title: TNF-α gene promoter polymorphisms and risk of venous thromboembolism in gastrointestinal cancer patients undergoing chemotherapy.
abstract: BACKGROUND
  TNF-α has been proposed as a predictive factor for venous thromboembolism (VTE). Genetic polymorphisms could regulate TNF-α production. However, the relationship between TNFA gene variants and VTE is not clarified. This study aims to investigate the predictive role of five different TNFA gene promoter SNPs, or their haplotype combination(s), for a first VTE episode in gastrointestinal cancer out-patients treated with chemotherapy.
  
  
  METHODS
  Serum TNF-α levels and TNFA -863C/A, -857C/T, -376G/A, -308G/A and -238G/A gene promoter polymorphisms were retrospectively evaluated in 314 subjects, including 157 controls and 157 Caucasian patients with histologically diagnosed GI cancers beginning chemotherapy delivery (5-fluorouracil either as monotherapy or in combination with platinum compounds or irinotecan).
  
  
  RESULTS
  Haplotype analysis showed that a five-loci haplotype (CTGGG haplotype) has higher frequency in GI cancer patients who developed VTE (n = 15) during chemotherapy [odds ratio = 2.7, 95% confidence interval (CI) 1.04-7.11, P = 0.04]. GI patients who remained VTE-free did not differ in CTGGG haplotype frequency from controls. No association was observed between serum TNF-α levels and TNFA haplotype, but both were independent predictors of VTE. Approximately 20% of GI cancer patients carrying the CTGGG haplotype developed VTE compared with 4% of the remaining 101 patients (hazard ratio = 5.6, 95% CI 1.8-17.6, P = 0.003).
  
  
  CONCLUSIONS
  These results suggest that TNFA might represent a candidate gene contributing to VTE pathogenesis in GI cancer patients and suggest that VTE risk during chemotherapy might be genetically identified. Validation studies are needed for translation into clinical practice.
authors.affiliation: Medical Oncology, Department of System Medicine, Tor Vergata Clinical Center, University of Rome 'Tor Vergata', Rome.
authors.forename: M
authors.initials: M
authors.lastname: Roselli
authors.affiliation: Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Ferroni
authors.affiliation: Phase I - Early Clinical Trials Unit, Department of Oncology, Antwerp University Hospital (UZA); MOCA (Multidisciplinary Oncology Center Antwerp), Antwerp University Hospital, Edegem, Belgium. Electronic address: christian.rolfo@uza.be.
authors.forename: C
authors.initials: C
authors.lastname: Rolfo
authors.affiliation: MOCA (Multidisciplinary Oncology Center Antwerp), Antwerp University Hospital, Edegem, Belgium.
authors.forename: M
authors.initials: M
authors.lastname: Peeters
authors.affiliation: Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Palmirotta
authors.affiliation: Medical Oncology, Department of System Medicine, Tor Vergata Clinical Center, University of Rome 'Tor Vergata', Rome.
authors.forename: V
authors.initials: V
authors.lastname: Formica
authors.affiliation: Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Ludovici
authors.affiliation: Medical Oncology, Department of System Medicine, Tor Vergata Clinical Center, University of Rome 'Tor Vergata', Rome.
authors.forename: A
authors.initials: A
authors.lastname: Laudisi
authors.affiliation: Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: M L
authors.initials: ML
authors.lastname: De Marchis
authors.affiliation: Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: La Farina
authors.affiliation: Section of Medical Oncology, Department of Surgical and Oncology Sciences, University of Palermo, Palermo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Russo
authors.affiliation: Department of Advanced Biotechnologies and Bioimaging, IRCCS San Raffaele Pisana, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Guadagni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012189:Retrospective Studies; D012306:Risk; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000235:genetics*; D054556:Venous Thromboembolism / Q000139:chemically induced* / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D014409:Tumor Necrosis Factor-alpha; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin
keywords: chemotherapy; gastrointestinal cancer; single nucleotide polymorphisms; tumour necrosis factor-α; venous thromboembolism