Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer.
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Hung Rayjean J, Ulrich Cornelia M, Goode Ellen L, Brhane Yonathan, Muir Kenneth, Chan Andrew T, Marchand Loic Le, Schildkraut Joellen, Witte John S, Eeles Rosalind, Boffetta Paolo, Spitz Margaret R, Poirier Julia G, Rider David N, Fridley Brooke L, Chen Zhihua, Haiman Christopher, Schumacher Fredrick, Easton Douglas F, Landi Maria Teresa, Brennan Paul, Houlston Richard, Christiani David C, Field John K, Bickeböller Heike, Risch Angela, Kote-Jarai Zsofia, Wiklund Fredrik, Grönberg Henrik, Chanock Stephen, Berndt Sonja I, Kraft Peter, Lindström Sara, Al Olama Ali Amin, Song Honglin, Phelan Catherine, Wentzensen Nicholas, Peters Ulrike, Slattery Martha L, GECCO, Sellers Thomas A, FOCI, Casey Graham, Gruber Stephen B, CORECT, Hunter David J, DRIVE, Amos Christopher I, Henderson Brian, GAME-ON Network
Аннотация
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.