Integrated pathway and epistasis analysis reveals interactive effect of genetic variants at TERF1 and AFAP1L2 loci on melanoma risk.
Abstract
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.
Type
Journal articleSubject
gene-gene interactiongenome-wide association studies
melanoma
pathway analysis
Adaptor Proteins, Signal Transducing
Epistasis, Genetic
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Melanoma
Polymorphism, Single Nucleotide
Signal Transduction
Skin Neoplasms
Telomere-Binding Proteins
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https://hdl.handle.net/10161/10671Published Version (Please cite this version)
10.1002/ijc.29570Publication Info
Brossard, Myriam; Fang, Shenying; Vaysse, Amaury; Wei, Qingyi; Chen, Wei V; Mohamdi,
Hamida; ... Demenais, Florence (2015). Integrated pathway and epistasis analysis reveals interactive effect of genetic variants
at TERF1 and AFAP1L2 loci on melanoma risk. Int J Cancer, 137(8). pp. 1901-1909. 10.1002/ijc.29570. Retrieved from https://hdl.handle.net/10161/10671.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Qingyi Wei
Professor in Population Health Sciences
Qingyi Wei, MD, PhD, Professor in the Department of Medicine, is Associate Director
for Cancer Control and Population Sciences, Co-leader of CCPS and Co-leader of Epidemiology
and Population Genomics (Focus Area 1). He is a professor of Medicine and an internationally
recognized epidemiologist focused on the molecular and genetic epidemiology of head
and neck cancers, lung cancer, and melanoma. His research focuses on biomarkers and
genetic determinants for the DNA repair deficient phenotype and

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