Science in medicine
The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 4 April 2005
Melanoma genetics and the development
of rational therapeutics
Yakov Chudnovsky, Paul A. Khavari, and Amy E. Adams
Veterans Affairs Palo Alto Healthcare System, Palo Alto, California. Program in Epithelial Biology, Stanford University School of Medicine,
Stanford, California, USA.
Melanoma is a cancer of the neural crest–derived cells that provide pigmentation to skin and other
tissues. Over the past 4 decades, the incidence of melanoma has increased more rapidly than that
of any other malignancy in the United States. No current treatments substantially enhance patient
survival once metastasis has occurred. This review focuses on recent insights into melanoma genet-
ics and new therapeutic approaches being developed based on these advances.
History and clinical features of melanoma
The first accredited report of melanoma is found in the writings
of Hippocrates (born c. 460 BC), where he described “fatal black
tumors with metastases.” Paleopathologists discovered diffuse
bony metastases and round melanotic masses in the skin of Peru-
vian mummies of the fourth century BC (1). However, it was not
until 1806, when René Laennec described “la melanose” to the
Faculté de Médecine in Paris, that the disease was characterized
in detail and named (2). General practitioner William Norris sug-
gested that melanoma may be hereditary in an 1820 manuscript
describing a family with numerous moles and several family mem-
bers with metastatic lesions (3). Molecular insights over the past
20 years have confirmed Norris’s theory of a significant genetic
contribution to the etiology of melanoma.
Melanoma develops from the malignant transformation of
melanocytes, the pigment-producing cells that reside in the
basal epidermal layer in human skin (Figure 1). Recognized as
the most common fatal skin cancer, melanoma incidence has
increased 15-fold in the past 40 years in the United States, a
rate more rapid than that described for any other malignancy
(4). Every hour, an American will die from melanoma (5), and
it remains one of the most common types of cancer among
young adults (6). Furthermore, according to US statistics for
1973–1997, the increase in the mortality rate for melanoma in
individuals 65 years of age and older, especially men, was the
second highest among all cancers (4).
As in many cancers, both genetic predisposition and exposure
to environmental agents are risk factors for melanoma develop-
ment. Case-control studies have identified several risk factors in
populations susceptible to developing melanoma (7). Melanoma
primarily affects fair-haired and fair-skinned individuals, and
those who burn easily or have a history of severe sunburn are at
higher risk than their darkly pigmented, age-matched controls.
The UV component of sunlight causes skin damage and increas-
es the risk for skin cancers such as melanoma. It appears that
melanoma risk is typically associated with intermittent, intense
sun exposure rather than cumulative sun exposure (an excep-
tion is lentigo maligna melanoma). The exact mechanism and
wavelengths of UV light that are the most critical remain con-
troversial, but both UV-A (wavelength 320–400 nm) and UV-B
(290–320 nm) have been implicated (4, 8). This is in contrast to
the nonmelanoma skin cancers, basal cell carcinoma and squa-
mous cell carcinoma, which arise from epidermal keratinocytes
and are more strongly associated with cumulative sun exposure.
Melanoma incidence in fair-skinned people is inversely related to
latitude of residence, with the highest incidence found in Austra-
lia, which supports the role of UV-induced damage in melanoma
pathogenesis (9). In the 1920s, women’s fashions became more
revealing, and French fashion designer Coco Chanel, who devel-
oped a suntan when cruising from Paris to Cannes, is credited
with initiating the modern sunbathing trend (10). As our social
dress has moved from petticoat and parasol or topcoat and hat to
tank top and sunglasses, the incidence of skin cancers, including
melanoma, has increased significantly.
Family history of melanoma, increased numbers of both com-
mon and dysplastic moles, and a tendency to freckle also increase
risk (11). Ten percent of melanoma patients have an affected rela-
tive. In a small number of cases, melanomas occur in the setting of
the familial atypical multiple mole and melanoma syndrome, also
referred to as the dysplastic nevus syndrome (DNS) (12, 13). DNS-
affected kindreds develop many atypical moles (dysplastic nevi)
at a young age and acquire melanoma with a higher penetrance
and earlier onset than are typical of sporadic melanoma. Some
evidence suggests that dysplastic nevi may be melanoma precur-
sors in a subset of cases; however, this correlation is controversial
and difficult to clearly document (4, 12). More than 50% of mela-
nomas likely arise de novo without a precursor lesion.
Cutaneous melanoma can be subdivided into several subtypes,
primarily based on anatomic location and patterns of growth (see
Table 1 for key clinical features of subtypes; reviewed in ref. 4). The
majority of melanoma subtypes are observed to progress through
distinct histologic phases (Figure 1). As melanomas progress
from the radial growth phase (RGP) to the vertical growth phase
(VGP), treatment options, cure rates, and survival rates decrease
dramatically. Most melanoma subtypes demonstrate a slow RGP
Nonstandard abbreviations used: ADI, arginine deiminase; CDK, cyclin-dependent
kinase; CDKN2A, cyclin-dependent kinase inhibitor 2A; DNS, dysplastic nevus syndrome;
MEK, MAPK kinase; PEG, polyethylene glycol; pRb, Rb protein; PTEN, phosphatase
and tensin homolog; Rb, retinoblastoma; RCC, renal cell carcinoma; RGP, radial
growth phase; siRNA, small interfering RNA; SLNB, sentinel lymph node biopsy;
VGP, vertical growth phase.
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J. Clin. Invest. 115:813–824 (2005).
science in medicine
814 The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 4 April 2005
science in medicine
The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 4 April 2005
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