title: Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.
abstract: BACKGROUND
  Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer.
  
  
  OBJECTIVE
  The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors.
  
  
  METHODS
  FHIT immunostaining was performed on 305 tumor samples. The methylation status of FHIT promoter was assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples of which a subset of 187 patients had available normal/tumor DNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers.
  
  
  RESULTS
  Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7% of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was present when methylation and LOH were analyzed together (P = 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P < 0.0001) and in smokers (P = 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P = 0.0415).
  
  
  CONCLUSIONS
  Our results indicate that different molecular mechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.
authors.affiliation: Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Verri
authors.forename: Luca
authors.initials: L
authors.lastname: Roz
authors.forename: Davide
authors.initials: D
authors.lastname: Conte
authors.forename: Triantafillos
authors.initials: T
authors.lastname: Liloglou
authors.forename: Anna
authors.initials: A
authors.lastname: Livio
authors.forename: Aurelien
authors.initials: A
authors.lastname: Vesin
authors.forename: Alessandra
authors.initials: A
authors.lastname: Fabbri
authors.forename: Francesca
authors.initials: F
authors.lastname: Andriani
authors.forename: Christian
authors.initials: C
authors.lastname: Brambilla
authors.forename: Luca
authors.initials: L
authors.lastname: Tavecchio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calarco
authors.forename: Elisa
authors.initials: E
authors.lastname: Calabrò
authors.forename: Andrea
authors.initials: A
authors.lastname: Mancini
authors.forename: Diego
authors.initials: D
authors.lastname: Tosi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bossi
authors.forename: John K
authors.initials: JK
authors.lastname: Field
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D018570:Risk Assessment; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase