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Int J Cancer. 2015 Oct 15;137(8):1901-1909. doi: 10.1002/ijc.29570. Epub 2015 May 26.

Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk.

Author information

INSERM, Genetic Variation and Human Diseases Unit, UMR-946, Paris, France.
Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France.
Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Duke Cancer Institute, Duke University Medical center and Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
Laboratory Informatics System, Department of Clinical Applications & Support, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA.
AP-HP (Assistance Publique-Hôpitaux de Paris), Hôpital Bichat, Service de Dermatologie, Université Paris Diderot, Paris, France.
INSERM, UMR U557; Institut national de la Recherche Agronomique,U1125; Conservatoire national des arts et métiers, Centre de Recherche en Nutrition Humaine, Ile de France, Bobigny, France.
McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
AP-HP, Hôpital Cochin et Université Paris Descartes, Paris, France.
Department of Community and Family Medicine, Geisel College of Medicine, Dartmouth College, Hanover, New Hampshire, USA.
Contributed equally


Genome-wide association studies (GWASs) have characterized 13 loci associated with melanoma, which only account for a small part of melanoma risk. To identify new genes with too small an effect to be detected individually but which collectively influence melanoma risk and/or show interactive effects, we used a two-step analysis strategy including pathway analysis of genome-wide SNP data, in a first step, and epistasis analysis within significant pathways, in a second step. Pathway analysis, using the gene-set enrichment analysis (GSEA) approach and the gene ontology (GO) database, was applied to the outcomes of MELARISK (3,976 subjects) and MDACC (2,827 subjects) GWASs. Cross-gene SNP-SNP interaction analysis within melanoma-associated GOs was performed using the INTERSNP software. Five GO categories were significantly enriched in genes associated with melanoma (false discovery rate ≤ 5% in both studies): response to light stimulus, regulation of mitotic cell cycle, induction of programmed cell death, cytokine activity and oxidative phosphorylation. Epistasis analysis, within each of the five significant GOs, showed significant evidence for interaction for one SNP pair at TERF1 and AFAP1L2 loci (pmeta-int  = 2.0 × 10(-7) , which met both the pathway and overall multiple-testing corrected thresholds that are equal to 9.8 × 10(-7) and 2.0 × 10(-7) , respectively) and suggestive evidence for another pair involving correlated SNPs at the same loci (pmeta-int  = 3.6 × 10(-6) ). This interaction has important biological relevance given the key role of TERF1 in telomere biology and the reported physical interaction between TERF1 and AFAP1L2 proteins. This finding brings a novel piece of evidence for the emerging role of telomere dysfunction into melanoma development.


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

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