This review summarises the current knowledge of alterations in these two pathways at G1/S transition and specifically the role of the key cell cycle regulatory proteins pRb, p16INK4a (p16), cyclin D1, p27Kip1 (p27), p53 and p21Waf1/Cip1 (p21) in the pathogenesis of melanoma.
Since hypoxic microenvironments select for tumor cells with diminished therapeutic response, we investigated whether hypoxia unequally increases resistance to 3-BrPA in wt p53 MelJuso melanoma harbouring (Q61L)-mutant NRAS and wt BRAF, C8161 melanoma with (G12D)-mutant KRAS (G464E)-mutant BRAF, and A549 lung carcinoma with a KRAS (G12S)-mutation.
With FISH, three malignant melanomas had clones with only one p53-allele and an additional four malignant melanomas showed a reduced number of signals at the p53 tumour-suppressor gene locus compared with signals for the centromeric region of chromosome 17.
Since mutations in the p53 tumor suppressor gene contribute to drug resistance, we used genetically-matched human C8161 melanoma harbouring wt or DN-R175H mutant p53, to investigate the influence of p53 status on the potentiation of H(2)O(2) toxicity by: (a) intact sodium nitroprusside or nitroferricyanide (SNP), (b) its light-exhausted NO-depleted form (lex-SNP), (c) potassium ferricyanide, or (d) ferric ammonium sulphate.
The distributions of the p53 codon 72 genotypes in the basal cell carcinoma and malignant melanoma group were also not significantly different from the control group. p53 codon 72 arginine homozygosity does not appear to represent a significant risk factor for cutaneous squamous cell carcinoma and screening seems not to be indicated.Mol.Carcinog.30:56-61, 2001.
We have analyzed a combination of three functionally relevant variants of the p53 pathway in 258 individuals with sporadic malignant melanomas, 50 with hereditary malignant melanomas, and 799 healthy controls.
In this hospital-based case-control study we used allele-specific polymerase chain reaction for p53 codon 72 genotyping in blood specimens from 107 Greek patients with sporadic cutaneous melanoma and 145 healthy controls.
It is also suggested that there is no positive relationship between tetraploidy and poorer prognosis, and mutation and allelic loss of the p53 gene might be markers of aggressive form of malignant melanoma.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
In conclusion, this study found some evidence that in subjects over 50, p53 Arg/Arg genotype is associated with increased risk of CM as compared to genotypes Arg/Pro or Pro/Pro.
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.
The majority of the XP melanomas were of the lentigo maligna melanoma (LMM) type, as found in the elderly. p53 point mutations were found in 60% of XP-C melanomas and in only 10% of XPV melanomas, this latter frequency being similar to what has been reported in the general population.
The cytotoxicity of topoisomerase I inhibiting camptothecin, topoisomerase II inhibiting etoposide and their combination were investigated in wild type p53 Bowes and mutant p53 SK-MEL-28 melanoma cell lines during 24h.
As p53 gene mutations occur infrequently in malignant melanoma, other mechanisms are proposed to influence p53 protein expression in melanocytic lesions.
In this review, we will describe different p53 mutation spectra, in relation to the various histopathological types of skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and malignant melanoma as well as to the DNA repair efficiency of the patients.
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.
A number of genes previously recognized to have an important role in the development and progression of melanoma were identified including homozygous deletions of CDKN2A (13 of 39 samples), CDKN2B (10 of 39), PTEN (3 of 39), PTPRD (3 of 39), TP53 (1 of 39), and amplifications of CCND1 (2 of 39), MITF (2 of 39), MDM2 (1 of 39), and NRAS (1 of 39).
Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%-35%), another neural crest-derived malignancy.