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There had been little cause for excitement about the development of targeted therapeutics for melanoma until the discovery that a high proportion of melanomas have activating mutations in the gene encoding the signaling molecule BRAF.1 Many melanomas that do not have BRAF mutations carry activating mutations in another oncogene, N-RAS. Signaling mediated by BRAF and N-RAS has proved to be a driving force in the growth of melanomas, and investigators are now developing therapies directed at this pathway. However, a complete understanding of the genetics of melanoma remains a distant goal.
In this issue of the Journal, Curtin et al. (pages 2135–2147) bring us closer to that goal (see diagram). They studied the DNA profiles of a diverse set of melanoma samples from acral and mucosal sites as well as the usual cutaneous melanomas. Cutaneous samples were also characterized according to the degree of solar elastosis, a marker of chronic sun-induced damage. In addition to determining the frequency of BRAF and N-RAS mutations, the authors also used a technique called array-based comparative genomic hybridization to scan the whole genome.
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Heterogeneity is a strong feature that has become progressively more apparent as techniques for the molecular profiling of cancers have improved. It has been studied extensively at the level of gene expression and is also apparent at the DNA level. Recognizing and accounting for tumor heterogeneity are likely to be of central importance, both for the investigation of the fundamental mechanisms of carcinogenesis and for the development of therapeutic and preventive strategies tailored to individual patients. Curtin et al. found remarkably distinct patterns of DNA alterations in melanomas that varied according to the site of origin in a manner that was independent of the histologic subtype of the tumor. Using array-based comparative genomic hybridization, they were able to distinguish melanomas arising from skin without chronic sun-induced damage from those in regions with such damage.
Although both acral and mucosal melanomas have a higher frequency of changes in copy number and gene amplification (gain of multiple copies of a gene) than the more common cutaneous melanomas, distinct regions of the genome are affected in each type. Interestingly, acral and mucosal tumors as well as tumors arising in areas of chronic sun-induced damage have a substantially lower frequency of BRAF mutations than melanomas that arise in areas of the trunk, arms, and legs that are intermittently exposed to the sun.2 Although Curtin et al. did not find a clear relationship between the tumor-DNA profile and the histologic subtype of the tumor, this point may bear further investigation.
Epidemiologic and experimental data strongly support a role for exposure to the sun (particularly sunburn at a young age) in the development of melanoma, but so far, no consistent signature of ultraviolet exposure has been found in any gene mutated in melanoma.3 Although this may simply mean that the true target of ultraviolet light has yet to be discovered, it may also indicate that mechanisms mediated by processes other than direct absorption of ultraviolet light by DNA are responsible. Melanin, particularly the pheomelanin abundant in red-haired people, may lead to the formation of free radicals, which damage DNA. It has also been suggested that the response of melanocytes to ultraviolet light varies depending on their location in the body.4 Certainly, other processes must be at work in mucosal areas that are not exposed to the sun. Remarkably, some epidemiologic evidence even suggests that exposure to the sun has a protective role. The current data are consistent with the view that melanomas arise along distinct genetic pathways. The probability that a melanocyte follows a particular route to malignancy is most likely the result of a complex interaction of factors related to anatomy, heredity, and environment. Interestingly, the overall pattern of mutation, amplification, and loss of cancer genes suggests that melanomas tend to acquire genetic changes that, though diverse, have convergent effects on key biochemical pathways (such as the mitogen-activated protein kinase and phosphatidylinositol 3' kinase pathways).
Although the immediate clinical implications of DNA profiling in melanoma are limited, there is every reason to expect that this information will become increasingly important to the management of melanoma. Certainly, a strong case can be made for monitoring BRAF mutational status in clinical trials of BRAF antagonists. Recognizing that BRAF mutations are uncommon in certain subgroups of patients suggests that these groups will require uniquely tailored therapies. Clues from the gain of oncogenes identified by array-based comparative genomic hybridization may help identify new drug targets.
In a broader context, it is interesting to consider the future role of DNA profiling in clinical oncology. Although there are always issues related to the handling and quality of specimens, DNA-based analysis is attractive because of the inherent stability of DNA. Microarray technologies for array-based comparative genomic hybridization and high-density genotyping have the distinct advantage of providing a genome-wide view. The information provided by both array-based comparative genomic hybridization and sequencing of genes encoding relevant molecular targets could be regarded as essential for the interpretation of therapeutic outcomes. Increased incorporation of molecular-profiling data into routine clinical care will go hand in hand with the development of treatment protocols that consider the underlying biology of cancer.
Beyond the simple cataloguing of mutations in cancer, fascinating and crucial questions remain to be answered. How much will we need to individualize cancer therapy? Will it be necessary to tailor treatment according to the specific pattern of mutations in each patient? Will it be possible to develop therapies directed at downstream targets in common pathways that are affected by mutations at many different levels? One thing is clear: understanding the vulnerabilities revealed by tumor-DNA profiling will be critical to the development of more effective cancer therapy.
Source Information
Dr. Meltzer is head of the Section of Molecular Genetics, Cancer Genetics Branch, of the National Human Genome Research Institute, Bethesda, Md.
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