6533b82cfe1ef96bd12901c6

RESEARCH PRODUCT

Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma

David M. LevineTania NoderJakob R. IzbickiHauke LangMarino VeneritoHugh BarrLaura ChegwiddenTimo HessHorst NeuhausKirsten B. MoysichDavid C. WhitemanChristine B. AmbrosonePeter H. WatsonDouglas A. CorleyDouglas A. CorleyHarvey A. RischJessica BeckerRebecca HarrisonSharon B. LoveJames Y. DaiArnulf H. HölscherJesper LagergrenJesper LagergrenAndrea MayLeslie BernsteinAnna H. WuThomas RöschGeoffrey LiuMarkus M. NöthenPaul MoayyediKatja OttMario AndersMichael ViethStuart MacgregorJohannes SchumacherOliver PechQianchuan HeBrigitte SchumacherRupert MayershoferLothar VeitsWong Ho ChowMatthew F. BuasLesley A. AndersonPuya GharahkhaniJohn DecaesteckerMargaret M. MadeleineMargaret M. MadeleineJosef WeismüllerClaire PallesLynn OnstadNicholas J. ShaheenSusanne MoebusChristian GergesMarilie D. GammonChristian EllYogesh K. VashistAnne C. BöhmerLaura J. HardieInes GockelThomas SchmidtDavid MacdonaldStephen AttwoodShruti G. DigheHendrik MannerJianhong ChenNicole KreuserDietmar LorenzJanusz JankowskiHans PrenenPrasad G. IyerWeimin YeMichael KnappLi YanThomas L. VaughanThomas L. VaughanIan TomlinsonClaudia Schmidt

subject

0301 basic medicineOncologyMaleCancer Researchmedicine.medical_specialtyEsophageal NeoplasmsMedizinSingle-nucleotide polymorphismGenome-wide association studyBiologyAdenocarcinomaPolymorphism Single NucleotideReceptor IGF Type 103 medical and health sciencesBarrett Esophagus0302 clinical medicineRisk FactorsSomatomedinsInternal medicineGenetic variationmedicineBiomarkers TumorSNPHumansGenetic Predisposition to DiseaseRisk factorGerm-Line MutationCancer Biomarkers and Molecular EpidemiologyInsulin-like growth factor 1 receptorGenetic associationAgedGeneral MedicineMiddle Agedmedicine.diseaseRenal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]030104 developmental biology030220 oncology & carcinogenesisBarrett's esophagusFemaleHuman medicineCarrier ProteinsGenome-Wide Association StudySignal Transduction

description

Contains fulltext : 235640.pdf (Publisher’s version ) (Closed access) Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS meta-analysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

yearjournalcountryeditionlanguage
2020-12-10Carcinogenesis
10.1093/carcin/bgaa132https://hdl.handle.net/10067/1758980151162165141