五种常见癌症（肺癌、卵巢癌、前列腺癌、乳腺癌和结直肠癌）炎症通路的跨癌症基因组研究
Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer.
作者信息
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, Sellers Thomas A, Casey Graham, Gruber Stephen B, Hunter David J, Amos Christopher I, Henderson Brian
机构信息
: 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).
出版信息
J Natl Cancer Inst. 2015 Aug 29;107(11). doi: 10.1093/jnci/djv246. Print 2015 Nov.
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.
背景
炎症被假定为作为引发剂或促进剂增加癌症发生风险，但尚未进行过跨癌症部位的遗传变异大规模研究。
方法
我们基于美国国立癌症研究所GAME-ON网络内针对五个常见癌症部位的48项全基因组关联研究，对炎症通路进行了跨癌症基因组分析，共有64591例癌症患者和74467例对照患者。基于子集的荟萃分析用于考虑可能的疾病异质性，并采用层次模型来估计炎症通路内各亚组分的效应。通过富集图对网络进行可视化。所有统计检验均为双侧检验。
结果
我们在炎症通路中鉴定出三个多效性位点，包括位于12号染色体q24区域的一个新位点，其编码SH2B3（rs3184504），达到全基因组关联研究显著性水平，P值为1.78×10⁻⁸，并且它与肺癌（P = 2.01×10⁻⁶）、结直肠癌（GECCO研究P = 6.72×10⁻⁶；CORECT研究P = 3.32×10⁻⁵）和乳腺癌（P = 0.009）相关。我们还鉴定出五个关键亚通路组分，其遗传变异与这五个癌症部位的风险相关：结直肠癌的炎症反应（P = 0.006）、肺癌的炎症相关细胞周期基因（P = 1.35×10⁻⁶）以及卵巢癌的免疫反应激活（P = 0.009）。此外，免疫系统发育中的序列变异在乳腺癌病因学中起作用（P = 0.001），固有免疫反应与结直肠癌（P = 0.022）和卵巢癌（P = 0.003）的风险均有关。
结论
炎症及其相关亚通路组分的遗传变异是肺癌、结直肠癌、卵巢癌和乳腺癌发生的关键，包括与肺癌、结直肠癌和乳腺癌相关的SH2B3。
Zotero 插件