SYMPOSIUM ON SOLID TUMORS
Malignant Melanoma in the 21st Century: The Emerging Molecular Landscape

https://doi.org/10.4065/83.7.825Get rights and content

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 and personalized melanoma patient management. Recent progress in the understanding of the molecular aberrations that underlie melanoma oncogenesis will likely advance the diagnosis, prognosis, and treatment of melanoma. The emerging pattern of molecular complexity in melanoma tumors mirrors the clinical diversity of the disease and highlights the notion that melanoma, like other cancers, is not a single disease but a heterogeneous group of disorders that arise from complex molecular changes. Understanding of molecular aberrations involving important cellular processes, such as cellular signaling networks, cell cycle regulation, and cell death, will be essential for better diagnosis, accurate assessment of prognosis, and rational design of effective therapeutics. Defining an individual patient's unique tumor characteristics may lead to personalized prediction of outcomes and selection of therapy. We review the emerging molecular landscape of melanoma and its implications for better management of patients with melanoma.

Section snippets

CELL CYCLE CHANGES IN MELANOMA

The cellular cycle of growth and division (the cell cycle) is a carefully orchestrated sequence of events influenced by many factors, including the general state of cellular differentiation, activation of cell surface receptors, availability of nutrients, and level of cellular stress (eg, DNA damage). Almost all these factors lead to changes in cell-signaling patterns that ultimately converge on a set of molecularregulators of cell cycle progression—cyclins, cyclin-dependent kinases (CDKs), and

CELL SIGNALING CHANGES IN MELANOMA

Key signaling pathways that are important in melanoma and that represent potential novel therapeutic targets have been identified, and their regulatory mechanisms are beginning to be understood. The processes that are important in the development and progression of melanoma can be divided into the following categories: cellular proliferation, prosurvival signaling, growth factor receptor activation, differentiation regulation, cell adhesion, and migration.

THE GENOMICS OF MELANOMA

Recent advances in high-resolution genome-wide molecular techniques have greatly increased our ability to examine and understand molecular changes in cancer, including melanoma. The essence of these methods lies in the inherent property of DNA strands to form a duplex when two complementary DNA strands meet. This quality was exploited for design of DNA array platforms capable of measuring global changes in gene expression levels (ie, gene expression profiling), changes in gene copy number (eg,

UVEAL MELANOMA

Uveal melanomas (melanomas of the eye) are the most common primary intraocular malignancy. Melanomas of the eye can be divided into four predominant types: ciliary and choroidal melanomas, which account for most uveal melanomas, and iris and conjunctival melanomas, which are less common. This section will focus mainly on ciliary and choroidal melanomas, ie, uveal melanomas, and specific molecular characteristics of iris and conjunctival melanoma will be highlighted for comparison.

Uveal melanoma

MELANOMA STEM CELLS

The concept of cancer stem cells, or cancer-initiating cells, has gained considerable momentum in recent years. Although the identification of cancer stem cell-specific molecular aberrations is still in its infancy, the extent of the changes documented thus far and their potential implications for cancer therapy warrant a brief review.

Normal adult stem cells can be found in most somatic tissues, where they participate in renewal, repair, and maintenance of normal tissues. This essential

TARGETED MOLECULAR THERAPY

Despite decades of investigation, no systemic treatment that improves overall survival in most patients with unresectable metastatic melanoma has been developed. Occasional durable complete responses do occur in patients with metastatic disease who receive high-dose interleukin 2, biochemotherapy, and even chemotherapy alone; however, these occur in only 1% to 6% of patients, and no definitive tests exist to reliably predict these outcomes. During the past decade, only one agent has been

CONCLUSION

Our understanding of the molecular basis of melanoma has grown exponentially during the past decade. These scientific advances are likely to greatly affect the practice of medicine, including the diagnosis, prognosis, and treatment of melanoma. The enormous molecular complexity of melanoma and the realization that a clinical diagnosis of melanoma likely covers a spectrum of molecularly and mechanistically distinct entities highlight the need for better molecular disease classification and point

Glossary

ABC
adenosine triphosphate-binding casette
ABCB5
ABC subfamily B (MDR/TAP) member 5
AIF
apoptosis-inducing factor
AIM1
absent in melanoma 1
AKT
v-akt murine thymoma viral oncogene homolog
APAF1
apoptotic peptidase-activating factor 1
ARAF
v-raf murine sarcoma 3611 viral oncogene homolog
BAD
BCL2 antagonist of cell death
BAK
BCL2 homologous antagonist/killer
BAX
BCL2-associated X protein
BCL2
B cell chronic lymphocytic leukemia/lymphoma 2
BID
BH3-interacting domain death agonist
BNIP3L
BCL2/adenovirus E1B 19kDa

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    Current Members of the Melanoma Study Group. Jacob B. Allred, BA; Panagiotis Z. Anastasiadis, PhD, MS; Keith H. Baratz, MD; Uldis Bite, MD; Elizabeth A. Bradley; Renee K. Bradshaw, MD; J. Douglas Cameron, MD; Ricky P. Clay, MD; Suzanne M. Connolly, MD; John A. Copland III, PhD; Edward T. Creagan, MD; Gary A. Croghan, MD, PhD; Mark Denis P. Davis, MD; Allan B. Dietz, PhD; John H. Donohue, MD; Lori A. Erickson, MD; David R. Farley, MD; Thomas J. Flotte, MD; Evanthia Galanis, MD; Yolanda I. (Nina) Garces, MD; James A. Garrity, MD; Dennis A. Gastineau, MD; Bobbie S. Gostout, MD; Clive S. Grant, MD; Jennifer L. Hand, MD; James N. Ingle, MD; Amer N. Kalaaji, MD; Jan L. Kasperbauer, MD; Judith S. Kaur, MD; Lisa A. Kottschade, RN; James Keeling, MD; Susan D. Laman, MD; Katherine K. Lim, MD; Noralane M. Lindor, MD; Charles L. Loprinzi, MD; Val Lowe, MD; Joseph Lustgarten, PhD; Leo J. Maguire, MD; William J. Maples, MD; Svetomir N. Markovic, MD, PhD; Colin A. McCannel, MD; Elizabeth S. McDonald, MD, PhD; Robert R. McWilliams, MD; Jane M. Milburn, MBA; Steven L. Moran, MD; Wendy K. Nevala, BS; Kerry D. Olsen, MD; Clark C. Otley, MD; Animesh Pardanani, MBBS, PhD; Galen Perdikis, MD; Mark R. Pittelkow, MD; Jeanette M. Pitts, MD; Barbara A. Pockaj, MD; Karl C. Podratz, MD, PhD; Jose S. Pulido, MD; Michael G. Rock, MD; Randall K. Roenigk, MD; John R Salassa, MD; Diva R. Salomao, MD; Steven E. Schild, MD; Aleksandar Sekulic, MD, PhD; Thomas C. Shives, MD; Franklin H. Sim, MD; John L. Snow, MD; C. Robert Stanhope, MD; W. P. Daniel Su, MD; Vera J. Suman, PhD; David L. Swanson, MD; Winston Tan, MD; Sarvam P. TerKonda, MD; Nho V. Tran, MD; Celine M. Vachon, PhD; Richard G. Vile, PhD; Stanimir Vuk-Pavlovic, PhD; James C. Waldorf, MD; Roger H. Weenig, MD; Ryan A. Wilcox, MD, PhD; Timothy O. Wilson, MD; Gregory A. Wiseman, MD

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