The molecular pathology of cutaneous melanoma

Issue title: Translational Pathology of Early Cancer

Guest editors: Sudhir Srivastavax and William E. Grizzley

Article type: Research Article

Authors: Bogenrieder, Thomas^a | Herlyn, Meenhard^{b; *}

Affiliations: [a] Boehringer Ingelheim RCV, Dr. Boehringer Gasse 5-11, 1121 Vienna, Austria | [b] The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, USA | [x] Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, Rockville, MD, USA | [y] Department of Pathology, Division of Anatomic Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

Correspondence: [*] Corresponding author. E-mail: herlynm@wistar.org.

Abstract: Cutaneous melanoma is a highly aggressive cancer with still limited, but increasingly efficacious, standard treatment options. Recent preclinical and clinical findings support the notion that cutaneous melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma already has great implications for the management of cutaneous melanoma. Herein, we review our rapidly growing understanding of the molecular biology of cutaneous melanoma, including the pathogenic roles of the mitogen-associated protein kinase (MAPK) pathway, the phosphatidylinositol 3 kinase [PI3K]/phosphatase and tensin homologue deleted on chromosome 10 [PTEN]/Akt/mammalian target of rapamycin [mTOR])PTEN (phosphatase and tensin homolog) pathway, MET (hepatocyte growth factor), Notch signaling, and other key molecules regulating cell cycle progression and apoptosis. The mutation Val600Glu in the BRAF oncogene (designated BRAF(V600E)) has been associated with clinical benefit from agents that inhibit BRAF(V600E) or MEK (a kinase in the MAPK pathway). Cutaneous melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. These findings suggest that prospective genotyping of patients with melanoma, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, should be used increasingly as we work to develop new and more effective treatments for this devastating disease.

Keywords: Melanoma, cell cycle, pRb pathway, p16INK4A, p14ARF, cyclins, CDKs, Apaf1, Bcl2, MAPK pathway, Ras, BRAF, PTEN, PI3K/AKTpathway, SCF, ckit, HGF, cmet, cmyc, Notch

DOI: 10.3233/CBM-2011-0164

Journal: Cancer Biomarkers, vol. 9, no. 1-6, pp. 267-286, 2011