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Issues affecting molecular staging in the management of patients with melanoma.

Palmieri G, Casula M, Sini MC, Ascierto PA, Cossu A - J. Cell. Mol. Med. (2007 Sep-Oct)

Bottom Line: Detection of occult melanoma cells in peripheral blood (circulating metastatic cells [CMC]) or in sentinel lymph nodes (sentinel node metastatic cells [SNMC]), could significantly contribute to better predict survival in melanoma patients.Increasing evidence suggest that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic lineage.The different molecular mechanisms may have separate roles or cooperate during all evolutionary phases of melanocytic tumourigenesis, generating different subsets of melanoma patients with distinct aggressiveness, clinical behaviour, and response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Li Punti-Sassari, Italy. gpalmieri@yahoo.com

ABSTRACT
Prediction of metastatic potential remains one of the main goals to be pursued in order to better assess the risk subgroups of patients with melanoma. Detection of occult melanoma cells in peripheral blood (circulating metastatic cells [CMC]) or in sentinel lymph nodes (sentinel node metastatic cells [SNMC]), could significantly contribute to better predict survival in melanoma patients. An overview of the numerous published studies indicate the existence of several drawbacks about either the reliability of the approaches for identification of occult melanoma cells or the clinical value of CMC and SNMC as prognostic factors among melanoma patients. In this sense, characterization of the molecular mechanisms involved in development and progression of melanoma (referred to as melanomagenesis) could contribute to better classify the different subsets of melanoma patients. Increasing evidence suggest that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic lineage. The different molecular mechanisms may have separate roles or cooperate during all evolutionary phases of melanocytic tumourigenesis, generating different subsets of melanoma patients with distinct aggressiveness, clinical behaviour, and response to therapy. All these features associated with either the dissemination of occult metastatic cells or the melanomagenesis might be useful to adequately manage the melanoma patients with different prognosis as well as to better address the different melanoma subsets toward more appropriate therapeutic approaches.

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Related in: MedlinePlus

Molecular pathways involved in melanomagenesis. The proteins have been ordered according to their position into the functional molecular cascade. Straight arrows and barred lines (in blue) indicate induction and inhibition, respectively; bent arrows (in red) indicate interaction between the different pathways.
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fig02: Molecular pathways involved in melanomagenesis. The proteins have been ordered according to their position into the functional molecular cascade. Straight arrows and barred lines (in blue) indicate induction and inhibition, respectively; bent arrows (in red) indicate interaction between the different pathways.

Mentions: Re-arrangements or deletions of the short arm of chromosome 9 represent a common genetic alteration detected in tumour tissues from patients with melanoma [7, 81]. Molecular and cytogenetic investigations have indicated the CDKN genetic locus at the chromosome 9p21 as a candidate region involved in melanoma pathogenesis [81–82]. The CDKN2A gene maps at the CDKN locus and encodes two proteins: the cyclin-dependent kinase inhibitor p16CDKN2A, which is a component of the CyclinD1-RB pathway, and the tumour suppressor p14CDKN2A, which has been functionally linked to the MDM2-p53 pathway [83] (Fig. 2). Alterations of the CDKN2A gene have been widely reported as the most common cause of inherited susceptibility to melanoma [84–87]. In melanocytic cells, the p16CDKN2A protein acts as a proliferation inhibitor by binding the CDK4/6 kinases and blockingphospho-rylation of the RB protein, which lead cells to cycle arrest [6, 78]. Dysfunction of the proteins involved into the p16CDKN2A pathway has been demonstrated to promote a de-regulation of the cell cycle with an uncontrolled cell growth, which may induce cell proliferation and increase aggressiveness of transformed melanocytic cells [88]. Therefore, genetic (deletion or mutation) [6, 78, 84–87] or epigenetic (gene silencing) [89–90] inactivation of the CDKN2A gene may be required for tumour progression and metastasis formation (melanoma cells tend to inactivate both alleles of such a tumour suppressor gene and increase their aggressiveness and malignancy).


Issues affecting molecular staging in the management of patients with melanoma.

