Interleukin promoter polymorphisms and prognosis in colorectal cancer.

There is strong evidence that cancer-associated inflammation promotes tumor growth and progression. This is especially true for colorectal cancer (CRC). Interleukins (ILs) are important modulators for inflammation. We examined whether promoter polymorphisms in key IL genes (IL4, IL4R, IL6, IL8 and IL10) are associated with the risk or clinical outcome of CRC. Five single-nucleotide polymorphisms (SNPs) were analyzed in genomic DNA from a cohort including 308 Swedish incident cases of CRC with data on Dukes' stage and up to 16 years of follow-up and 585 healthy controls. The selected SNPs have previously been shown to be functional and/or associated with cancer. None of the analyzed SNPs associated with the risk of CRC. When stratifying by tumor stage, significantly more patients carrying at least one G allele of IL10-1082 had tumors with Dukes' stages A + B than with stages C + D (P(trend) = 0.035 for genotype distribution). Analyzing associations with overall survival time, we found the rare T allele of IL4-590 to be related to a longer survival [CT versus CC Cox proportional hazard ratio 0.69, 95% confidence intervals 0.46-1.03, TT versus CC 0.32 (0.10-1.03)]. For IL6-174, the CG genotype was associated with a longer survival when compared with the CC genotype [0.64 (0.40-1.01)]. The present study was particularly suitable for survival analysis because all patients were sampled before the diagnosis of CRC. Our results suggest that the SNPs IL4-590 and IL6-174 may be useful markers for CRC prognosis. The predicted biological effect of these SNPs in relation to promotion of cancer progression is consistent with the observed increased survival time.

[1]  Oliver Sieber,et al.  A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk , 2007, Nature Genetics.

[2]  Leah E. Mechanic,et al.  Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier. , 2007, Journal of the National Cancer Institute.

[3]  Steven Gallinger,et al.  Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 , 2007, Nature Genetics.

[4]  Oliver Sieber,et al.  A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21 , 2007, Nature Genetics.

[5]  Simon C. Potter,et al.  Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls , 2007, Nature.

[6]  Federica Gemignani,et al.  Interleukin-4 and interleukin-4 receptor polymorphisms and colorectal cancer risk. , 2007, European journal of cancer.

[7]  Pär Stattin,et al.  Nordic biological specimen banks as basis for studies of cancer causes and control – more than 2 million sample donors, 25 million person years and 100 000 prospective cancers , 2007, Acta oncologica.

[8]  M. Takagi,et al.  Study of interleukin-6 in the spread of colorectal cancer: the diagnostic significance of IL-6. , 2006, Acta medica Okayama.

[9]  Judy H. Cho,et al.  A Genome-Wide Association Study Identifies IL23R as an Inflammatory Bowel Disease Gene , 2006, Science.

[10]  C. Caruso,et al.  Regulatory Cytokine Gene Polymorphisms and Risk of Colorectal Carcinoma , 2006, Annals of the New York Academy of Sciences.

[11]  S. Jee,et al.  White Blood Cell Count and the Risk of Colon Cancer , 2006, Yonsei medical journal.

[12]  N. Crawford,et al.  New perspectives on hereditary influences in metastatic progression. , 2006, Trends in genetics : TIG.

[13]  Yuan‐Chiang Chung,et al.  Clinical significance of tissue expression of interleukin-6 in colorectal carcinoma. , 2006, Anticancer research.

[14]  M. Gazouli,et al.  Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. , 2006, World journal of gastroenterology.

[15]  Xin Wei Wang,et al.  Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. , 2006, Cancer cell.

[16]  R. Sinha,et al.  Inflammation-Related Gene Polymorphisms and Colorectal Adenoma , 2006, Cancer Epidemiology Biomarkers & Prevention.

[17]  D. Consonni,et al.  Relationship between interleukin 6 promoter polymorphism at position -174, IL-6 serum levels, and the risk of relapse/recurrence in polymyalgia rheumatica. , 2006, The Journal of rheumatology.

[18]  R. Zeillinger,et al.  A Common Interleukin-6 Promoter Polymorphism in Patients With Vulvar Cancer , 2005, The Journal of the Society for Gynecologic Investigation: JSGI.

[19]  D. Tan,et al.  Interleukin-6 polymorphism is associated with more aggressive prostate cancer. , 2005, The Journal of urology.

[20]  L. Padyukov,et al.  Haplotypes of the interleukin‐4 receptor α chain gene associate with susceptibility to and severity of atopic asthma , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[21]  A. Chapelle,et al.  Genetic predisposition to colorectal cancer , 2004, Nature Reviews Cancer.

[22]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[23]  D. Clayton,et al.  Betting odds and genetic associations. , 2004, Journal of the National Cancer Institute.

