title: Colorectal carcinomas with microsatellite instability display a different pattern of target gene mutations according to large bowel site of origin.
abstract: BACKGROUND
  Only a few studies have addressed the molecular pathways specifically involved in carcinogenesis of the distal colon and rectum. We aimed to identify potential differences among genetic alterations in distal colon and rectal carcinomas as compared to cancers arising elsewhere in the large bowel.
  
  
  METHODS
  Constitutional and tumor DNA from a test series of 37 patients with rectal and 25 patients with sigmoid carcinomas, previously analyzed for microsatellite instability (MSI), was studied for BAX, IGF2R, TGFBR2, MSH3, and MSH6 microsatellite sequence alterations, BRAF and KRAS mutations, and MLH1 promoter methylation. The findings were then compared with those of an independent validation series consisting of 36 MSI-H carcinomas with origin from each of the large bowel regions. Immunohistochemical and germline mutation analyses of the mismatch repair system were performed when appropriate.
  
  
  RESULTS
  In the test series, IGFR2 and BAX mutations were present in one and two out of the six distal MSI-H carcinomas, respectively, and no mutations were detected in TGFBR2, MSH3, and MSH6. We confirmed these findings in the validation series, with TGFBR2 and MSH3 microsatellite mutations occurring less frequently in MSI-H rectal and sigmoid carcinomas than in MSI-H colon carcinomas elsewhere (P = 0.00005 and P = 0.0000005, respectively, when considering all MSI-carcinomas of both series). No MLH1 promoter methylation was observed in the MSI-H rectal and sigmoid carcinomas of both series, as compared to 53% found in MSI-H carcinomas from other locations (P = 0.004). KRAS and BRAF mutational frequencies were 19% and 43% in proximal carcinomas and 25% and 17% in rectal/sigmoid carcinomas, respectively.
  
  
  CONCLUSIONS
  The mechanism and the pattern of genetic changes driving MSI-H carcinogenesis in distal colon and rectum appears to differ from that occurring elsewhere in the colon and further investigation is warranted both in patients with sporadic or hereditary disease.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute - Porto, Rua Dr, António Bernardino Almeida, 4200-072 Porto, Portugal.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.forename: Terje
authors.initials: T
authors.lastname: Ahlquist
authors.forename: Stine A
authors.initials: SA
authors.lastname: Danielsen
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.forename: Vera
authors.initials: V
authors.lastname: Costa
authors.forename: Luís
authors.initials: L
authors.lastname: Afonso
authors.forename: Olga
authors.initials: O
authors.lastname: Sousa
authors.forename: Maria
authors.initials: M
authors.lastname: Fragoso
authors.forename: Lúcio
authors.initials: L
authors.lastname: Santos
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Paula
authors.initials: P
authors.lastname: Lopes
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D020137:Base Pair Mismatch; D045744:Cell Line, Tumor; D012809:Colon, Sigmoid / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D004260:DNA Repair; D005091:Exons; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D015689:Oncogene Protein p21(ras) / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012004:Rectal Neoplasms / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D048493:Proto-Oncogene Proteins B-raf; D000070957:MutL Protein Homolog 1; D015689:Oncogene Protein p21(ras)