Molecular bases of cutaneous and uveal melanomas.

Sudeep Gaudi,Jane L Messina

doi:10.4061/2011/159421

Abstract

Intensive research in recent years has begun to unlock the mysteries surrounding the molecular pathogenesis of melanoma, the deadliest of skin cancers. The high-penetrance, low-frequency susceptibility gene CDKN2A produces tumor suppressor proteins that function in concert with p53 and retinoblastoma protein to thwart melanomagenesis. Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma. Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes. The proliferative effects of the MAPK pathway may be complemented by the antiapoptotic signals of the PI3K/AKT pathway. After skin, melanoma most commonly affects the eye. Data for the constitutive activation of the MAPK pathway in uveal melanoma exists as well, however, not through mutations of RAS and RAF. Rather, evidence implicates the proto-oncogene GNAQ. In the following discussion, we review the major molecular pathways implicated in both familial and sporadic cutaneous melanomagenesis, the former accounting for approximately 10% of cases. Additionally, we discuss the molecular pathways for which preliminary evidence suggests a role in uveal melanomagenesis.

Highlights

Melanoma remains a disproportionate cause of death among skin cancers [1, 2]
We review the major molecular pathways implicated in both familial and sporadic cutaneous melanomagenesis, the former accounting for approximately 10% of cases [7]
Knowledge of some of the earliest molecular pathways involved in melanomagenesis derived from investigations of familial cutaneous melanoma

Summary

Introduction

Melanoma remains a disproportionate cause of death among skin cancers [1, 2]. Currently, early diagnosis followed by complete surgical removal of the tumor offers the best hope for cure [3]. The two most commonly employed modalities for the treatment of uveal melanoma, the most lethal of ocular melanomas, are radiation therapy and enucleation [5]. Despite these valiant efforts at local disease control, up to 50% of patients succumb to their disease, and impact on patient survival remains questionable at best [6]. A great need for improved therapy exists for the treatment of uveal melanoma. We review the major molecular pathways implicated in both familial and sporadic cutaneous melanomagenesis, the former accounting for approximately 10% of cases [7]. We discuss the molecular pathways for which preliminary evidence suggests a role in uveal melanomagenesis

Familial Cutaneous Melanoma

Sporadic Cutaneous Melanoma

Ocular Melanoma

Uveal Melanoma

Findings

Conclusion