Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Albert Rosenberger; Nils Muttray; Rayjean J. Hung; David C. Christiani; Neil E. Caporaso; Geoffrey Liu; Stig E. Bojesen; Loic Le Marchand; Demetrios Albanes; Melinda C. Aldrich; Adonina Tardon; Guillermo Fernández-Tardón; Gad Rennert; John K. Field; Michael P.A. Davies; Triantafillos Liloglou; Lambertus A. Kiemeney; Philip Lazarus; Bernadette Wendel; Aage Haugen; Shanbeh Zienolddiny; Stephen Lam; Matthew B. Schabath; Angeline S. Andrew; Eric J. Duell; Susanne M. Arnold; Gary E. Goodman; Chu Chen; Jennifer A. Doherty; Fiona Taylor; Angela Cox; Penella J. Woll; Angela Risch; Thomas R. Muley; Mikael Johansson; Paul Brennan; Maria Teresa Landi; Sanjay S. Shete; Christopher I. Amos; Heike Bickeböller; The INTEGRAL-ILCCO Consortium

doi:10.1186/s40001-022-00638-7

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

Albert Rosenberger^*, Nils Muttray, Rayjean J. Hung, David C. Christiani, Neil E. Caporaso, Geoffrey Liu, Stig E. Bojesen, Loic Le Marchand, Demetrios Albanes, Melinda C. Aldrich, Adonina Tardon, Guillermo Fernández-Tardón, Gad Rennert, John K. Field, Michael P.A. Davies, Triantafillos Liloglou, Lambertus A. Kiemeney, Philip Lazarus, Bernadette Wendel, Aage HaugenShanbeh Zienolddiny, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Eric J. Duell, Susanne M. Arnold, Gary E. Goodman, Chu Chen, Jennifer A. Doherty, Fiona Taylor, Angela Cox, Penella J. Woll, Angela Risch, Thomas R. Muley, Mikael Johansson, Paul Brennan, Maria Teresa Landi, Sanjay S. Shete, Christopher I. Amos, Heike Bickeböller, The INTEGRAL-ILCCO Consortium

^*Corresponding author for this work

2 Citations (Scopus)

Abstract

Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10^–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10^–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

Original language	English
Article number	14
Journal	European Journal of Medical Research
Volume	27
Issue number	1
ISSN	0949-2321
DOIs	https://doi.org/10.1186/s40001-022-00638-7
Publication status	Published - Dec 2022

Keywords

Association
Decision trees
Gene–gene integration
Never smoker
Polygenic risk score
Prediction
Small cell lung cancer
Susceptibility

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10.1186/s40001-022-00638-7

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Rosenberger, A., Muttray, N., Hung, R. J., Christiani, D. C., Caporaso, N. E., Liu, G., Bojesen, S. E., Le Marchand, L., Albanes, D., Aldrich, M. C., Tardon, A., Fernández-Tardón, G., Rennert, G., Field, J. K., Davies, M. P. A., Liloglou, T., Kiemeney, L. A., Lazarus, P., Wendel, B., ... The INTEGRAL-ILCCO Consortium (2022). Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer. European Journal of Medical Research, 27(1), Article 14. https://doi.org/10.1186/s40001-022-00638-7

Rosenberger, A, Muttray, N, Hung, RJ, Christiani, DC, Caporaso, NE, Liu, G, Bojesen, SE, Le Marchand, L, Albanes, D, Aldrich, MC, Tardon, A, Fernández-Tardón, G, Rennert, G, Field, JK, Davies, MPA, Liloglou, T, Kiemeney, LA, Lazarus, P, Wendel, B, Haugen, A, Zienolddiny, S, Lam, S, Schabath, MB, Andrew, AS, Duell, EJ, Arnold, SM, Goodman, GE, Chen, C, Doherty, JA, Taylor, F, Cox, A, Woll, PJ, Risch, A, Muley, TR, Johansson, M, Brennan, P, Landi, MT, Shete, SS, Amos, CI, Bickeböller, H & The INTEGRAL-ILCCO Consortium 2022, 'Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer', European Journal of Medical Research, vol. 27, no. 1, 14. https://doi.org/10.1186/s40001-022-00638-7

