A paragraph describing the group
The skin cancer research program of the Dept. of Dermatology includes three main lines of research:
1. malignant melanoma
2. non-melanoma skin cancer
3. cutaneous lymphoma
1. In collaboration with the Center for Human and Clinical Genetics, the melanoma group has focused particularly on the genetic aspects of the Familial Atypical Multiple Mole-Melanoma syndrome. FAMMM is an excellent example of a multi-factorial disorder in which gene-gene and gene-environment interactions play a crucial role. Studies on a large collection of families with the FAMMM syndrome demonstrated that 80% of the families had a founder mutation in the cell cycle regulator gene CDKN2A. The highly variable risk for p16-Leiden carriers to develop melanoma suggests a role for other genetic and/or environmental factors. Furthermore, absence of the p16-Leiden mutation in family members with many atypical nevi suggests that additional genes are responsible for the presence of these moles. Linkage analysis is currently followed within the FAMMM families to identify the crucial nevus gene(s). To speed up the analysis, we now combine linkage data and gene expression profiling of affected sibpairs.
Gene expression profiling by Affymetrix oligonucleotide arrays is furthermore used to identify genetic pathways involved in early melanoma development. Gene expression profiles of normal melanocytes compared to atypical melanocytes revealed a genomic pathway that causes accumulation of oxidative stress in atypical melanocytes.
We have furthermore evaluated a modifying factor of melanoma risk. Variants of the melanocortin 1 receptor (MC1R) gene were shown to be associated with red hair, fair skin and melanoma in humans. A typical fair skin type variant, turns out to be over-represented in melanoma patients in Dutch FAMMM families 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 or as a component in an alternative-signaling pathway. In addition to this genetic factor, the role of UV light and internal metabolic oxidative stress, in relation to type and degree of pigmentation and melanoma risk is investigated.
Next to the cutaneous melanoma our group is also interested in uveal melanoma. In collaboration with the Department of Ophthalmology, microarray technology has been used to identify genes that are differentially expressed in uveal melanoma compared to normal uveal melanocytes. This technology allows to study the processes that are involved in the development of uveal melanoma and that discriminate uveal melanoma from cuteanous melanoma.
2. Research in non-melanoma skin cancer focuses on the role of genetic factors, such as HLA, MC1R and p53, as well as environmental factors (UV light, smoking, infections with human papillomavirus and immunosuppression) in the development of these skin tumors. The availability of a human reconstructed skin equivalent and several validated wound-healing models offers a unique opportunity to study the role of genes involved in the regulation of proliferation and differentiation of benign and malignant keratinocytes and melanocytes and the effect of environmental factors in these processes.
3. The availibility of a national database for patients with a cutaneous lymphoma has enabled the Cutaneous Lymphoma Group to define new types of cutaneous B-cell and T-cell lymphomas, and to propose a new classification for this group of diseases. Current research focuses on genetic and immunologic factors involved in the development and progression of these different types of skin lymphoma. The potential therapeutic effect of the CXCR3 targeting chemokine IP-9/I-TAC is investigated. Furthermore, tumor-mediated impairment of skin dendritic cell function, such as altered maturation and early apoptosis, is studied. |
