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Int J Cancer. 2016 Nov 1;139(9):2012-20. doi: 10.1002/ijc.30245. Epub 2016 Jul 23.

A comprehensive genome-wide analysis of melanoma Breslow thickness identifies interaction between CDC42 and SCIN genetic variants.

Author information

1
INSERM, Genetic Variation and Human Diseases Unit, UMR-946, Paris, France.
2
Université Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Université Paris Diderot, Paris, France.
3
Department of Surgical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX.
4
Duke Cancer Institute, Duke University Medical Center and Department of Medicine, Duke University School of Medicine, Durham, NC.
5
Laboratory Informatics System, Department of Clinical Applications & Support, the University of Texas M. D. Anderson Cancer Center, Houston, TX.
6
AP-HP, Hôpital Cochin Et Université Paris Descartes, Paris, France.
7
AP-HP, Service De Dermatologie, Hôpital Avicenne, t Université Paris 13, Bobigny, France.
8
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
9
Department of Community and Family Medicine, Geisel College of Medicine, Dartmouth College, Hanover, NH.

Abstract

Breslow thickness (BT) is a major prognostic factor of cutaneous melanoma (CM), the most fatal skin cancer. The genetic component of BT has only been explored by candidate gene studies with inconsistent results. Our objective was to uncover the genetic factors underlying BT using an hypothesis-free genome-wide approach. Our analysis strategy integrated a genome-wide association study (GWAS) of single nucleotide polymorphisms (SNPs) for BT followed by pathway analysis of GWAS outcomes using the gene-set enrichment analysis (GSEA) method and epistasis analysis within BT-associated pathways. This strategy was applied to two large CM datasets with Hapmap3-imputed SNP data: the French MELARISK study for discovery (966 cases) and the MD Anderson Cancer Center study (1,546 cases) for replication. While no marginal effect of individual SNPs was revealed through GWAS, three pathways, defined by gene ontology (GO) categories were significantly enriched in genes associated with BT (false discovery rate ≤5% in both studies): hormone activity, cytokine activity and myeloid cell differentiation. Epistasis analysis, within each significant GO, identified a statistically significant interaction between CDC42 and SCIN SNPs (pmeta-int =2.2 × 10(-6) , which met the overall multiple-testing corrected threshold of 2.5 × 10(-6) ). These two SNPs (and proxies) are strongly associated with CDC42 and SCIN gene expression levels and map to regulatory elements in skin cells. This interaction has important biological relevance since CDC42 and SCIN proteins have opposite effects in actin cytoskeleton organization and dynamics, a key mechanism underlying melanoma cell migration and invasion.

KEYWORDS:

Breslow thickness; gene-gene interaction; genome-wide association studies; melanoma; pathway analysis

PMID:
27347659
PMCID:
PMC5116391
DOI:
10.1002/ijc.30245
[Indexed for MEDLINE]
Free PMC Article

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