20 patients with multiple metastases showed similar deletion patterns in all analyzed tumors. There was no significant association between any of the clinicopathologic variables and loss of INK4. However, loss of INK4 had an adverse effect on median survival from time of diagnosis. Patients with tumors with diploid INK4 had a median survival of 142 months, whereas those with monoallelic or biallelic loss in INK4 had a median survival of only 47 months (P = 0.006). Conclusions: Our results point to homozygous deletions in the INK4 region as being one of the most common genetic alterations in malignant cutaneous melanoma. INK4 deletions are associated with an adverse prognosis.

Hansson, J.; Grafström, E.; Omholt, K.; Egyházi, S.; Ringborg, U.; Platz, A. Author Information

Immunohistochemical analysis of the N-ras p21 and the p53 proteins was carried out on formalin-fixed sections of naevi, primary melanomas and metastases from patients with sporadic melanoma (SCMM) and with hereditary melanoma (HCMM)/dysplastic naevus syndrome (DNS), Seven out of 11 (64%) common naevi and three out of nine (33%) dysplastic naevi showed increased cytoplasmic N-ras expression. No p53 immunopositivity could be recognized in any of the naevus samples, However, strong N-ras expression as well as immunopositivity for p53 was recognized among primary melanomas and metastases with significantly higher frequency among samples from patients with HCMM compared with samples from SCMM cases (for N-ras, 40% vs 10%, P < 0.01; and for p53 43% vs 17%, P < 0.05). We have earlier registered N-ras codon 61 mutations among metastases from 59% of patients with HCMM and from 24% of subjects with SCMM, A comparison of the genetic data with the immunohistochemical results showed occurrence of increased N-ras p21 expression in the presence and absence of detectable N-ras mutant alleles, Increased expression of wildtype N-ras p21 may contribute to tumorigenicity in the absence of mutational activation, at least in a subset of melanomas, Altogether, N-ras p21 alterations are registered at earlier stages than p53 alterations in melanoma development and may be of aetiological importance, whereas p53 alterations may be associated with tumour progression in the late stages, The increased frequency of phenotypic alterations registered among samples from HCMM/DNS patients may be a result of genetic instability and hypermutability and may be caused by various genetic changes such as altered gene dosage or regulatory as well as structural mutations.

Expression of the detoxication enzyme glutathione transferase P1-1 (GST P1-1) at elevated levels has been noted in many types of human tumors, including melanomas. The products of the human H-RAS, K-RAS and N-RAS genes play a key role in intracellular signal transduction leading to transcriptional activation of AP-1 (Fos/Jun) responsive genes. The oncogenic mutated forms of the ras proteins are constitutively active and interfere with normal signal transduction. Mutated RAS genes as well as increased expression of wild-type ras proteins are common features in human tumors including melanoma. We have characterized 30 melanoma metastases from 23 melanoma patients with reference to N-RAS expression and mutation as well as to GST P1 expression (immunohistochemistry and genetic analysis). Twenty-three of 30 samples (70%) had high N-Ras p21 and/or N-RAS codon 61 mutations and 18 of these 23 samples also had high GST P1-1 immunoreactivity. Seven of 30 (23%) samples had low N-Ras p21 immunoreactivity and no detectable N-RAS codon 61 mutations. Six of these 7 samples (86%) also had low GST P1-1 immunoreactivity. The results indicate a statistically significant correlation (Spearman correlation coefficient, r = 0.56, p = 0.001, 2-tailed test) and provide, for the first time, indirect evidence for a possible coregulation of N-RAS and GST P1 in human malignant melanoma which should be further evaluated.

Melanoma Research is a well established international forum for the dissemination of new findings relating to melanoma. The aim of the Journal is to promote the level of informational exchange between those engaged in the field. Melanoma Research aims to encourage an informed and balanced view of experimental and clinical research and extend and stimulate communication and exchange of knowledge between investigators with differing areas of expertise. This will foster the development of translational research. The reporting of new clinical results and the effect and toxicity of new therapeutic agents and immunotherapy will be given emphasis by rapid publication of Short Communications. ​Thus, Melanoma Research seeks to present a coherent and up-to-date account of all aspects of investigations pertinent to melanoma. Consequently the scope of the Journal is broad, embracing the entire range of studies from fundamental and applied research in such subject areas as genetics, molecular biology, biochemistry, cell biology, photobiology, pathology, immunology, and advances in clinical oncology influencing the prevention, diagnosis and treatment of melanoma.