Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape

Abstract

Malignant melanoma presents a substantial clinical challenge. Current diagnostic methods are limited in their ability to diagnose early disease and accurately predict individual risk of disease progression and outcome. The lack of adequate approaches to properly define disease subgroups precludes rational treatment design and selection. Better tools are urgently needed to provide more accurate

Genetic and clinico-pathologic analysis of metastatic uveal melanoma

“…13 Uveal melanomas lack activating mutations in BRAF or NRAS, 14 which commonly occur in cutaneous melanoma (approximately 50% and 20%, respectively). 15 Eighty to 90% of uveal melanomas harbor activating mutations in GNAQ or GNA11 9,16 in a mutually exclusive pattern. The original report of GNA11 mutations showed a substantial difference in the distribution of mutations in primary and metastatic tumors.…”

Biomarkers for Melanoma Diagnosis and the Technologies Used to Identify Them

“…The AKT/mTOR pathway suppresses apoptosis by decreasing the levels of pro-apoptotic proteins (e.g., BAD and caspase-9). Among the three AKT members (AKT1, AKT2, and AKT3), it is AKT3 that is often overexpressed in melanoma (Stahl et al, 2004) and is regulated by the phosphatase and tensin homolog (PTEN), which degrades the products of PI3K (Wu et al, 2003;Becker et al, 2006;Sekulic et al, 2008). In addition, many antigens, which have immunostimulatory or activator roles in tumorigenesis, have been identified in metastatic melanoma.…”

“…Cancer/testis antigens are abundant in normal tissues during development, but in mature cells, their expression is restricted to the male germ cells in the testis and to various tumors (Simpson et al, 2005). As indicated, several gene mutations such as NRAS (Q61K/R), BRAF (V600E), PTEN, and CDKN2A mutation play an important role in the occurrence of melanoma (Tsao et al, 2004;Wan et al, 2004;Gray-Schopfer et al, 2005;Becker et al, 2006;Sekulic et al, 2008). These mutations are excellent targets for the diagnosis of melanoma.…”

“…Activated ERK1 and 2 has been found to modulate the gene expression necessary for survival and proliferation of melanoma cells, and has been linked to the increase resistance of melanoma cells to apoptosis by inhibiting the activation of caspase 8 (Becker et al, 2006;Sekulic et al, 2008). The BRAF mutation is necessary for ERK-mediated survival and proliferation and participates in the reduction of proapoptotic proteins (e.g., Bcl-2 family), while RAF genes consist of ARAF, BRAF, and CRAF (also known as Raf-1) (Becker et al, 2006;Cartlidge et al, 2008;Sekulic et al, 2008).…”

“…Activated ERK1 and 2 has been found to modulate the gene expression necessary for survival and proliferation of melanoma cells, and has been linked to the increase resistance of melanoma cells to apoptosis by inhibiting the activation of caspase 8 (Becker et al, 2006;Sekulic et al, 2008). The BRAF mutation is necessary for ERK-mediated survival and proliferation and participates in the reduction of proapoptotic proteins (e.g., Bcl-2 family), while RAF genes consist of ARAF, BRAF, and CRAF (also known as Raf-1) (Becker et al, 2006;Cartlidge et al, 2008;Sekulic et al, 2008). The BRAF mutation, predominantly V600E (substitution of glutamate to valine; previously known to V599E), frequently occurs in melanoma and is strongly related to exposure to UV radiation (Tsao et al, 2004;Wan et al, 2004;Gray-Schopfer et al, 2005;Becker et al, 2006;Sekulic et al, 2008).…”