title: Abnormal Fhit protein expression and high frequency of microsatellite instability in sporadic colorectal cancer.
abstract: The role of Fhit protein in the oncogenesis of colorectal cancer is still in debate. Recent studies have revealed that reduced Fhit protein expression is associated with a deficiency of the mismatch repair protein. One hundred and twenty unselected patients who underwent curative resection for sporadic colorectal cancer in a three-year period were evaluated for microsatellite instability (MSI) using six microsatellite markers, and for the presence of Fhit and mismatch repair (MMR) proteins (Mlh1 and Msh2) by means of immunostaining. The relations between these markers were analysed. Reduced or absent Fhit expression was noted in 18 out of 118 patients. This altered expression was significantly higher in right-sided cancer (P = 0.005), mucinous tumours (P = 0.005) and in poorly differentiated histological types (P = 0.0001). MSI was found in 22 out of 109 patients, more so in right-sided cancer (P = 0.0001), poorly differentiated histology (P = 0.0001), and mucinous tumours (P = 0.0001). No association was found with TNM stage. MSI was present in 66.7% of tumours with altered Fhit expression and in only 10% of tumours with preserved or intermediate Fhit expression (P = 0.0001). Of the tumours with reduced or absent Fhit expression, 72.2% had loss of nuclear Mlh1 or Msh2 expression compared with only 14% of the preserved or intermediate Fhit expression tumours (P = 0.0001). These results support the hypothesis that deficiency in a MMR gene could be a cause of the high frequency of alterations in Fhit expression, and they permit the suggestion that FHIT gene alteration may be part of the genetic pathway involving MSI through which some colorectal cancers arise.
authors.affiliation: Department of Surgical Sciences, Section of General Surgical Clinics and Surgical Therapy, Parma University, Medical School, Via Gramsci 14, 43100 Parma, Italy. leosarli@unipr.it
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Sarli
authors.forename: Lorena
authors.initials: L
authors.lastname: Bottarelli
authors.forename: Cinzia
authors.initials: C
authors.lastname: Azzoni
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Campanini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Di Cola
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bader
authors.forename: Domenico
authors.initials: D
authors.lastname: Iusco
authors.forename: Carlo
authors.initials: C
authors.lastname: Salvemini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caruso
authors.forename: Enrico
authors.initials: E
authors.lastname: Donadei
authors.forename: Silvia
authors.initials: S
authors.lastname: Pizzi
authors.forename: Tiziana
authors.initials: T
authors.lastname: D'Adda
authors.forename: Costi
authors.initials: C
authors.lastname: Renato
authors.forename: Luigi
authors.initials: L
authors.lastname: Roncoroni
authors.forename: Cesare
authors.initials: C
authors.lastname: Bordi
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000235:genetics* / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins; D016133:Polymerase Chain Reaction / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C501486:MLH1 protein, human; C497172:MSH2 protein, human