Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer

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

doi:10.1093/jnci/djv246

Cross Cancer Genomic Investigation of Inflammation Pathway for Five Common Cancers: Lung, Ovary, Prostate, Breast, and Colorectal Cancer

J Natl Cancer Inst. 2015 Aug 29;107(11):djv246. doi: 10.1093/jnci/djv246. Print 2015 Nov.

Authors

Rayjean J Hung¹, Cornelia M Ulrich², Ellen L Goode², Yonathan Brhane², Kenneth Muir², Andrew T Chan², Loic Le Marchand², Joellen Schildkraut², John S Witte², Rosalind Eeles², Paolo Boffetta², Margaret R Spitz², Julia G Poirier², David N Rider², Brooke L Fridley², Zhihua Chen², Christopher Haiman², Fredrick Schumacher², Douglas F Easton², Maria Teresa Landi², Paul Brennan², Richard Houlston², David C Christiani², John K Field², Heike Bickeböller², Angela Risch², Zsofia Kote-Jarai², Fredrik Wiklund², Henrik Grönberg², Stephen Chanock², Sonja I Berndt², Peter Kraft², Sara Lindström², Ali Amin Al Olama², Honglin Song², Catherine Phelan², Nicholas Wentzensen², Ulrike Peters², Martha L Slattery²; GECCO; Thomas A Sellers²; FOCI; Graham Casey², Stephen B Gruber²; CORECT; David J Hunter²; DRIVE; Christopher I Amos², Brian Henderson²; GAME-ON Network

Collaborators

Mike Birrer, Ann Chen, Julie Cunningham, Ed Iversen, John McLaughlin, Steven Narod, Harvey Risch, Jenny Permuth-Wey, Paul Pharoah, Simon Gayther, Susan Ramus

Affiliations

¹ : 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.
² : 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).

Abstract

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.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Adaptor Proteins, Signal Transducing
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism
Female
Genome-Wide Association Study
Humans
Inflammation / genetics*
Inflammation / metabolism
Intracellular Signaling Peptides and Proteins
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Male
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / metabolism
Prostatic Neoplasms / genetics*
Prostatic Neoplasms / metabolism
Proteins / genetics*
Signal Transduction*

Substances

Adaptor Proteins, Signal Transducing
Intracellular Signaling Peptides and Proteins
Proteins
SH2B3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding