title: Integrating gene expression and epidemiological data for the discovery of genetic interactions associated with cancer risk.
abstract: Dozens of common genetic variants associated with cancer risk have been identified through genome-wide association studies (GWASs). However, these variants only explain a modest fraction of the heritability of disease. The missing heritability has been attributed to several factors, among them the existence of genetic interactions (G × G). Systematic screens for G × G in model organisms have revealed their fundamental influence in complex phenotypes. In this scenario, G × G overlap significantly with other types of gene and/or protein relationships. Here, by integrating predicted G × G from GWAS data and complex- and context-defined gene coexpression profiles, we provide evidence for G × G associated with cancer risk. G × G predicted from a breast cancer GWAS dataset identified significant overlaps [relative enrichments (REs) of 8-36%, empirical P values < 0.05 to 10(-4)] with complex (non-linear) gene coexpression in breast tumors. The use of gene or protein data not specific for breast cancer did not reveal overlaps. According to the predicted G × G, experimental assays demonstrated functional interplay between lipoma-preferred partner and transforming growth factor-β signaling in the MCF10A non-tumorigenic mammary epithelial cell model. Next, integration of pancreatic tumor gene expression profiles with pancreatic cancer G × G predicted from a GWAS corroborated the observations made for breast cancer risk (REs of 25-59%). The method presented here can potentially support the identification of genetic interactions associated with cancer risk, providing novel mechanistic hypotheses for carcinogenesis.
authors.affiliation: Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Barcelona 08908, Catalonia, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Bonifaci
authors.forename: Eva
authors.initials: E
authors.lastname: Colas
authors.forename: Jordi
authors.initials: J
authors.lastname: Serra-Musach
authors.forename: Nazanin
authors.initials: N
authors.lastname: Karbalai
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.forename: Antonio
authors.initials: A
authors.lastname: Gómez
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.forename: Enrique
authors.initials: E
authors.lastname: Fernández-Taboada
authors.forename: Antoni
authors.initials: A
authors.lastname: Berenguer
authors.forename: Jaume
authors.initials: J
authors.lastname: Reventós
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.forename: Laufey
authors.initials: L
authors.lastname: Amundadottir
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Duell
authors.forename: Miquel Àngel
authors.initials: MÀ
authors.lastname: Pujana
mesh_terms: D045744:Cell Line, Tumor; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D012307:Risk Factors