PTEN/MMAC1 expression in melanoma resection specimens

Abstract

PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semiquantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/ MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas.

PTEN regulates motility but not directionality during leukocyte chemotaxis

“…This contrasts with Dictyostelium cells, in which around 10% of PTEN associates the cell perimeter after chemoattractant stimulation (Iijima and Devreotes, 2002). Our data are nonetheless consistent with other studies in mammalian cells, which indicate that the bulk of PTEN is in the cytoplasm and/or nucleus (Deichmann et al, 2002;Gimm et al, 2000;Wu et al, 2000). The mechanisms regulating PTEN activity and subcellular distribution are not yet fully known.…”

BRAF alterations are associated with complex mutational profiles in malignant melanoma

“…For the P38S variant, already reported (Guldberg et al, 1997), only the mutated allele was detected, suggesting that the wild-type allele has been deleted. The P246S missense mutation is a novel variant ( Figure 1b); it affects a region next to phosphate acceptor sites (residues 233-240) possibly altering the PTEN protein function (Deichmann et al, 2002). A third PTEN point mutation leading to a substitution of cysteine by arginine at position 105 was detected in one sample (30966 M) in association with a deletion (T313C þ 314delT) inducing a frame shift and a novel stop codon in position 112 (C105fsX112).…”

Immunohistochemical characteristics of melanoma

“…117,118 PTEN is another tumor suppressor gene that is also involved in the phosphatidylinositol-3 kinase pathway that does not distinguish benign nevi from melanoma. [119][120][121] Ilmonen et al 122 describe ezrin, a 70 kDa protein involved in the phosphatidylinositol-3 kinase pathway, and report its expression to be inversely correlated with survival in 95 melanomas studied, although the correlation did not reach statistical significance.…”

“…The p75 nerve growth factor receptor, a 75 kDa protein which functions as a low affinity receptor for nerve growth factor, was found by Kanik et al 52 to be positive in 10/13 spindle cell melanomas and only 3/8 non-spindle cell melanomas. They also reported that p75 was positive in 5/5 Ôneurotized' nevi, nevi that have undergone neural/ Dai et al 117 reported Akt as an independent risk factor in thin melanomas PTEN No distinction between nevi and melanomas [119][120][121] Ezrin No distinction between nevi and melanomas 122 Ilmonen et al 122 report statistically insignificant inverse correlation between positive staining and survival Fig. 1.…”