title: Replication error in colorectal carcinoma: association with loss of heterozygosity at mismatch repair loci and clinicopathological variables.
abstract: Instability of microsatellite DNA or replication error (RER) is characteristic of tumours caused by mismatch repair (MMR) deficiency. Germline mutations in MMR genes are associated with Hereditary non-polyposis colorectal carcinoma (HNPCC) and somatic mutations in these genes are also found in a substantial fraction of colorectal cancers (CRC). In this study we concurrently screened colorectal tumours for the RER phenotype and loss of heterozygosity (LOH) at MMR gene loci. The RER phenotype was evident in 47/197 (24%) tumours. RER was more commonly detected in young patients (< 50 years) and in tumours located in the proximal colon. RER was positively associated with LOH at the hMSH2/hMSH6 loci on chromosome 2p, where LOH was observed in 46% of the RER+ tumours. LOH at hMLH1 and hPMS1 loci was more frequent in the younger patients (< 50 years). RER was not associated with clinicopathological parameters, such as Duke's stage and tumour differentiation (grade). The RER phenotype was associated with better overall survival, but there was a trend towards significance when multivariate analysis was used. This indicates that loss of MMR genes generate a less aggressive phenotype, and raises the question about RER being a useful indicator of prognosis for CRC patients.
authors.affiliation: Department of Pathology, National University Hospital, Reykjavik, Iceland.
authors.forename: J T
authors.initials: JT
authors.lastname: Johannsdottir
authors.forename: J T
authors.initials: JT
authors.lastname: Bergthorsson
authors.forename: S
authors.initials: S
authors.lastname: Gretarsdottir
authors.forename: A K
authors.initials: AK
authors.lastname: Kristjansson
authors.forename: G
authors.initials: G
authors.lastname: Ragnarsson
authors.forename: J G
authors.initials: JG
authors.lastname: Jonasson
authors.forename: V
authors.initials: V
authors.lastname: Egilsson
authors.forename: S
authors.initials: S
authors.lastname: Ingvarsson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000251:Adenosine Triphosphatases; D000328:Adult; D017668:Age of Onset; D000368:Aged; D002352:Carrier Proteins; D002454:Cell Differentiation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000401:mortality / Q000473:pathology; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004261:DNA Replication; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins; D005260:Female; D005500:Follow-Up Studies; D005656:Fungal Proteins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D010641:Phenotype; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012189:Retrospective Studies; D029701:Saccharomyces cerevisiae Proteins; D016019:Survival Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C501486:MLH1 protein, human; C098790:MSH6 protein, S cerevisiae; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D011518:Proto-Oncogene Proteins; D029701:Saccharomyces cerevisiae Proteins; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes