Inflammatory response gene polymorphisms and their relationship with colorectal cancer risk

BackgroudPatients with chronic inflammatory bowel disease (IBD) are at an increased risk of colorectal cancer (CRC) and it is estimated that one in six persons diagnosed with IBD will develop CRC. This fact suggests that genetic variations in inflammatory response genes may act as CRC disease risk modifiers.MethodsIn order to test this hypothesis we investigated a series of polymorphisms in 6 genes (NOD2, DLG5, OCTN1, OCTN2, IL4, TNFα) associated with the inflammatory response on a group of 607 consecutive newly diagnosed colorectal cancer patients and compared the results to controls (350 consecutive newborns and 607 age, sex and geographically matched controls).ResultsOf the six genes only one polymorphism in TNFα(-1031T/T) showed any tendency to be associated with disease risk (64.9% for controls and 71.4% for CRC) which we further characterized on a larger cohort of CRC patients and found a more profound relationship between the TNFα -1031T/T genotype and disease (64.5% for controls vs 74.7% for CRC cases above 70 yrs). Then, we investigated this result and identified a suggestive tendency, linking the TNFα -1031T/T genotype and a previously identified change in the CARD15/NOD2 gene (OR = 1.87; p = 0,02 for CRC cases above 60 yrs).ConclusionThe association of polymorphisms in genes involved in the inflammatory response and CRC onset suggest that there are genetic changes capable of influencing disease risk in older persons.

[1]  M. Gazouli,et al.  Association between mutations in the CARD15/NOD2 gene and colorectal cancer in a Greek population , 2005, International journal of cancer.

[2]  G. Pawelec,et al.  Association of cytokine gene polymorphisms with malignant melanoma in Caucasian population , 2006, Cancer Immunology, Immunotherapy.

[3]  G. Chatta,et al.  Aging and the dendritic cell system: implications for cancer. , 2007, Critical reviews in oncology/hematology.

[4]  S. Fisher,et al.  Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations , 2001, The Lancet.

[5]  H. Sugimura,et al.  Different effects of polymorphisms of tumor necrosis factor‐alpha and interleukin‐1 beta on development of peptic ulcer and gastric cancer , 2007, Journal of gastroenterology and hepatology.

[6]  K. Pavelić,et al.  TNF alpha promoter polymorphisms analysis in benign and malignant breast lesions. , 2007, Experimental and molecular pathology.

[7]  S. Yamaoka,et al.  Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB* , 2001, The Journal of Biological Chemistry.

[8]  L. Aaltonen,et al.  NOD2 3020insC Alone Is Not Sufficient for Colorectal Cancer Predisposition , 2004, Cancer Research.

[9]  J. Chun,et al.  The -238 tumor necrosis factor-alpha promoter polymorphism is associated with decreased susceptibility to cancers. , 2001, Cancer letters.

[10]  Shirley A. Miller,et al.  A simple salting out procedure for extracting DNA from human nucleated cells. , 1988, Nucleic acids research.

[11]  Helen H. W. Chen,et al.  Evaluation of the Associations Between the Single Nucleotide Polymorphisms of the Promoter Region of the Tumor Necrosis Factor‐α Gene and Nasopharyngeal Carcinoma , 2006, Journal of the Chinese Medical Association : JCMA.

[12]  Thomas Lengauer,et al.  Genetic variation in DLG5 is associated with inflammatory bowel disease , 2004, Nature Genetics.

[13]  G. Pajno,et al.  Molecular analysis of sequence variants in the Fcɛ receptor I β gene and IL‐4 gene promoter in Italian atopic families , 2004, Allergy.

[14]  R. Gearry,et al.  Caspase recruitment domain-containing protein 15 mutations in patients with colorectal cancer. , 2006, Cancer research.

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

[16]  E. Guinó,et al.  Polymorphisms within inflammatory genes and colorectal cancer , 2006, Journal of Negative Results in BioMedicine.

[17]  G. Veres,et al.  Common NOD2/CARD15 variants are not associated with susceptibility or the clinicopathologic characteristics of sporadic colorectal cancer in Hungarian patients , 2007, BMC Cancer.

[18]  P. Munkholm.  Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease , 2003, Alimentary pharmacology & therapeutics.

[19]  Judy H. Cho,et al.  [Letters to Nature] , 1975, Nature.

[20]  Y. Ogura,et al.  Human Nod1 Confers Responsiveness to Bacterial Lipopolysaccharides* , 2001, The Journal of Biological Chemistry.

[21]  Rodney J Scott,et al.  The NOD2 3020insC Mutation and the Risk of Colorectal Cancer , 2004, Cancer Research.

[22]  J. Lammers,et al.  Increased frequency of the uncommon tumor necrosis factor -857T allele in British and Dutch patients with sarcoidosis. , 2002, American journal of respiratory and critical care medicine.

[23]  M. Hudson,et al.  Association of single nucleotide polymorphisms in the interleukin-4 gene and interleukin-4 receptor gene with Crohn’s disease in a British population , 2001, Genes and Immunity.

[24]  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.

[25]  Joan Valls,et al.  SNPStats: a web tool for the analysis of association studies , 2006, Bioinform..

[26]  K. Boberg,et al.  Association of the tumour necrosis factor á − 308 but not the interleukin 10 − 627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis , 2001 .

[27]  Bill Newman,et al.  Functional variants of OCTN cation transporter genes are associated with Crohn disease , 2004, Nature Genetics.

[28]  T. Shimosegawa,et al.  Crohn's disease is associated with novel polymorphisms in the 5'-flanking region of the tumor necrosis factor gene. , 1999, Gastroenterology.

[29]  M. Färkkilä,et al.  CARD15/NOD2 gene variants are associated with familially occurring and complicated forms of Crohn’s disease , 2003, Gut.

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

[31]  Yasunori Ogura,et al.  Induction of Nod2 in Myelomonocytic and Intestinal Epithelial Cells via Nuclear Factor-κB Activation* , 2002, The Journal of Biological Chemistry.