@article{627111c9c802467ba00b4a01e0880102,

title = "Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer",

abstract = "Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.",

keywords = "Association, Decision trees, Gene–gene integration, Never smoker, Polygenic risk score, Prediction, Small cell lung cancer, Susceptibility",

author = "Albert Rosenberger and Nils Muttray and Hung, {Rayjean J.} and Christiani, {David C.} and Caporaso, {Neil E.} and Geoffrey Liu and Bojesen, {Stig E.} and {Le Marchand}, Loic and Demetrios Albanes and Aldrich, {Melinda C.} and Adonina Tardon and Guillermo Fern{\'a}ndez-Tard{\'o}n and Gad Rennert and Field, {John K.} and Davies, {Michael P.A.} and Triantafillos Liloglou and Kiemeney, {Lambertus A.} and Philip Lazarus and Bernadette Wendel and Aage Haugen and Shanbeh Zienolddiny and Stephen Lam and Schabath, {Matthew B.} and Andrew, {Angeline S.} and Duell, {Eric J.} and Arnold, {Susanne M.} and Goodman, {Gary E.} and Chu Chen and Doherty, {Jennifer A.} and Fiona Taylor and Angela Cox and Woll, {Penella J.} and Angela Risch and Muley, {Thomas R.} and Mikael Johansson and Paul Brennan and Landi, {Maria Teresa} and Shete, {Sanjay S.} and Amos, {Christopher I.} and Heike Bickeb{\"o}ller and {The INTEGRAL-ILCCO Consortium}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1186/s40001-022-00638-7",

language = "English",

volume = "27",

journal = "European Journal of Medical Research",

issn = "0949-2321",

publisher = "Holzapfel Verlag GmbH",

number = "1",

}

TY - JOUR

T1 - Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

AU - Rosenberger, Albert

AU - Muttray, Nils

AU - Hung, Rayjean J.

AU - Christiani, David C.

AU - Caporaso, Neil E.

AU - Liu, Geoffrey

AU - Bojesen, Stig E.

AU - Le Marchand, Loic

AU - Albanes, Demetrios

AU - Aldrich, Melinda C.

AU - Tardon, Adonina

AU - Fernández-Tardón, Guillermo

AU - Rennert, Gad

AU - Field, John K.

AU - Davies, Michael P.A.

AU - Liloglou, Triantafillos

AU - Kiemeney, Lambertus A.

AU - Lazarus, Philip

AU - Wendel, Bernadette

AU - Haugen, Aage

AU - Zienolddiny, Shanbeh

AU - Lam, Stephen

AU - Schabath, Matthew B.

AU - Andrew, Angeline S.

AU - Duell, Eric J.

AU - Arnold, Susanne M.

AU - Goodman, Gary E.

AU - Chen, Chu

AU - Doherty, Jennifer A.

AU - Taylor, Fiona

AU - Cox, Angela

AU - Woll, Penella J.

AU - Risch, Angela

AU - Muley, Thomas R.

AU - Johansson, Mikael

AU - Brennan, Paul

AU - Landi, Maria Teresa

AU - Shete, Sanjay S.

AU - Amos, Christopher I.

AU - Bickeböller, Heike

AU - The INTEGRAL-ILCCO Consortium

PY - 2022/12

Y1 - 2022/12

N2 - Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

AB - Background: Aberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility. Aim: To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods: Odds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants. Conclusions: The role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

KW - Association

KW - Decision trees

KW - Gene–gene integration

KW - Never smoker

KW - Polygenic risk score

KW - Prediction

KW - Small cell lung cancer

KW - Susceptibility

UR - http://www.scopus.com/inward/record.url?scp=85124816563&partnerID=8YFLogxK

U2 - 10.1186/s40001-022-00638-7

DO - 10.1186/s40001-022-00638-7

M3 - Journal article

C2 - 35101137

AN - SCOPUS:85124816563

SN - 0949-2321

VL - 27

JO - European Journal of Medical Research

JF - European Journal of Medical Research

IS - 1

M1 - 14

ER -

Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

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Keywords

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