© 2003 by Oxford University Press
© 2003 Oxford University Press
BRIEF COMMUNICATION |
Determinants of BRAF Mutations in Primary Melanomas
Affiliations of authors: Departments of Dermatology (JLM, BCB), Laboratory Medicine (JF, ANJ, DGA, DP), and Pathology (BCB), Cancer Research Institute (JF, ANJ, DGA), Comprehensive Cancer Center (HP, ANJ, DGA, DP, BCB), University of California, San Francisco, San Francisco; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY (KB); Department of Dermatology, Kumamoto University School of Medicine, Kumamoto, Japan (TK, TO).
Correspondence to: Boris C. Bastian, MD, Department of Dermatology and Pathology, University of California, San Francisco, 2340 Sutter St., Rm. N461, San Francisco, CA 94115 (e-mail: bastian{at}cc.ucsf.edu)
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ABSTRACT |
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 TopNotes Abstract References |
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The RAS/mitogen-activated protein kinase pathway sends external growth-promoting signals to the nucleus. BRAF, a critical serine/threonine kinase in this pathway, is frequently activated by somatic mutation in melanoma. Using a cohort of 115 patients with primary invasive melanomas, we show that BRAF mutations are statistically significantly more common in melanomas occurring on skin subject to intermittent sun exposure than elsewhere (23 of 43 patients; P<.001, two-sided Fisher’s exact test). By contrast, BRAF mutations in melanomas on chronically sun-damaged skin (1 of 12 patients) and melanomas on skin relatively or completely unexposed to sun, such as palms, soles, subungual sites (6 of 39 patients), and mucosal membranes (2 of 21 patients) are rare. We found no association of mutation status with clinical outcome or with the presence of an associated melanocytic nevus. The mutated BRAF allele was frequently found at an elevated copy number, implicating BRAF as one of the factors driving selection for the frequent copy number increases of chromosome 7q in melanoma. In summary, the uneven distribution of BRAF mutations strongly suggests distinct genetic pathways leading to melanoma. The high mutation frequency in melanomas arising on intermittently sun-exposed skin suggests a complex causative role of such exposure that mandates further evaluation.
The majority of melanomas of light-skinned people occur on the trunk and extremities, and epidemiologic evidence suggests that intermittent sun exposure is a major pathogenetic factor (1). In contrast, melanomas that occur on skin subject to chronic sun damage, such as the face, tend to occur later in life, develop more slowly, and differ in their clinical and histologic presentation from those that occur on sun-exposed skin without chronic sun damage (2). Melanomas also develop in relatively sun-protected sites, such as the non–hair-bearing (glabrous) skin of soles, palms, and nail beds, or even in sites that are completely sun protected, such as the nasal, oral, and anogenital mucosa. Glabrous skin is relatively well protected from UV radiation in sunlight through a thick cornified layer or a nail plate, and mucosal sites have essentially no UV exposure. A classification of melanomas into several histogenetic types has been proposed (3). In general, melanomas that occur on skin with chronic sun damage differ considerably from melanomas that occur on skin without chronic sun damage by their preferential anatomic location on the face, association with older age, and a sun-exposure pattern that is chronic rather than intermittent (4). However, controversy remains as to whether the clinicopathologic variations among cutaneous melanomas reflect inherent biologic differences or are secondary effects that depend on the skin architecture of different anatomic sites (5). Recently, a high frequency of BRAF mutations at a single site in the kinase domain of exon 15 has been reported in melanoma (1). To study the distribution of this mutation among different melanoma types, we sequenced that portion of the BRAF gene from specimens from 125 patients with invasive primary melanomas.
All specimens were embedded in paraffin and were retrieved from the Departments of Pathology at both the University of California, San Francisco, and the Memorial Sloan-Kettering Cancer Center and from the Department of Dermatology, Kumamoto University School of Medicine, Kumamoto, Japan. The melanoma specimens were selected to represent the four groups of primary invasive melanomas and to contain no more than 50% normal cells by histologic examination (Table 1). The skin was separated into glabrous skin (i.e., skin devoid of hair follicles, such as palms, soles, and subungual sites) and skin with hair follicles (i.e., the remainder of the skin, which for simplicity we refer to hereafter as skin). Melanomas on the skin were further distinguished by whether signs of chronic sun damage (chronic sun damage versus non–chronic sun damage) were found, as reflected by the presence or absence of severe solar elastosis (i.e., a dermis with a homogenous blue-gray discoloration) in sections stained with hematoxylin–eosin. The fourth group consisted of melanomas that arose on mucosal membranes. All tumors except for those on the mucosa had a median thickness of 3.6 mm (range = 1–15 mm); mucosal tumors had a median thickness of 5 mm (range = 2.4–85 mm).
