title: Aberrant protein expression and frequent allelic loss of MSH3 in colorectal cancer with low-level microsatellite instability.
abstract: OBJECTIVE
  High level of microsatellite instability (MSI-H) in colorectal cancer (CRC) is caused by the inactivation of mismatch repair (MMR) genes; however, it is unknown for tumors with low level MSI (MSI-L). The protein complex involving MSH3 preferentially recognizes insertion/deletion loops (IDLs) of two to eight bases and di- and tetranucleotide repeats are affected in the majority of MSI-L CRC.
  
  
  METHODS
  We selected 10 and eight MSI-L CRCs from 228 and 204 patients with sporadic and hereditary disease, respectively. The tumors were analyzed for protein expression of MSH3, MSH2, MSH6, MLH1, and PMS2, and for mutations and loss of heterozygosity (LOH) in MSH3.
  
  
  RESULTS
  Four tumors showed a markedly reduced MSH3 expression, whereas all 18 tumors had normal expression of the remaining MMR proteins. Twenty-five different sequence variants were identified. None of these results in a truncated protein, though L902W represents the first constitutional missense mutation in MSH3 predicted to be functional based on conservation among mutS homologues. All variants have also been found in normal DNA of the patients and in controls. LOH intragenic to MSH3 was evident for 12 of 16 (75%) informative tumors.
  
  
  CONCLUSIONS
  Occurrence of sequence variants in normal DNA of the patients and in controls excludes somatic mutations and mutations specific to the CRC patient population, respectively. In contrast, the high frequency of LOH as well as the aberrant protein expression in some tumors indicates an involvement of MSH3 impairment in MSI-L CRC.
authors.affiliation: Department of Surgical Research, Carl Gustav Carus Klinikum, Technical University Dresden, Fetscherstr. 74, 01307 Dresden, Germany. j.plaschke@gmx.de
authors.forename: Jens
authors.initials: J
authors.lastname: Plaschke
authors.forename: Mark
authors.initials: M
authors.lastname: Preußler
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D008969:Molecular Sequence Data; D000074081:MutS Homolog 3 Protein; D010641:Phenotype; D017422:Sequence Analysis, DNA
chemical_list: D004268:DNA-Binding Proteins; C078444:MSH3 protein, human; D000074081:MutS Homolog 3 Protein