LUMC Dermatology

Group Leader

Dr. Nelleke A. Gruis, Phd

Department of dermatology – skin research laboratory
LUMC, P.O. Box 9600
Room C3-76, C3-S
2300 RC, Leiden
The Netherlands

Group members

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 (

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.

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.



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.

LUMC Clinical Genetics

Our institution

Leiden University Medical Center
Albinusdreef 2
2333 ZA Leiden
The Netherlands

Our group

Department of Clinical Genetics
Leiden University Medical Center
Postbus 9600
2300 RC Leiden
The Netherlands

Department of Clinical Genetics
LUMC building 2
Post zone S-06-P
PO box 9600
2300 RC Leiden

The name, address and contact e-mail, tel of the group leader

Prof. Dr. M. H. Breuning
Department of Clinical Genetics
Leiden University Medical Center
Postbus 9600
2300 RC Leiden
The Netherlands

Phone: 071-5266090 / 5266060
Fax: 071-526 6749

Our knowledge of mankind’s hereditary characteristics is growing at a tremendous pace. As a result we are becoming more and more successful at tracking down the causes of congenital defects and hereditary diseases.

The Department of Clinical Genetics at the Leiden University Medical Center (LUMC) strives to apply all of this new knowledge as quickly and well as possible in medical practice. Through close collaboration with the Department of Human Genetics at the Center for Human and Clinical Genetics (CHCG) we are able to speedily put into practice the very latest developments in the diagnosis of hereditary diseases.

Related Links

Clinical Genetics, LUMC

Leiden University Medical Center (LUMC)

The Netherlands Foundation for the Detection of Hereditary Tumours

The names and e-mail addresses of group members with a description of their contribution

