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What is human melanoma?
Human melanoma is usually, but not always, a cancer of the skin. It begins in melanocytes – the cells that produce the pigment melanin that colors the skin, hair, and eyes. Melanocytes also form moles, where melanoma often develops. Having moles can be a risk factor for melanoma, but it’s important to remember that most moles do not become melanoma.
There are three general categories of melanoma:
- Cutaneous Melanoma is melanoma of the skin. Since most pigment cells are found in the skin, cutaneous melanoma is the most common type of melanoma. Cutaneous melanoma can be described in four main ways:
- Superficial Spreading Melanoma
- Nodular Melanoma
- Acral Lentiginous Melanoma
- Lentigo Maligna Melanoma
- Desmoplastic Melanoma
- Mucosal Melanoma can occur in any mucous membrane of the body, including the nasal passages, the throat, the vagina, the anus, or in the mouth
- Ocular Melanoma, also known as uveal melanoma or choroidal melanoma, is a rare form of melanoma that occurs in the eye. Learn more about CURE OM, an initiative that is focused on ocular melanoma
Unlike other cancers, melanoma can often be seen on the skin, making it easier to detect in its early stages. If left undetected, however, melanoma can spread to distant sites or distant organs. Once melanoma has spread to other parts of the body (known as stage IV), it is referred to as metastatic melanoma, and is very difficult to treat. In its later stages, melanoma most commonly spreads to the liver, lungs, bones and brain; at this point, the prognosis is very poor.
A new unexpected key player in melanoma development identified
Identification and functional validation of proteins involved in tumorigenesis are essential steps toward advancing cancer precision medicine.
Identification and functional validation of proteins involved in tumorigenesis are essential steps towards advancement in cancer precision medicine. In The Journal of Clinical Investigation researchers from VIB, KU Leuven (Belgium) together with colleagues from INSERM (France) now report the important role for FES in the initiation and progression of melanoma, a malignant type of skin cancer, that is notoriously quick to metastasize and that responds poorly to existing cancer treatments. Unexpectedly, the expression of FES, which encodes a kind of protein better known for their ability to promote cancer developments, is lost in a large fraction of human melanoma. The researchers also identified a pharmacological way through which FES expression can be restored in human melanoma. This can be the first step in a novel therapeutic strategy against melanoma.
Human melanoma is a very aggressive skin cancer, but very little is known about the mechanisms that cause the disease to progress. The fact that melanoma often exhibits UV-induced genetic alterations makes it, among other features, a very complex disease to study. Prof. Jean-Christophe Marine (VIB-KU Leuven) and others developed mouse models recapitulating some of the key histopathological features of the human disease. Importantly, the mouse melanoma lesions are far less complex than their human counterparts. Taking advantage of these ‘simplified’ versions of melanoma, the researchers identified a dozen of new genes that are likely to play key roles in the initiation and/or progression of human melanoma. To further validate their findings, they studied the role of one of the genes, namely FES, and established its important contribution to the development of both mouse and human melanoma. Previous research identified FES as an ‘oncogene’ – a gene that is able to transform a normal cell into a cancer cell under certain conditions – in leukemia, for example.
However, its role in melanoma appears very different. Prof. Jean-Christophe Marine (VIB-KU Leuven): “To our surprise, we obtained clear evidence that FES strongly suppresses melanoma growth and viability. Its expression is silenced in more than 30% of human melanoma lesions. Importantly, we showed that FES deletion in mice accelerated the growth of melanoma tumors.” The research team also showed that FES modulates the WNT signaling pathway. This key cancer pathway is activated in virtually all melanoma, but the mechanisms that contribute to this activation remain largely unclear. So this study provides one route through which this pathway is activated in about 30% of the cases.
Pharmacological implications of FES
Prof. Marine and his research team also identified a pharmacological way of restoring the expression of FES in human melanoma. The approach involved the use of epigenetic drugs that promote DNA demethylation; some of which are currently tested in clinical trials for melanoma. It will be interesting to assess whether the efficacy of these drugs can be linked, at least partly, to the restoration of FES expression.
Prof. Jean-Christophe Marine: “We will definitely further explore this new putative therapeutic strategy. Importantly, in the same time, our data raise concerns about ongoing clinical trials with broad-spectrum tyrosine kinase inhibitors. Some of these inhibitors inactivate FES and therefore may lead to undesired effects.”
Article: Comparative oncogenomics identifies tyrosine kinase FES as a tumor suppressor in melanoma, Jean-Christophe Marine et al., The Journal of Clinical Investigation, doi: 10.1172/JCI91291, published 2 May 2017.
Diagnosing Melanomas Is Not Easy
The pathologists were only accurate with 25% of class II moderately atypical lesions; 40% of class III severely atypical lesions and melanoma in situ; and 43% of class IV early-stage invasive melanoma.
Hong Wu, MD, Ph.D., director of Dermatopathology at Fox Chase Cancer Center in Philadelphia, Pennsylvania, pointed out that with respect to misclassifications, it is “most important to avoid misdiagnosing an invasive melanoma (especially as T1b or above) as benign; and in the other direction, a benign nevus as an invasive melanoma (especially as a class V lesion).
“This is most important because misinterpretation between class I/II and class V lesions will lead to very different treatment and follow-up of the patient,” he explained.
Dr. Wu, who was not involved in the study, took a deep dive into the study data and found some results that he took “most seriously.”
He highlighted that among patients classified with invasive melanoma (class IV or V) by study pathologists, an estimated 16% would be reclassified downward as having benign lesions (class I or II) by the experienced consensus panel.
Furthermore, among patients classified with benign lesions (I or II) by study pathologists, an estimated 0.5% would be classified as having invasive melanoma (IV or V) by the experienced consensus panel, Dr Wu said.
The study also yielded another troublesome insight about the pathologists when they described biopsy samples as class II-IV (ie, intermediate). There was a lack of reproducibility of the pathologists’ interpretations of the same case on two different occasions, which was part of the study design. The concordance between the pathologists’ first and second diagnoses ranged from 35.2% to 63.2% for these intermediate cases.
At a population level, the study authors estimate that 82.8% of pathologists’ diagnoses would be verified if reviewed by a consensus reference panel of experienced pathologists, with 8% of cases over-interpreted by the initial pathologist and 9% under-interpreted.
To make this population-level estimate, the team performed a calculation that changed the prevalence of skin biopsy classifications to reflect the distribution found in clinical practice. The study authors acknowledged that their study sample of lesions included more cases that were intermediate and thus “more difficult to determine.”
Looking to the future, the study authors hope that “reliable and objective techniques” can be developed to support pathologists’ visual assessments of melanocytic lesions.
The study was supported by the National Cancer Institute. Dr Elmore and Dr Wu have disclosed no relevant financial relationships.