Research Melanoma

Genetics of melanoma predisposition

The melanoma research group has a longstanding interest in the genetic aspects of familial melanoma, also known as familial atypical multiple mole-melanoma syndrome (FAMMM). Familial melanoma is an example of a disorder in which gene-environment interactions play a crucial role in addition to heritable genetic alterations. Studies on a large collection of families with multiple melanoma cases in The Netherlands demonstrated that 80% of them had a founder mutation in the CDKN2A gene (p16-Leiden mutation). This tumor suppressor gene encodes for the p16 and p14 proteins that are primarily involved in cell cycle regulation. The highly variable risk for p16-Leiden mutation carriers to develop melanoma suggests a role for other genetic and environmental factors. These are the subject of current research, which is mostly performed through participation in the international melanoma genetics consortium GenoMEL (www.genomel.org). In our search to identify melanoma-predisposing genetic variants we also focus on large sporadic melanoma case-control cohorts. SNP-based genome wide approaches have identified genomic loci that are primarily related to genes in pigmentation pathways. We are involved in validation of these SNPs in additional cohorts and functional analysis of genetic variants in relation to melanoma progression.  

MC1R & oxidative stress management

We have furthermore evaluated a modifying factor of melanoma risk. Variants of the melanocortin 1 receptor (MC1R) gene are associated with red hair, fair skin and increased risk of melanoma in humans. A typical fair skin type variant turns out to be over-represented in sporadic and familial melanoma patients and is associated with an increased melanoma risk independent of skin type. These findings suggest that MC1R variants are involved in melanoma tumorigenesis in a dual manner; as determinant of fair skin and in a pigmentation signalling-independent pathway. In this regard, the role of UV light and oxidative stress, in relation to type and degree of pigmentation and melanoma risk is investigated.

Epigenetics of melanoma

The identification and functional assessment of epigenetic alterations in melanoma is one of the research lines pursued in our reseach group. Epigenetic alterations, in particular aberrant DNA methylation, have been recognized as important contributors to the malignant phenotype of melanoma cells. Dozens of tumor suppressor genes have been reported to be affected by promoter hypermethylation in melanoma including CDKN2A, PTEN, APAF1, E-cadherin and RASSF1A. Our research lab has been among the first to demonstrate promoter hypermethylation in melanoma and we investigate the contribution of this mechanism to its malignant progression.

Melanoma skin model

The research laboratory has extensive experience in developing and studying human skin equivalent models, which are engineered by introducing fibroblasts into a dermal matrix onto which keratinocytes are seeded. The engineered skin models generated at our research laboratory are among the most advanced in their resemblance to native skin. Tissue engineered models of cutaneous melanoma and its precursors are used to study the growth and invasive behavior of melanoma cells in their proper microenvironment. In addition to in vitro melanoma models, organotypic skin cultures containing melanocytes are generated to investigate melanocyte biology.

Clinical Research

The department has the largest pigmented lesion clinic in The Netherlands and serves as a tertiary referral center for (familial) melanoma. The well-organized management of patients with dysplastic naevi and melanoma ensures the availability of clinically annotated patient material for research purposes and the possibility for clinical ‘translation’ of research findings. The special position of our clinic as a melanoma center in The Netherlands is related to a large population of patients with familial melanoma carrying the p16-Leiden mutation living in the vicinity of Leiden. Optimizing the management of patients predisposed to the development of melanoma is one of the goals of our research group. To this end epidemiological studies of genetic and environmental influences on melanoma risk are performed and application of imaging devices in the early diagnosis of melanoma is studied by clinical researchers attached to our department.


Figure 1: Shown is cross section of a melanoma skin model. In figure 1A the invasive behaviour of melanoma is mimicked in a human skin model using a cell line. These invasive cells have a high proliferative capacity (brown coloured cells stained for protein ki67) as shown in figure 1B 

fig.1A  fig.1B