Management Team Department

Mrs. Dr. C.J. van Asperen
Head Genetic Counseling Section

Prof. Dr. E. Bakker
Head Laboratory Diagnostics sub-department

Prof. Dr. M. H. Breuning
Head Department of Clinical Genetics

Mrs. J.E.M. van Diemen-Homan
Quality Manager Genetic Counseling Section

Mrs. Drs. E. Voorhoeve
quality manager  Laboratory Diagnostics sub-department

Genetic Counselling Section

Mrs. Dr. C.J. van Asperen
head Genetic Counseling Section

Mrs. Dr. E.K. Bijlsma
clinical geneticist

Prof. Dr. M.H. Breuning
clinical geneticist

Mrs. Dr. A.H.J.T. Bröcker-Vriends
clinical geneticist

Mrs. B.T.J. van Brussel
genetic consultant

Mrs. J.E.M. van Diemen-Homan
genetic consultant

Drs. A. van Haeringen
clinical geneticist

Mrs. Drs. A.T.J.M. Helderman – v.d. Enden
clinical geneticist

Mrs. Drs. Y.M. Hendriks
medical assistant clinical genetics

Dr. F.J.H. Hes
clinical geneticist

Mrs. Drs. Y. Hilhorst-Hofstee
clinical geneticist

Mrs. Dr. N.S. den Hollander
clinical geneticist

Mrs. Dr. S.G. Kant
clinical geneticist

Mrs. Drs. M. Kriek
medical assistant clinical genetics

Mrs. Dr. S.A.M.J. Lesnik Oberstein
medical assistant clinical genetics

Mrs. A.M. van Mil
genetic consultant

Mrs. I. v.d. Schoot-van Velzen
genetic consultant in training

Mrs. Drs. F. de Snoo
medical assistant clinical genetics

Prof. Dr. A. Tibben



Prof. Dr. E. Bakker
ad interim laboratory head

Mrs. Dr. K.B.M. Hansson
clinical cytogeneticist, laboratory head

Mrs. Dr. M.J.V. Hoffer
clinical cytogeneticist

Mrs. Drs. W.G.M. Kroes
clinical cytogeneticist

Mrs. Dr. C. Ruivenkamp
clinical cytogeneticist in training

Mrs. Drs. S.L. van Zelderen – Bhola
clinical cytogeneticist

Molecular Genetics

Prof. Dr. E. Bakker
laboratory head

Mrs. Dr. E.M.J. Boon
clinical molecular geneticist in training

Mrs. Dr. M.J. van Belzen
clinical molecular geneticist in training

Mrs. Dr. H.B. Ginjaar
clinical molecular geneticist

Ing. A.L.J. Kneppers
head technician

Mrs. Dr. M. Losekoot
clinical molecular geneticist, laboratory head

Mrs. Dr. C.M.J. Tops
clinical molecular geneticist

Mrs. Dr. M.M. Weiss
clinical molecular geneticist in training

Dr. J.T.H. Wijnen
clinical molecular geneticist

Hemoglobinopathies Laboratory

Dr. P.C. Giordano
clinical biochemic geneticist, laboratory head

Dr. C.L. Harteveld
clinical molecular geneticist


 Pavel S, van Nieuwpoort F, van der Meulen H, Out C, Pizinger K, Cetkovska P, Smit NP, Koerten HK.
Disturbed melanin synthesis and chronic oxidative stress in dysplastic naevi.
Eur J Cancer 2004, 40:1423-30.

Hayes MJ, Koundouris A, Gruis N, Bergman W, Peters GG, Sinclair AJ.
P16(INK4A)-independence of Epstein-Barr virus-induced cell proliferation and virus latency.
J Gen Virol. 2004, 85:1381-6.

Zuidervaart W, van der Velden PA, Hurks MH, van Nieuwpoort FA, Out-Luiting CJ, Singh AD, Frants RR, Jager MJ, Gruis NA.
Gene expression profiling identifies tumour markers potentially playing a role in uveal melanoma development.
Br J Cancer. 2003, 89:1914-9.

de Snoo FA, Bergman W, Gruis NA.
Familial melanoma: a complex disorder leading to controversy on DNA testing.
Fam Cancer. 2003,2:109-16.

de vos tot Nederveen Cappel WH, Offerhaus GJ, van Puijenbroek M, Caspers E,Gruis NA, De Snoo FA, Lamers CB, Griffioen G, Bergman W, Vasen HF, Morreau H.
Pancreatic carcinoma in carriers of a specific 19 base pair deletion of CDKN2A/p16 (p16-leiden).
Clin Cancer Res. 2003, 9:3598-605.

van der Velden PA, Zuidervaart W, Hurks MH, Pavey S, Ksander BR, Krijgsman E, Frants RR, Tensen CP, Willemze R, Jager MJ, Gruis NA.
Expression profiling reveals that methylation of TIMP3 is involved in uveal melanoma development.
Int J Cancer. 2003, 106:472-9.

 Gillanders E, Juo SH, Holland EA, Jones M, Nancarrow D, Freas-Lutz D, Sood R, Park N, Faruque M, Markey C, Kefford RF, Palmer J, Bergman W, Bishop DT,Tucker MA, Bressac-de Paillerets B, Hansson J, Stark M, Gruis N, Bishop JN,Goldstein AM, Bailey-Wilson JE, Mann GJ, Hayward N, Trent J; Lund Melanoma Study Group; Melanoma Genetics Consortium.
Localization of a novel melanoma susceptibility locus to 1p22.
Am J Hum Genet. 2003,73:301-13.

Pavel S, Smit NP, van der Meulen H, Kolb RM, de Groot AJ, van der Velden PA,Gruis NA, Bergman W.
Homozygous germline mutation of CDKN2A/p16 and glucose-6-phosphate dehydrogenase deficiency in a multiple melanoma case.
Melanoma Res. 2003,13:171-8.

Bishop DT, Demenais F, Goldstein AM, Bergman W, Bishop JN, Bressac-de Paillerets B, Chompret A, Ghiorzo P, Gruis N, Hansson J, Harland M, Hayward N,Holland EA, Mann GJ, Mantelli M, Nancarrow D, Platz A, Tucker MA; Melanoma Genetics Consortium.
Geographical variation in the penetrance of CDKN2A mutations for melanoma.
J Natl Cancer Inst. 2002,94:894-903.