[24]  L. Christiansen,et al.  The IL-6 −174G>C polymorphism is associated with cardiovascular diseases and mortality in 80-year-old humans , 2004, Experimental Gerontology.

[25]  B. Weber,et al.  Interleukin-6 -174G-->C polymorphism is associated with improved outcome in high-risk breast cancer. , 2003, Cancer research.

[26]  S. Blecher,et al.  Upregulation of Reactive Oxygen Species Generation and Phagocytosis, and Increased Apoptosis in Human Neutrophils During Severe Sepsis and Septic Shock , 2003, Shock.

[27]  Stefano Landi,et al.  Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor alpha, NFKB1, and peroxisome proliferator-activated receptor gamma with colorectal cancer. , 2003, Cancer research.

[28]  M. Beckmann,et al.  An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. , 2003, Cancer research.

[29]  C. Franceschi,et al.  -174 G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[30]  E. Riboli,et al.  Prospective study of IGF-I, IGF-binding proteins, and breast cancer risk, in Northern and Southern Sweden , 2002, Cancer Causes & Control.

[31]  J. Powell,et al.  Interleukin-6 (IL-6) and the Prognosis of Abdominal Aortic Aneurysms , 2001, Circulation.

[32]  E. Kliewer,et al.  Cancer risk in patients with inflammatory bowel disease , 2001, Cancer.

[33]  G. Fantuzzi,et al.  Production of IL‐1 receptor antagonist by hepatocytes is regulated as an acute‐phase protein in vivo , 2001, European journal of immunology.

[34]  D. Kwiatkowski,et al.  Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families , 2000, Thorax.

[35]  J. Kaprio,et al.  Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from Sweden, Denmark, and Finland. , 2000, The New England journal of medicine.

[36]  F. Green,et al.  Cooperative Influence of Genetic Polymorphisms on Interleukin 6 Transcriptional Regulation* , 2000, The Journal of Biological Chemistry.

[37]  J. Jessup,et al.  Interleukin-6 Blood Level Is Associated With Circulating Carcinoembryonic Antigen and Prognosis in Patients With Colorectal Cancer , 2000, Annals of Surgical Oncology.

[38]  P. Woo,et al.  Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. , 1999, Arthritis and rheumatism.

[39]  L. Påhlman,et al.  Improved survival and reduction in local failure rates after preoperative radiotherapy: evidence for the generalizability of the results of Swedish Rectal Cancer Trial. , 1999, Annals of surgery.

[40]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[41]  M. Lazarus,et al.  An investigation of polymorphism in the interleukin-10 gene promoter. , 1997, European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics.

[42]  T. Nakamura,et al.  Interleukin 4 inhibits hepatocyte growth factor‐induced invasion and migration of colon carcinomas , 1996, Journal of cellular biochemistry.

[43]  Santa Jeremy Ono,et al.  Polymorphic nucleotides within the human IL-4 promoter that mediate overexpression of the gene. , 1996, Journal of immunology.

[44]  M. Klinnert,et al.  Promoter polymorphisms in the chromosome 5 gene cluster in asthma and atopy , 1995, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[45]  B. Ryffel,et al.  Growth inhibition of human colorectal‐carcinoma cells by interleukin‐4 and expression of functional interleukin‐4 receptors , 1994, International journal of cancer.

[46]  Takashi Ueda,et al.  Serum levels of cytokines in patients with colorectal cancer: Possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis , 1994, Journal of Gastroenterology.

[47]  G. Thomas,et al.  [Genetic predisposition to colorectal cancer]. , 1993, Annales de gastroenterologie et d'hepatologie.

[48]  R. Cortese,et al.  The two C/EBP isoforms, IL6DBP/NFIL6 and CEBP6δ/NFIL63, are induced by IL6β to promote acute phase gene transcription via different mechanisms , 1993 .

[49]  C. Maliszewski,et al.  The interleukin-4 receptor: structure, function, and signal transduction. , 1992, Chemical immunology.

[50]  M. Toi,et al.  Inhibition of colon and breast carcinoma cell growth by interleukin-4. , 1992, Cancer research.

[51]  M. Rose-Zerilli,et al.  Interleukin-10 Polymorphisms, Cancer Susceptibility and Prognosis , 2005, Familial Cancer.

[52]  C. Franceschi,et al.  C Polymorphism of Interleukin 6 Gene Promoter Affects Interleukin 6 Serum Level in Patients with Colorectal Cancer , 2003 .

[53]  Taylor Murray,et al.  Cancer statistics, 2000 , 2000, CA: a cancer journal for clinicians.

[54]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[55]  R. Cortese,et al.  The two C/EBP isoforms, IL-6DBP/NF-IL6 and C/EBP delta/NF-IL6 beta, are induced by IL-6 to promote acute phase gene transcription via different mechanisms. , 1993, Nucleic acids research.

[56]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[57]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.