Palmieri G, Casula M, Sini MC, Ascierto PA, Cossu A - J. Cell. Mol. Med. (2007 Sep-Oct)

Molecular pathways involved in melanomagenesis. The proteins have been ordered according to their position into the functional molecular cascade. Straight arrows and barred lines (in blue) indicate induction and inhibition, respectively; bent arrows (in red) indicate interaction between the different pathways.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401272&req=5

fig02: Molecular pathways involved in melanomagenesis. The proteins have been ordered according to their position into the functional molecular cascade. Straight arrows and barred lines (in blue) indicate induction and inhibition, respectively; bent arrows (in red) indicate interaction between the different pathways.
Mentions: Re-arrangements or deletions of the short arm of chromosome 9 represent a common genetic alteration detected in tumour tissues from patients with melanoma [7, 81]. Molecular and cytogenetic investigations have indicated the CDKN genetic locus at the chromosome 9p21 as a candidate region involved in melanoma pathogenesis [81–82]. The CDKN2A gene maps at the CDKN locus and encodes two proteins: the cyclin-dependent kinase inhibitor p16CDKN2A, which is a component of the CyclinD1-RB pathway, and the tumour suppressor p14CDKN2A, which has been functionally linked to the MDM2-p53 pathway [83] (Fig. 2). Alterations of the CDKN2A gene have been widely reported as the most common cause of inherited susceptibility to melanoma [84–87]. In melanocytic cells, the p16CDKN2A protein acts as a proliferation inhibitor by binding the CDK4/6 kinases and blockingphospho-rylation of the RB protein, which lead cells to cycle arrest [6, 78]. Dysfunction of the proteins involved into the p16CDKN2A pathway has been demonstrated to promote a de-regulation of the cell cycle with an uncontrolled cell growth, which may induce cell proliferation and increase aggressiveness of transformed melanocytic cells [88]. Therefore, genetic (deletion or mutation) [6, 78, 84–87] or epigenetic (gene silencing) [89–90] inactivation of the CDKN2A gene may be required for tumour progression and metastasis formation (melanoma cells tend to inactivate both alleles of such a tumour suppressor gene and increase their aggressiveness and malignancy).

Bottom Line: Detection of occult melanoma cells in peripheral blood (circulating metastatic cells [CMC]) or in sentinel lymph nodes (sentinel node metastatic cells [SNMC]), could significantly contribute to better predict survival in melanoma patients.Increasing evidence suggest that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic lineage.The different molecular mechanisms may have separate roles or cooperate during all evolutionary phases of melanocytic tumourigenesis, generating different subsets of melanoma patients with distinct aggressiveness, clinical behaviour, and response to therapy.

View Article: PubMed Central - PubMed

Affiliation: Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Li Punti-Sassari, Italy. gpalmieri@yahoo.com

ABSTRACT
Prediction of metastatic potential remains one of the main goals to be pursued in order to better assess the risk subgroups of patients with melanoma. Detection of occult melanoma cells in peripheral blood (circulating metastatic cells [CMC]) or in sentinel lymph nodes (sentinel node metastatic cells [SNMC]), could significantly contribute to better predict survival in melanoma patients. An overview of the numerous published studies indicate the existence of several drawbacks about either the reliability of the approaches for identification of occult melanoma cells or the clinical value of CMC and SNMC as prognostic factors among melanoma patients. In this sense, characterization of the molecular mechanisms involved in development and progression of melanoma (referred to as melanomagenesis) could contribute to better classify the different subsets of melanoma patients. Increasing evidence suggest that melanoma develops as a result of accumulated abnormalities in genetic pathways within the melanocytic lineage. The different molecular mechanisms may have separate roles or cooperate during all evolutionary phases of melanocytic tumourigenesis, generating different subsets of melanoma patients with distinct aggressiveness, clinical behaviour, and response to therapy. All these features associated with either the dissemination of occult metastatic cells or the melanomagenesis might be useful to adequately manage the melanoma patients with different prognosis as well as to better address the different melanoma subsets toward more appropriate therapeutic approaches.

Show MeSH
Related in: MedlinePlus