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10.1245/s10434-006-9122-9
Annals of Surgical Oncology 14:329-339 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Host Cytokine Genotype is Related to Adverse Prognosis and Systemic Inflammation in Gastro-Oesophageal Cancer

Chris Deans, MBChB1, Matthew Rose-Zerilli, BSc2, Stephen Wigmore, MD1, James Ross, PhD1, Martin Howell, PhD3, Alan Jackson, MD4, Robert Grimble, PhD4 and Kenneth Fearon, MD1,5

1 Cell Injury and Apoptosis Section, Tissue Injury and Repair Group, MRC Centre for Inflammation Research, Department of Clinical and Surgical Sciences, Medical School, Edinburgh University, Edinburgh, EH8 9AG, UK
2 Histocompatibility and Immunogenetics Laboratory, Human Genetics Division, University of Southampton, Southampton, UK
3 Department of Histocompatibility and Immunogenetics, National Blood Service, Holland Drive, Newcastle-upon-Tyne, NE2 4NQ, UK
4 Institute of Human Nutrition, School of Medicine, University of Southampton, SO16 7PX, Southampton, UK
5 University Department of Surgery, Royal Infirmary, 51 Little France Crescent, Edinburgh, EH16 4SA, UK

Correspondence: Address correspondence and reprint requests to: Kenneth Fearon, MD; E-mail: K.Fearon{at}ed.ac.uk

Background: Systemic inflammation has been linked with reduced survival in cancer, however, the role of the host cytokine genotype versus tumour phenotype in the generation of this response is not clearly established. This study examined the relationship between cytokine polymorphisms (IL-1ß 511, IL-6 174, IL-10 1082, TNF{alpha} 308 and LT{alpha} +252) and serum cytokine concentrations, serum CRP concentration and survival duration in patients with gastro-oesophageal malignancy.

Methods: Two hundred and three newly diagnosed patients with gastric or oesophageal cancer had serum CRP and cytokine concentrations determined by ELISA. SNP genotyping was performed by Taqman allelic discrimination genotyping and compared with the genotype observed in 266 healthy volunteers. Clinico-pathological information was collected prospectively and survival duration was recorded.

Results: Distribution of the cytokine genotypes was similar between patients and controls. The IL-6 174 CC and IL-10 1082 GG genotypes were associated with elevated serum CRP (P = .03, P = .01, respectively; Mann–Whitney U test) and sTNF-R (P = .015, P = .02) concentrations. These genotypes were also associated with reduced survival duration (P = .01, P = .047; log-rank test). TNF{alpha} AA genotype was also associated with reduced survival duration on univariate (P = .032) and multivariate analysis (P = .006, multivariate model), but not with inflammatory markers. No other cytokine polymorphisms were associated with systemic inflammatory markers or prognosis.

Conclusions: There is a pro-inflammatory cytokine haplotype (IL-6 CC, IL-10 GG, TNF{alpha} AA) that is associated with adverse prognosis that may act, at least in part, through an inflammatory mediated mechanism. Determining patients’ cytokine haplotype may improve prognostication and allow stratification for intervention studies.

Key Words: Cytokines • Polymorphisms • Cancer • Survival • Inflammation






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