TY - JOUR
T1 - Cross cancer genomic investigation of inflammation pathway for five common cancers
T2 - Lung, ovary, prostate, breast, and colorectal cancer
AU - Hung, Rayjean J.
AU - Ulrich, Cornelia M.
AU - Goode, Ellen L.
AU - Brhane, Yonathan
AU - Muir, Kenneth
AU - Chan, Andrew T.
AU - Marchand, Loic Le
AU - Schildkraut, Joellen
AU - Witte, John S.
AU - Eeles, Rosalind
AU - Boffetta, Paolo
AU - Spitz, Margaret R.
AU - Poirier, Julia G.
AU - Rider, David N.
AU - Fridley, Brooke L.
AU - Chen, Zhihua
AU - Haiman, Christopher
AU - Schumacher, Fredrick
AU - Easton, Douglas F.
AU - Landi, Maria Teresa
AU - Brennan, Paul
AU - Houlston, Richard
AU - Christiani, David C.
AU - Field, John K.
AU - Bickeböller, Heike
AU - Risch, Angela
AU - Kote-Jarai, Zsofia
AU - Wiklund, Fredrik
AU - Grönberg, Henrik
AU - Chanock, Stephen
AU - Berndt, Sonja I.
AU - Kraft, Peter
AU - Lindström, Sara
AU - Al Olama, Ali Amin
AU - Song, Honglin
AU - Phelan, Catherine
AU - Wentzensen, Nicholas
AU - Peters, Ulrike
AU - Slattery, Martha L.
AU - Sellers, Thomas A.
AU - Casey, Graham
AU - Gruber, Stephen B.
AU - Hunter, David J.
AU - Amos, Christopher I.
AU - Henderson, Brian
N1 - Publisher Copyright:
© The Author 2015. Published by Oxford University Press. All rights reserved.
PY - 2015/11
Y1 - 2015/11
N2 - Background: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. Methods: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. Results: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10-8, and it showed an association with lung cancer (P = 2.01 x 10-6), colorectal cancer (GECCO P = 6.72x10-6; CORECT P = 3.32x10-5), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10-6), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). Conclusions: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.
AB - Background: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted. Methods: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided. Results: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10-8, and it showed an association with lung cancer (P = 2.01 x 10-6), colorectal cancer (GECCO P = 6.72x10-6; CORECT P = 3.32x10-5), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10-6), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003). Conclusions: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer.
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U2 - 10.1093/jnci/djv246
DO - 10.1093/jnci/djv246
M3 - Article
C2 - 26319099
AN - SCOPUS:84964921042
SN - 0027-8874
VL - 107
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 11
ER -