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 - Funding Information:
GECCO (Genetics and Epidemiology of Colorectal Cancer Consortium): National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (U01 CA137088; R01 CA059045). ASTERISK: a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC). DACHS: German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS: National Institutes of Health (R01 CA48998 to MLS); HPFS is supported by the National Institutes of Health (P01 CA 055075, UM1 CA167552, R01 137178, R01 CA 151993, and P50 CA 127003), NHS by the National Institutes of Health (R01 CA137178, P01 CA 087969, R01 CA151993, and P50 CA 127003), and PHS by the National Institutes of Health (R01 CA042182). OFCCR: National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CFR section. Additional funding toward genetic analyses of OFCCR includes the Ontario Research Fund, the Canadian Institutes of Health Research, and the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Additionally, a subset of control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (Yeager M, et al. Nat Genet. 2007;39(5):645–649), Colon CGEMS pancreatic cancer scan (PanScan) (Amundadottir L, et al. Nat Genet. 2009;41(9):986–990 and Petersen GM, et al. Nat Genet. 2010;42(3):224–228), and the Lung Cancer and Smoking study. The prostate and PanScan study datasets were accessed with appropriate approval through the dbGaP online resource (http:// cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung datasets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/ gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by National Institutes of Health (NIH), Genes, Environment, and Health Initiative (GEI) Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438. For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination, and the Johns Hopkins University Center for Inherited Disease Research conducted genotyping. PMH: National Institutes of Health (R01 CA076366 to PA Newcomb). VITAL: National Institutes of Health (K05 CA154337). WHI: The WHI program is funded by the National Heart, Lung, and Blood
Funding Information:
FOCI: FOCI consortium would like to thank the following investigators for their contribution: Mike Birrer, Ann Chen, Julie Cunningham, Ed Iversen, John McLaughlin, Steven Narod, Harvey Risch, Jenny Permuth-Wey, Paul Pharoah, Simon Gayther, and Susan Ramus. UK ovarian cancer GWAS: We thank all the individuals who took part in this study. We thank all the researchers, clinicians, and administrative staffs who have enabled the many studies contributing to this work. This study made use of data generated by the Wellcome Trust Case Control consortium with its project funding provided by the Wellcome Trust under award 076113. We thank the support of the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge and University College Hospital.
Funding Information:
TRICL (Transdisciplinary Research for Cancer of Lung) and International Lung Cancer Consortium (ILCCO): National Institute of Health U19 CA148127-01 (PI: Amos), Canadian Cancer Society Research Institute (no. 020214, PI: Hung). DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): National Institute of Health U19 CA148065. CORECT (ColoRectal Transdisciplinary Study): National Institute of Health U19 CA148107; R01 CA81488, P30 CA014089. ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility): This work was support by the GAME-ON U19 initiative for prostate cancer (ELLIPSE), U19 CA148537. FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies): National Institutes of Health U19 CA148112-01 (PI: Sellers), R01-CA122443, P50-CA136393, P30-CA15083 (PI: Goode), Cancer Research UK (C490/A8339, C490/A16561, C490/A10119, C490/A10124 [PI: Pharoah]).
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.
UR - http://www.scopus.com/inward/record.url?scp=84964921042&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964921042&partnerID=8YFLogxK
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 -