The Longer Your Telomeres, the Larger Your Nevus?

One way to classify melanocytic nevi is a division into congenital and acquired types. Applied strictly, this would put all nevi that are present at birth in the congenital category, and all others in the acquired. However, the exact history is commonly not available and clinical or histopathological criteria are frequently used for classifying nevi as congenital or acquired. Dermatopathologists often feel quite comfortable in diagnosing congenital nevi based on their histomorphologic pattern alone. However, there are studies showing no correlation of histomorphology and presence or absence of the lesion at birth (1,2). These studies suggest that the histopathologic pattern is a function of nevus size rather than absence or presence at birth. Large congenital nevi have an increased lifetime risk to develop melanoma (3). However, nevi that are large are always congenital, and small nevi that are present at birth do not have an increased risk of melanoma. This also indicates that size is more important than whether a nevus is congenital or not. For these reasons the boundary between congenital and acquired nevi is blurry, and perhaps ill chosen. Birth as a time point is not directly linked to a defined state of development. Babies can be born early, late, or on time. Although, there are obvious limits to this variation, these differences could well matter given the pace of development in utero. Clearly there appears to be an obvious connection between the age the nevus first appears, its ultimate size, and its risk to progress to melanoma. Here, I would like to put forward the concept that all nevi are acquired, i.e., caused by, genetic events that happen after conception. It is the time point in life at which the genetic event(s) occur that determines their ultimate size and probably their risk of progression. This view is based on several recent studies that have shown mutations in nevi that affect a critical pathway of growth factor signaling, the MAP-kinase pathway. This signaling cascade conveys growth-signals from receptortyrosine kinases to the nucleus and induces proliferation. Members of the ras protein family are critical components of this pathway and mutations of ras family members have been shown in congenital nevi (NRAS) (4), and in acquired nevi such as Spitz nevi (HRAS) (5). The genetic alterations found in melanocytic nevi are thought to lead to a constitutive activation of these pathways, uncoupling the transcriptional response from its receptors. If one overexpresses hepatocyte growth factor (HGF, or scatter factor) in the melanocytes of mice, they develop lesions that clinically and histologically resemble congenital nevi (6). Hepatocyte growth factor binds to the receptor tyrosine kinase MET, which signals via ras to the MAP kinase pathway. Overexpression of MET has been shown in human congenital nevi (7). The finding of mutations in the MAP-kinase pathway in human congenital nevi, and the experimental observation that activation of this pathway can lead to nevi in mice provide strong evidence for the biological relevance of these alterations. Ras genes are oncogenes frequently mutated in human cancers, and mutations of ras genes (predominantly NRAS) are also seen in about 25% of melanomas (8). However, nevi with ras mutations do not seem to progress to melanoma. One essential feature that distinguishes them from melanoma is that their proliferative stimulus eventually ceases. The proliferative halt of nevi is typically stable with no further extension in size. One concept would explain the link of nevus size to the time point in life when it started to grow and why nevi ultimately undergoes growth arrest. This has to do with the finite replicative potential of most human somatic cells, e.g., human diploid fibroblasts can undergo 60–80 population doublings in culture until they cease dividing and enter a senescent state in which they stay metabolically active and can be maintained in culture for several years. The molecular mechanisms that determine the intrinsic replicative lifespan of human cells seem to be controlled by a single process—telomere(definition) shortening (9). Telomeres are the repetitive DNA sequences bound by a complex of proteins at the end of chromosomes. Telomeres shorten slightly with each cell division until they reach a critical length at which a damage signal requiring p53 and RB is triggered which leads to permanent cell cycle arrest. This arrest is termed replicative senescence(definition). Culture cells from young individuals undergo more divisions before they senesce than cells from older individuals. This is because of the longer telomeres of cells from younger individuals. A similar dependence of donor age and number of cell divisions before senescence has also been demonstrated for melanocytes (10). One would thus expect that an activating mutation such as ras occurring early in life would lead to a larger nevus than the same mutation occurring later in life. The mutation that constitutively activates growth-signal cascades in melanocytic nevi would drive proliferation until the normal replication limit determined by their telomere length is reached. Once the telomere checkpoint is triggered cells enter the state of replicative senescence. The longer the telomeres are at the time the initial mutation is acquired, the more population doublings could occur and the larger the number of cells would become. This seems to fit well with the clinical observation that nevi acquired in utero tend to grow much larger than those acquired later in life. In this scenario, the intactness of the telomere checkpoint would determine whether an oncogenic mutation will lead to a benign, i.e., limited proliferation, or to melanoma, i.e., unlimited proliferation. Senescence could also explain the increased risk of larger nevi to develop melanoma. Nevi with a higher cell number have a higher number of targets for additional genetic events, increasing the likelihood that one cell will