title: Single nucleotide polymorphisms within interferon signaling pathway genes are associated with colorectal cancer susceptibility and survival.
abstract: Interferon (IFN) signaling has been suggested to play an important role in colorectal carcinogenesis. Our study aimed to examine potentially functional genetic variants in interferon regulatory factor 3 (IRF3), IRF5, IRF7, type I and type II IFN and their receptor genes with respect to colorectal cancer (CRC) risk and clinical outcome. Altogether 74 single nucleotide polymorphisms (SNPs) were covered by the 34 SNPs genotyped in a hospital-based case-control study of 1327 CRC cases and 758 healthy controls from the Czech Republic. We also analyzed these SNPs in relation to overall survival and event-free survival in a subgroup of 483 patients. Seven SNPs in IFNA1, IFNA13, IFNA21, IFNK, IFNAR1 and IFNGR1 were associated with CRC risk. After multiple testing correction, the associations with the SNPs rs2856968 (IFNAR1) and rs2234711 (IFNGR1) remained formally significant (P = 0.0015 and P<0.0001, respectively). Multivariable survival analyses showed that the SNP rs6475526 (IFNA7/IFNA14) was associated with overall survival of the patients (P = 0.041 and event-free survival among patients without distant metastasis at the time of diagnosis, P = 0.034). The hazard ratios (HRs) for rs6475526 remained statistically significant even after adjustment for age, gender, grade and stage (P = 0.029 and P = 0.036, respectively), suggesting that rs6475526 is an independent prognostic marker for CRC. Our data suggest that genetic variation in the IFN signaling pathway genes may play a role in the etiology and survival of CRC and further studies are warranted.
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Shun
authors.initials: S
authors.lastname: Lu
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Cheng
authors.affiliation: Human Genetics Foundation (HuGeF), Turin, Italy; Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Huhn
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Vymetalkova
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic; Biomedical Centre, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic.
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.affiliation: Department of Oncology, Thomayer Hospital, Prague, Czech Republic.
authors.forename: Thomas
authors.initials: T
authors.lastname: Buchler
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Center of Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic; Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Center of Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006761:Hospitals; D006801:Humans; D007372:Interferons / Q000235:genetics* / Q000378:metabolism; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D012307:Risk Factors; D015398:Signal Transduction
chemical_list: D007372:Interferons