Abstract
BackgroundBody mass index (BMI) has been implicated as a primary factor influencing cancer development. However, understanding the relationship between these two complex traits has been confounded by both environmental and genetic heterogeneity.MethodsIn order to gain insight into the genetic factors linking BMI and cancer, we performed chemical carcinogenesis on a genetically heterogeneous cohort of interspecific backcross mice ((Mus Spretus × FVB/N) F1 × FVB/N). Using this cohort, we performed quantitative trait loci (QTL) analysis to identify regions linked to BMI. We then performed an integrated analysis incorporating gene expression, sequence comparison between strains, and gene expression network analysis to identify candidate genes influencing both tumor development and BMI.ResultsAnalysis of QTL linked to tumorigenesis and BMI identified several loci associated with both phenotypes. Exploring these loci in greater detail revealed a novel relationship between the Pannexin 3 gene (Panx3) and both BMI and tumorigenesis. Panx3 is positively associated with BMI and is strongly tied to a lipid metabolism gene expression network. Pre-treatment Panx3 gene expression levels in normal skin are associated with tumor susceptibility and inhibition of Panx function strongly influences inflammation.ConclusionsThese studies have identified several genetic loci that influence both BMI and carcinogenesis and implicate Panx3 as a candidate gene that links these phenotypes through its effects on inflammation and lipid metabolism.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-016-0334-8) contains supplementary material, which is available to authorized users.
Highlights
Body mass index (BMI) has been implicated as a primary factor influencing cancer development
Pannexin 3 gene (Panx3) is in a lipid metabolism network associated with BMI In this work we have identified a potential role for Panx3, a member of the recently described Pannexin gene family, in both BMI and cancer susceptibility
Genome-wide linkage analysis identified several regions associated with BMI in this cohort, several of which were associated with tumor burden
Summary
Body mass index (BMI) has been implicated as a primary factor influencing cancer development. Elevated body mass index (BMI) has recently been highlighted as playing a profound role in the development of a diverse array of cancers. For some cancers, such as esophageal, endometrial, and uterine, BMI has been demonstrated to be associated with up to 40 % of all cases [1, 2]. By crossing tumor susceptible Mus musculus (FVB) mice with tumor resistant Mus spretus (SPRET) mice we developed a genetically heterogeneous cohort of F1 backcross mice that varies significantly in both tumor susceptibility and BMI This cohort was generated without using engineered susceptibilities to either obesity or tumorigenesis. This allows us to model more accurately the human condition of genetic heterogeneity and environmental (rather than genetic) tumor induction
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