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Sequence information was obtained from 115 (92%) of the 125 melanoma specimens. Tumors with evidence of an allelic mixture in both the forward and reverse sequencing traces were classified as containing a mutation. All 32 mutations occurred at position V599. Twenty-four (75%) of these mutations were the single base-pair substitution T1796A, and eight (25%) were tandem mutations either GT
AG (six [18.8%] of the eight mutations) and GTAA (two [6.2%] of the eight mutations), as previously described (6). The primary finding of our study is that BRAF mutations are highly unevenly distributed among the four groups of melanomas. Mutations were found in 23 (54%) of 43 specimens in the non–chronic sun-damage group (Table 1) but in only one (8%) of the 12 melanomas on chronically sun-damaged skin (chronic sun-damage group), six (15%) of 39 melanomas on glabrous skin, and two (10%) of 19 mucosal melanomas. To determine whether the BRAF mutation rate is associated with solar exposure patterns, we further stratified the non–chronic sun-damage group of melanomas by anatomic location. We assumed that melanomas on the trunk arise from skin that is typically subjected to intermittent sun exposure and that those on the extremities have a more continuous exposure pattern. Within the non–chronic sun-damage group, BRAF mutations were associated with melanomas of the trunk (15 [65%] of 23 specimens) compared with melanomas of the extremities or face (5 [33%] of 15 specimens) (P = .096, two-sided Fisher’s exact test). In concordance with published data (4), patients in our study with non–chronic sun damage whose melanoma arose on the trunk were younger than patients with melanomas arising on the extremities or face. To assess a possible influence of patient age, we compared the age distributions between melanomas with mutations and melanomas without mutations among those patients with non–chronic sun damage whose tumors occurred on the trunk. No difference in age was detected between patients with and without BRAF mutations among that relatively homogeneous group (P = .74, two-sided Wilcoxon rank sum test). Twenty-seven of the melanomas were from Japanese patients; 21 of the 27 melanomas were located on glabrous skin. No difference was observed between the frequency of mutations in Japanese patients and in the remaining patients.
The BRAF gene resides on chromosome 7q, which is frequently gained in melanoma (7). We analyzed specimens from 68 case patients (19 with mutations) with array comparative genomic hybridization (8,9) to determine whether the mutant BRAF allele was preferentially gained. Nine tumors had an increased 7q copy number and had gained a BRAF mutation. We estimated the ratio of mutant to normal BRAF sequences in each of these tumors by quantitatively comparing the forward and reverse sequencing traces to those of melanoma cell lines that contained only normal or mutant BRAF alleles. Fluorescence in situ hybridization analysis indicated that the tumors were near diploid. A near-diploid tumor containing 50% normal cells and a mutation in one of two alleles would be expected to have a mutant to normal allele ratio of 0.25, and such a tumor with an additional mutant allele would have a ratio of 0.4. In seven of the nine specimens with increased 7q copy number and BRAF mutations, the mutant-to-normal allele ratio was more than 0.5, which, after adjusting for the normal cell content of the specimens, indicates a gain of the mutant BRAF allele. In the other two specimens, the results do not clearly indicate which allele was gained. Thus, BRAF mutations are one of the factors that drive selection for the frequent gain of chromosome 7q in melanoma. However, because the distal chromosome 7q, including the BRAF region, was gained in 15 tumor specimens in which no mutations were found, additional genes are likely to be involved in this selection. Further studies are required to determine the effect of increased dosage of a mutated BRAF allele on the activation levels of mitogen-activated protein kinase and on melanocyte transformation.
BRAF mutations have been reported to occur in a large majority of nevi (10), suggesting that melanomas with a mutation may arise from preexisting nevi. Among the patients with a melanoma located on the skin, 11 patients had an associated melanocytic nevus microscopically and 35 did not (only those in which the entire width of the lesion could be evaluated microscopically were included in this analysis). Six (55%) of 11 nevus-associated melanomas and 15 (43%) of 35 unassociated melanomas had a BRAF mutation (P = .73, two-sided Fisher’s exact test). Thus, not all melanomas with an associated melanocytic nevus may arise from melanocytes with BRAF mutations. Importantly, there was no association between BRAF mutation status and outcome, as determined by metastasis or death from disease in 89 patients for whom clinical follow-up information (average follow-up time = 37 months) was available (data not shown).
In summary, our findings demonstrate that BRAF mutations are most frequent in melanoma types for which epidemiologic data suggest a pathogenetic role of intermittent sun exposure as opposed to chronic sun exposure (4,10). These melanomas occur predominantly on the trunk, are typically of the superficial spreading melanoma or nodular melanoma type, and occur earlier in life than melanomas on other sites. However, the relationship of BRAF mutations and sun exposure is complex. First, as previously noted (6), the mutations do not have the standard UVB signature. Second, mutation frequencies are low in anatomic areas that receive the lowest (e.g., mucosa) and the highest (e.g., chronic sun damage) sun exposure. Further studies are therefore necessary to determine whether exposure to UVA, other indirect mechanisms affected by sun exposure, or anatomic variation of melanocyte susceptibility contribute to the BRAF mutation spectrum in melanoma.
The association of BRAF mutation frequency with anatomic site and sun-exposure patterns supports the concept of distinct genetic paths of melanoma development, as suggested by a previous study (11). The frequent occurrence of BRAF mutations in the most common type of melanoma raises the possibility that specific BRAF inhibitors (12) may be useful therapeutic agents for this type of disease.
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NOTES |
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We thank Dr. John Ziegler from the University of California, San Francisco, Cancer Risk Program for helpful comments on the manuscript.
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REFERENCES |
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TopNotesAbstractReferences |
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Manuscript received April 14, 2003; revised October 1, 2003; accepted October 14, 2003.
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J Natl Cancer Inst 2005 97: 401-402.
J Natl Cancer Inst 2005 97: 402.
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