Brookes S, Rowe J, Ruas M, Llanos S, Clark PA, Lomax M, James MC, Vatcheva R, Bates S, Vousden KH, Parry D, Gruis N, Smit N, Bergman W, Peters G.
INK4a-deficient human diploid fibroblasts are resistant to RAS-induced senescence.
EMBO J. 2002,21:2936-45.

Kennedy C, Naipal A, Gruis NA, Struijk L, ter Schegget J, Willemze R, Claas FH, Bouwes Bavinck JN, Doxiadis II.
MICA gene polymorphism is not associated with an increased risk for skin cancer.
J Invest Dermatol. 2002,118:686-91.

Kennedy C, ter Huurne J, Berkhout M, Gruis N, Bastiaens M, Bergman W, Willemze R, Bavinck JN.
Melanocortin 1 receptor (MC1R) gene variants are associated with an increased risk for cutaneous melanoma which is largely independent of skin type and hair color.
J Invest Dermatol. 2001, 117:294-300.

van der Velden PA, Sandkuijl LA, Bergman W, Pavel S, van Mourik L, Frants RR, Gruis NA.
Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma.
Am J Hum Genet. 2001, 69:774-9.

Bastiaens M, ter Huurne J, Gruis N, Bergman W, Westendorp R, Vermeer BJ,Bouwes Bavinck JN.
The melanocortin-1-receptor gene is the major freckle gene.
Hum Mol Genet. 2001, 10:1701-8.

Metzelaar-Blok JA, ter Huurne JA, Hurks HM, Keunen JE, Jager MJ, Gruis NA.
Characterization of melanocortin-1 receptor gene variants in uveal melanoma patients.
Invest Ophthalmol Vis Sci. 2001, 42:1951-4.

van der Velden PA, Metzelaar-Blok JA, Bergman W, Monique H, Hurks H, Frants RR, Gruis NA, Jager MJ.
Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma.
Cancer Res. 2001, 61:5303-6.

Bastiaens MT, Struyk L, Tjong-A-Hung SP, Gruis N, ter Huurne J, Westendorp RG, Vermeer BJ, Bavinck JN, ter Schegget J.
Cutaneous squamous cell carcinoma and p53 codon 72 polymorphism: a need for screening?
Mol Carcinog. 2001, 30:56-61.

Bastiaens MT, ter Huurne JA, Kielich C, Gruis NA, Westendorp RG, Vermeer BJ, Bavinck JN; Leiden Skin Cancer Study Team.
Melanocortin-1 receptor gene variants determine the risk of nonmelanoma skin cancer independently of fair skin and red hair.
Am J Hum Genet. 2001, 68:884-94.

Gruis NA, Bergman W.
[From gene to disease; from p16 to melanoma].
Ned Tijdschr Geneeskd. 2000, 144:2100-2.

Vasen HF, Gruis NA, Frants RR, van Der Velden PA, Hille ET, Bergman W.
Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).
Int J Cancer. 2000, 87:809-11.

Dekker SK, van Doorn R, Kempenaar J, Gruis NA, Vermeer BJ, Ponec M.
Skin equivalent: an attractive model to evaluate early melanoma metastasis.
Melanoma Res. 2000, 10:127-40.

Gruis NA, van der Velden PA, Bergman W, Frants RR.
Familial melanoma; CDKN2A and beyond.
J Investig Dermatol Symp Proc. 1999, 4:50-4. Review.

van der Velden PA, Sandkuijl LA, Bergman W, Hille ET, Frants RR, Gruis NA.
A locus linked to p16 modifies melanoma risk in Dutch familial atypical multiple mole melanoma (FAMMM) syndrome families.
Genome Res. 1999,9:575-80.

Snels DG, Hille ET, Gruis NA, Bergman W.
Risk of cutaneous malignant melanoma in patients with nonfamilial atypical nevi from a pigmented lesions clinic.
J Am Acad Dermatol. 1999, 40:686-93.