Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 139, Issue 9, Pages 2012-2020Publisher
WILEY
DOI: 10.1002/ijc.30245
Keywords
genome-wide association studies; pathway analysis; gene-gene interaction; melanoma; Breslow thickness
Categories
Funding
- Programme Hospitalier de Recherche Clinique (PHRC) [AOM-07-195]
- Institut National du Cancer (INCa) [INCa_5982]
- Ligue Nationale Contre le Cancer [PRE 09/FD, 2010.239]
- Fondation pour la Recherche Medicale (FRM) [FDT20130928343]
- European Commission [LSH-CT-2006-018702]
- National Institutes of Health (NIH) [R01CA100264, 2P50CA093459, P30CA016672, R01CA083115, R01CA133996, 5R03CA17379202]
- National Cancer Institute [SPORE P50 CA093459]
- Philanthropic contributions to The University of Texas MD Anderson Cancer Center Moon Shots Program
- Miriam and Jim Mulva Research Fund
- Peterson Fund for Melanoma Research
- Patrick M. McCarthy Foundation
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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 (p(meta-int) =2.2 x 10(-6), which met the overall multiple-testing corrected threshold of 2.5 x 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.
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