Dighe, Shruti G., Chen, Jianhong, Yan, Li, He, Qianchuan, Gharahkhani, Puya ORCID: 0000-0002-4203-5952, Onstad, Lynn, Levine, David M., Palles, Claire, Ye, Weimin, Gammon, Marilie D., Iyer, Prasad G., Anderson, Lesley A., Liu, Geoffrey ORCID: 0000-0002-2603-7296, Wu, Anna H., Dai, James Y., Chow, Wong-Ho, Risch, Harvey A., Lagergren, Jesper, Shaheen, Nicholas J., Bernstein, Leslie, Corley, Douglas A., Prenen, Hans ORCID: 0000-0001-8802-7352, DeCaestecker, John, MacDonald, David, Moayyedi, Paul ORCID: 0000-0002-3616-9292, Barr, Hugh, Love, Sharon B., Chegwidden, Laura, Attwood, Stephen, Watson, Peter, Harrison, Rebecca, Ott, Katja, Moebus, Susanne, Venerito, Marino, Lang, Hauke, Mayershofer, Rupert, Knapp, Michael, Veits, Lothar, Gerges, Christian, Weismueller, Josef, Gockel, Ines, Vashist, Yogesh, Noethen, Markus M., Izbicki, Jakob R., Manner, Hendrik, Neuhaus, Horst, Roesch, Thomas, Boehmer, Anne C., Hoelscher, Arnulf H., Anders, Mario, Pech, Oliver, Schumacher, Brigitte, Schmidt, Claudia, Schmidt, Thomas, Noder, Tania, Lorenz, Dietmar, Vieth, Michael, May, Andrea, Hess, Timo, Kreuser, Nicole, Becker, Jessica, Ell, Christian, Ambrosone, Christine B., Moysich, Kirsten B., MacGregor, Stuart, Tomlinson, Ian, Whiteman, David C., Jankowski, Janusz, Schumacher, Johannes, Vaughan, Thomas L., Madeleine, Margaret M., Hardie, Laura J. and Buas, Matthew F. (2021). Germline variation in the insulin-like growth factor pathway and risk of Barrett's esophagus and esophageal adenocarcinoma. Carcinogenesis, 42 (3). S. 369 - 378. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2180

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Abstract

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 metaanalysis. 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dighe, Shruti G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, JianhongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yan, LiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
He, QianchuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gharahkhani, PuyaUNSPECIFIEDorcid.org/0000-0002-4203-5952UNSPECIFIED
Onstad, LynnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Levine, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palles, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ye, WeiminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gammon, Marilie D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iyer, Prasad G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anderson, Lesley A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liu, GeoffreyUNSPECIFIEDorcid.org/0000-0002-2603-7296UNSPECIFIED
Wu, Anna H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dai, James Y.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chow, Wong-HoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Risch, Harvey A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lagergren, JesperUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shaheen, Nicholas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernstein, LeslieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Corley, Douglas A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Prenen, HansUNSPECIFIEDorcid.org/0000-0001-8802-7352UNSPECIFIED
DeCaestecker, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacDonald, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moayyedi, PaulUNSPECIFIEDorcid.org/0000-0002-3616-9292UNSPECIFIED
Barr, HughUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Love, Sharon B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chegwidden, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Attwood, StephenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Watson, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harrison, RebeccaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ott, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moebus, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venerito, MarinoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, HaukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayershofer, RupertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knapp, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veits, LotharUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerges, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weismueller, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gockel, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vashist, YogeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Izbicki, Jakob R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manner, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, HorstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesch, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boehmer, Anne C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, Arnulf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Anders, MarioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pech, OliverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noder, TaniaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lorenz, DietmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vieth, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, TimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuser, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ell, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ambrosone, Christine B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moysich, Kirsten B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacGregor, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whiteman, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jankowski, JanuszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaughan, Thomas L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madeleine, Margaret M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hardie, Laura J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buas, Matthew F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-608089
DOI: 10.1093/carcin/bgaa132
Journal or Publication Title: Carcinogenesis
Volume: 42
Number: 3
Page Range: S. 369 - 378
Date: 2021
Publisher: OXFORD UNIV PRESS
Place of Publication: OXFORD
ISSN: 1460-2180
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; PROSTATE-CANCER RISK; BINDING-PROTEINS; FACTOR-I; CIRCULATING LEVELS; IGF-I; POLYMORPHISMS; OBESITY; SYSTEM; GENEMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60808

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