title: Distinct molecular patterns based on proximal and distal sporadic colorectal cancer: arguments for different mechanisms in the tumorigenesis.
abstract: OBJECTIVE
  Colorectal cancer (CRC) ranks as the fourth most frequently diagnosed cancer worldwide. CRCs that arise proximally or distally to the splenic flexure show differences in epidemiologic incidence, morphology, and molecular alterations, suggesting the existence of two categories of CRC based on the site of origin. The aim of the present work is to investigate the histological and molecular differences between CRCs located proximally and distally to the splenic flexure, and their potential involvement in tumor prognosis and therapeutic strategies.
  
  
  METHODS
  We evaluated 120 patients affected by sporadic CRC for clinicopathologic features, microsatellite instability (MSI), loss of heterozygosity (LOH) of chromosomes 18q, 8p, and 4p; they were also investigated for hMlh1, hMsh2, Fhit, p27, and Cox-2 immunostaining.
  
  
  RESULTS
  The mucinous histotype was more frequent in the proximal than in the distal CRCs (p<0.004). The frequency of MSI phenotype was higher in proximal than in distal tumors (p<0.001); moreover, reduced or absent hMlh1, Fhit, p27 immunohistochemical expressions were more frequent in proximal than in distal tumors (p<0.001 and 0.01 for p27). In contrast, the frequency of LOH in 18q was higher in distal than in proximal tumors (p=0.002). No significant differences were observed between proximal and distal tumors in the frequency of LOH in 8p and altered expression of hMsh2 and p53 protein.
  
  
  CONCLUSIONS
  These different features may reflect different genetic pathways of carcinogenesis and support the hypothesis of a different mechanism of cancer development between the proximal and the distal colon, with potential implications in the therapeutic approach.
authors.affiliation: Department of Pathology and Laboratory Medicine, Section of Pathological Anatomy, Parma University, Medical School, Parma, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Azzoni
authors.forename: Lorena
authors.initials: L
authors.lastname: Bottarelli
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: Antonio
authors.initials: A
authors.lastname: Mazzeo
authors.forename: Carlo
authors.initials: C
authors.lastname: Salvemini
authors.forename: Silvia
authors.initials: S
authors.lastname: Morari
authors.forename: Davide
authors.initials: D
authors.lastname: Di Mauro
authors.forename: Enrico
authors.initials: E
authors.lastname: Donadei
authors.forename: Luigi
authors.initials: L
authors.lastname: Roncoroni
authors.forename: Cesare
authors.initials: C
authors.lastname: Bordi
authors.forename: Leopoldo
authors.initials: L
authors.lastname: Sarli
mesh_terms: D017766:Acid Anhydride Hydrolases / Q000737:chemistry; D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000737:chemistry; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008297:Male; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000737:chemistry; D009363:Neoplasm Proteins / Q000737:chemistry; D009687:Nuclear Proteins / Q000737:chemistry; D018809:Proliferating Cell Nuclear Antigen / Q000737:chemistry; D016019:Survival Analysis; D000099170:Bis(5'-adenosyl)triphosphatase
chemical_list: D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D051546:Cyclooxygenase 2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D000099170:Bis(5'-adenosyl)triphosphatase; C501486:MLH1 protein, human; C413374:p27 antigen; C496540:PTGS2 protein, human; C497172:MSH2 protein, human