2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Genetic Alterations in Childhood Melanoma
Overview: Melanoma is rare in children. However, the clinical
features of the disease in this population have been welldocumented
through single-institution experiences and
population-based analyses. Still, our understanding of the
etiologic factors in children remains unclear and diagnosis of
DESPITE BEING the most common skin cancer in
childhood, melanoma is a rare childhood cancer, making
up less than 3% of all cancers seen in children. In the
United States, approximately 300 to 400 new cases per year
are diagnosed in patients younger than age 20; 80% of these
patients are between the ages of 15 and 19. 1 The incidence of
melanoma in this older population is rising yearly. 2 Most
information about the risk factors, natural history, treatment,
and outcome of cutaneous melanoma in children has
been derived from retrospective reports of single-institution
experiences and population-based analyses (i.e., Surveillance
Epidemiology and End Results [SEER] data). 3-8 The
results of some of these studies seem to indicate that the
natural history and response to therapy of melanoma in
children and adolescents are similar to those in adults and
are stage dependent; however, those of other studies refute
these points and suggest that the biology of the disease
might be different in children than in adults.
Understanding the biologic similarities and differences
between adult and pediatric melanoma may provide insight
into the causative factors of the disease in children and
influence treatment decisions. Such knowledge might also
aid clinicians dealing with diagnostically challenging issues
such as distinguishing between Spitz nevi and spitzoid
melanoma or between malignant transformation and benign
proliferation in congenital nevi. Emerging evidence suggests
that molecular characterization of these lesions may be
helpful. This article reviews common genetic alterations in
pediatric melanoma and their potential utility in differentiating
histologically challenging cases.
Common Genetic Alterations
During the past decade, several genetic alterations in
adult melanomas have been described. 9-12 These changes
are summarized in Table 1. Characterization of these aberrations
suggests that various distinct molecular pathways
are associated with the development of melanoma on the
basis of the tumor site, host phenotype, and amount of sun
exposure. 13,14 These findings highlight the heterogeneity of
adult melanomas and raise the possibility that the same
genetic alterations may not be present in childhood melanoma.
Large-scale genetic profiling studies of pediatric melanoma
performed by using comparative genomic
hybridization (CGH) or genome-wide association techniques
have not been reported and may not be feasible because of
the tumor’s rarity. However, some genes have been evaluated
in the pediatric population; findings about two that are
mutated in this setting are summarized below.
BRAF
The RAS/RAF/MAPK signaling pathway is the one most
commonly implicated in the pathogenesis of melanoma and
By Fariba Navid, MD
melanoma remains challenging in certain cases. This article
reviews emerging evidence indicating that molecular characterization
of these lesions in children may be of diagnostic and
therapeutic value.
is the focus of recent drug development efforts. This pathway
is dysregulated in approximately 50% of adult melanomas,
frequently having mutations in the BRAF gene (less
frequently NRAS). The most common BRAF mutation in
melanoma is a substitution of glutamic acid for valine at
position 600 (BRAF V600E ). This mutation accounts for more
than 90% of the BRAF mutations that occur in adult
melanomas and drives cell proliferation, invasion, and metastasis
in these tumors. The U.S. Food and Drug Administration
recently approved vemurafenib, an oral tyrosine
kinase inhibitor of mutated BRAF, because of its favorable
response rates in adult patients with BRAF-mutated melanoma.
15,16 BRAF V600E mutations in pediatric melanoma
have only been reported from one small study showing the
mutation in five of 10 pediatric tumors. 17 Finding
BRAF V600E and other aberrations of this pathway in more
samples would provide a rationale to test selective inhibitors
targeting this mutation and other RAS/RAF/MAPK signaling
molecules in pediatric melanoma.
CDKN2A
CDKN2A, located on chromosome 9p21, encodes two distinct
tumor suppressor genes, p16/INK4a and p14/ARF,
that play a key role in cell cycle regulation. The CDKN2A
locus is deleted in approximately 50% of sporadic adult
melanomas. 13 Daniotti and colleagues 17 found homozygous
CDKN2A deletions in nine of 14 pediatric melanomas (patients
aged 2 to 19). Alterations in CDKN2A are also
implicated in the pathogenesis of 25% to 40% of familial
cutaneous melanomas. 18 In these patients, melanoma tends
to develop when they are younger but not commonly when
they are younger than age 18. Whiteman and colleagues 19
analyzed DNA from 31 children in the Queensland Cancer
registry who were younger than age 15. One patient among
the 10 with a family history of melanoma had a germ-line
mutation in CDKN2A; she had a history of two primary
melanomas before the age of 13. Among 147 adolescents in
the same registry who were aged 15 to 19, two had germ-line
alterations in CDKN2A; however, neither had a family
history of melanoma. 20 In a retrospective review of 15
Swedish families with known germ-line CDKN2A mutations,
the youngest family member to develop melanoma
was 18 years. 21 The results of these studies suggest that
From the Division of Solid Malignancies, Department of Oncology, St. Jude Children’s
Research Hospital, Memphis, TN.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Fariba Navid, MD, Division of Solid Malignancies, Department
of Oncology, St. Jude Children’s Research Hospital, 262 Danny Thomas Pl., Memphis,
TN 38105-2794; email: fariba.navid@stjude.org.
© 2012 by American Society of Clinical Oncology.
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