Dr. Nelleke A. Gruis, Phd
Department of dermatology – skin research laboratory
LUMC, P.O. Box 9600
Room C3-76, C3-S
2300 RC, Leiden
Dr R van Doorn-dermatologist
Prof dr W Bergman-dermatologist
Dr N.A. Kukutsch-dermatologist
Dr. M Visser- postdoc
Drs. E Christodoulou- PhD student
Drs. C. Salgado- PhD student
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 25% 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 focused 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. Currently our main focus is to discover novel high penetrance melanoma susceptibility genes through application of whole exome and genome sequencing (WES and WGS). For several novel candidates functional studies have been started.
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 another research line 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 and prognosis.
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.
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.
1: Harland M, Petljak M, Robles-Espinoza CD, Ding Z, Gruis NA, van Doorn R, Pooley KA, Dunning AM, Aoude LG, Wadt KA, Gerdes AM, Brown KM, Hayward NK,Newton-Bishop JA, Adams DJ, Bishop DT. Germline TERT promoter mutations are rare in familial melanoma. Fam Cancer. 2016 Jan;15(1):139-44. doe: 10.1007/s10689-015-9841-9. PubMed PMID: 26433962; PubMed Central PMCID:PMC4698275.
2: Law MH, Bishop DT, Lee JE, Brossard M, Martin NG, Moses EK, Song F, Barrett JH, Kumar R, Easton DF, Pharoah PD, Swerdlow AJ, Kypreou KP, Taylor JC, Harland M, Randerson-Moor J, Akslen LA, Andresen PA, Avril MF, Azizi E, Scarrà GB, Brown KM, Dȩbniak T, Duffy DL, Elder DE, Fang S, Friedman E, Galan P, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Helsing P, Hočevar M, Höiom V, Ingvar C, Kanetsky PA, Chen WV; GenoMEL Consortium.; Essen-Heidelberg Investigators.; SDH Study Group.; Q-MEGA and QTWIN Investigators.; AMFS Investigators.; ATHENS Melanoma Study Group., Landi MT, Lang J, Lathrop GM, Lubiński J, Mackie RM, Mann GJ, Molven A, Montgomery GW, Novaković S, Olsson H, Puig S, Puig-Butille JA, Qureshi AA, Radford-Smith GL, van der Stoep N, van Doorn R, Whiteman DC, Craig JE, Schadendorf D, Simms LA, Burdon KP, Nyholt DR, Pooley KA, Orr N, Stratigos AJ, Cust AE, Ward SV, Hayward NK, Han J, Schulze HJ, Dunning AM, Bishop JA, Demenais F, Amos CI, MacGregor S, Iles MM. Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma. Nat Genet. 2015 Sep;47(9):987-95. doi: 10.1038/ng.3373. PubMed PMID: 26237428; PubMed Central PMCID: PMC4557485.
3: Gao L, van den Hurk K, Nsengimana J, Laye JP, van den Oord JJ, Beck S, Gruis NA, Zoutman WH, van Engeland M, Newton-Bishop JA, Winnepenninckx VJ, van Doorn R. Prognostic Significance of Promoter Hypermethylation and Diminished Gene Expression of SYNPO2 in Melanoma. J Invest Dermatol. 2015 Sep;135(9):2328-31. doi: 10.1038/jid.2015.163. PubMed PMID: 25918983.
4: Taylor NJ, Handorf EA, Mitra N, Avril MF, Azizi E, Bergman W, Bianchi-Scarrà G, Bishop DT, Bressac-de Paillerets B, Calista D, Cannon-Albright LA, Cuellar F, Cust AE, Demenais F, Elder DE, Friedman E, Gerdes AM, Ghiorzo P, Goldstein AM, Grazziotin TC, Hansson J, Hayward NK, Hocevar M, Höiom V, Holland EA, Ingvar C, Landi MT, Landman G, Larre-Borges A, Leachman SA, Mann GJ, Nagore E, Olsson H, Palmer J, Perić B, Pjanova D, Puig S, Schmid H, van der Stoep N, Tucker MA, Wadt KA, Whitaker L, Yang XR, Newton Bishop JA, Gruis NA, Kanetsky PA; GenoMEL Consortium.. Phenotypic and Histopathological Tumor Characteristics According to CDKN2A Mutation Status among Affected Members of Melanoma Families. J Invest Dermatol. 2016 May;136(5):1066-9. doi: 10.1016/j.jid.2016.01.009. PubMed PMID:26827760.
5: Gao L, van den Hurk K, Moerkerk PT, Goeman JJ, Beck S, Gruis NA, van den Oord JJ, Winnepenninckx VJ, van Engeland M, van Doorn R. Promoter CpG island hypermethylation in dysplastic nevus and melanoma: CLDN11 as an epigenetic biomarker for malignancy. J Invest Dermatol. 2014 Dec;134(12):2957-66. dos: 10.1038/jid.2014.270. PubMed PMID: 24999589.
6: Commandeur S, Sparks SJ, Chan HL, Gao L, Out JJ, Gruis NA, van Doorn R, El Ghalbzouri A. In-vitro melanoma models: invasive growth is determined by dermal matrix and basement membrane. Melanoma Res. 2014 Aug;24(4):305-14. dos: 10.1097/CMR.0000000000000079. PubMed PMID: 24892959.
7: van der Rhee JI, Boonk SE, Putter H, Cannegieter SC, Flinterman LE, Hes FJ, de Snoo FA, Mooi WJ, Gruis NA, Vasen HF, Kukutsch NA, Bergman W. Surveillance of second-degree relatives from melanoma families with a CDKN2A germline mutation. Cancer Epidemiol Biomarkers Prev. 2013 Oct;22(10):1771-7. dos: 10.1158/1055-9965.EPI-13-0130. PubMed PMID: 23897584.
8: Gao L, Smit MA, van den Oord JJ, Goeman JJ, Verdegaal EM, van der Burg SH,Stas M, Beck S, Gruis NA, Tensen CP, Willemze R, Peeper DS, van Doorn R. Genome-wide promoter methylation analysis identifies epigenetic silencing of MAPK13 in primary cutaneous melanoma. Pigment Cell Melanoma Res. 2013 Jul;26(4):542-54. doi: 10.1111/pcmr.12096. PubMed PMID: 23590314.
9: Gao L, van Nieuwpoort FA, Out-Luiting JJ, Hensbergen PJ, de Snoo FA, Bergman W, van Doorn R, Gruis NA. Genome-wide analysis of gene and protein expression of dysplastic naevus cells. J Skin Cancer. 2012;2012:981308. dos:10.1155/2012/981308. PubMed PMID: 23251804; PubMed Central PMCID: PMC3515917.
10: Quint KD, van der Rhee JI, Gruis NA, Ter Huurne JA, Wolterbeek R, van der Stoep N, Bergman W, Kukutsch NA. Melanocortin 1 receptor (MC1R) variants in high melanoma risk patients are associated with specific dermoscopic ABCD features. Acta Derm Venereol. 2012 Nov;92(6):587-92. doi: 10.2340/00015555-1457. PubMed PMID: 22965007.
11: Gruis NA, van Doorn R. Melanocortin 1 receptor function: shifting gears from determining skin and nevus phenotype to fetal growth. J Invest Dermatol. 2012 Aug;132(8):1953-5. doi: 10.1038/jid.2012.216. PubMed PMID: 22797298.