• : Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada (RJH, YB, JGP); National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany (CMU, AR); Mayo Clinic, Rochester, MN (ELG, DNR); The University of Warwick, Coventry, UK (KM); Massachusetts General Hospital, Boston, MA (ATC); University of Hawaii Cancer Center, Honolulu, HI (LLM); Duke University, Durham, NC (JS); University of California at San Francisco, San Francisco, CA (JSW); Institute of Cancer Research, London, UK (RE, RH, ZKJ); Mount Sinai School of Medicine, New York, NY (PBo); Baylor College of Medicine, Houston, TX (MRS); Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS (BLF); Moffitt Cancer Center, Tampa, FL (ZC, CP, TAS); University of South California, Los Angeles, CA (CH, FS, GC, SBG, BH); Cambridge University, Cambridge, UK (DFE, AAAO, HS); National Cancer Institute, Bethesda, MD (MTL, SC, SIB, NW); International Agency for Research on Cancer, Lyon, France (PBr); Harvard School of Public Health, Boston, MA (DCC, PK, SL, DJH); University of Liverpool, Liverpool, UK (JKF); University of Göttingen, Medical School, Göttingen, Germany (HB); Karolinska Institutet, Stockholm, Sweden (FW, HG); Fred Hutchinson Cancer Research Center, Seattle, WA (UP); University of Utah Health Sciences Center and Huntsman Cancer Institute, Salt Lake City, UT (CMU, MLS); Geisel School of Medicine, Dartmouth College, Lebanon, NH (CIA). rayjean.hung@lunenfeld.ca.
• : Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Canada (RJH, YB, JGP); National Center for Tumor Diseases and German Cancer Research Center (DKFZ), Heidelberg, Germany (CMU, AR); Mayo Clinic, Rochester, MN (ELG, DNR); The University of Warwick, Coventry, UK (KM); Massachusetts General Hospital, Boston, MA (ATC); University of Hawaii Cancer Center, Honolulu, HI (LLM); Duke University, Durham, NC (JS); University of California at San Francisco, San Francisco, CA (JSW); Institute of Cancer Research, London, UK (RE, RH, ZKJ); Mount Sinai School of Medicine, New York, NY (PBo); Baylor College of Medicine, Houston, TX (MRS); Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS (BLF); Moffitt Cancer Center, Tampa, FL (ZC, CP, TAS); University of South California, Los Angeles, CA (CH, FS, GC, SBG, BH); Cambridge University, Cambridge, UK (DFE, AAAO, HS); National Cancer Institute, Bethesda, MD (MTL, SC, SIB, NW); International Agency for Research on Cancer, Lyon, France (PBr); Harvard School of Public Health, Boston, MA (DCC, PK, SL, DJH); University of Liverpool, Liverpool, UK (JKF); University of Göttingen, Medical School, Göttingen, Germany (HB); Karolinska Institutet, Stockholm, Sweden (FW, HG); Fred Hutchinson Cancer Research Center, Seattle, WA (UP); University of Utah Health Sciences Center and Huntsman Cancer Institute, Salt Lake City, UT (CMU, MLS); Geisel School of Medicine, Dartmouth College, Lebanon, NH (CIA).

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.