Gene expression signature associated with BRAF mutations in human primary cutaneous melanomas

Kannengiesser, Caroline; Spatz, Alain; Michiels, Stefan; Eychène, Alain; Dessen, Philippe; Lazar, Vladimir; Winnepenninckx, Véronique; Lesueur, Fabienne; Druillennec, Sabine; Robert, Caroline; van den Oord, Joost J.; Sarasin, Alain; Bressac-de Paillerets, Brigitte; On behalf of the EORTC Melanoma group,

doi:10.1016/j.molonc.2008.01.002

« Previous Next »Molecular Oncology
Volume 1, Issue 4 , Pages 425-430, April 2008

Gene expression signature associated with BRAF mutations in human primary cutaneous melanomas

Caroline Kannengiesser
- Service de Génétique & CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France
Alain Spatz
- Department of BioPathology, Institut Gustave Roussy, Villejuif, France
- Corresponding author. Department of BioPathology, Institut Gustave Roussy, 94805 Villejuif Cedex, France. Tel.: +33 1 4211 4520; fax: +33 1 4211 5263.
Stefan Michiels
- Division of Biostatistics & Epidemiology, Institut Gustave Roussy, Villejuif, France
Alain Eychène
- Institut Curie, Centre de Recherche & CNRS UMR 146, Orsay, France
Philippe Dessen
- CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France
Vladimir Lazar
- Division of Functional Genomics, Institut Gustave Roussy, Villejuif, France
Véronique Winnepenninckx
- Department of Morphology and Molecular Pathology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium
- Present address: Department of Pathology, Academic Hospital, University of Maastricht, Maastricht, The Netherlands.
Fabienne Lesueur
- Service de Génétique & CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France
Sabine Druillennec
- Institut Curie, Centre de Recherche & CNRS UMR 146, Orsay, France
Caroline Robert
- Service de Dermatologie, Institut Gustave Roussy, Villejuif, France
Joost J. van den Oord
- Department of Morphology and Molecular Pathology, University Hospitals, Katholieke Universiteit Leuven, Leuven, Belgium
Alain Sarasin
- CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France
Brigitte Bressac-de Paillerets
- Service de Génétique & CNRS FRE 2939, Institut Gustave Roussy, Villejuif, France
On behalf of the EORTC Melanoma group

Received 28 November 2007; received in revised form 31 December 2007; accepted 7 January 2008. published online 20 February 2008.

Abstract

With the aim to correlate BRAF mutation status with gene expression in human primary cutaneous melanomas, and thus to get more insight on the consequences of BRAF mutation on cell biology, we analyzed all expression data obtained in melanomas from which DNA was extracted from the same tissue slides that were used for the expression study.

A cohort of 69 frozen primary melanoma whose oligonucleotide micro-array expression data were available, were genotyped for BRAF and NRAS genes. The expression data from these melanomas were re-analyzed according to BRAF mutational status.

A set of 250 probes representing 209 genes that were significantly (raw P≤0.001) associated with BRAF mutation status was identified and 17 of these were previously shown to be implicated in cutaneous melanoma progression or pigmentation pathway-associated genes driven by the microphthalmia transcription factor (MITF). The list of 34 top probes contained no more than 1% of false discoveries with a probability of 0.95. Among the genes that differentiated most strongly between BRAF mutated and non-mutated melanomas, there were those involved in melanoma immune response such as MAGE-D2, CD63, and HSP70.

These findings support the immunogenicity of BRAF^V600E, eliciting patients T-cell responses in various in vitro assays. The genes whose expression is associated with BRAF mutations are not simply restricted to the MAPK/ERK signaling but also converge to enhanced immune responsiveness, cell motility and melanosomes processing involved in the adaptative UV response.

Keywords: Melanoma, BRAF, Genomics