Defective mismatch-repair as a minor tumorigenic pathway in Barrett esophagus-associated adenocarcinoma.
The malignant transformation that characterizes the development of Barrett esophagus-associated adenocarcinomas is a multi-step process in which genetic alterations in various tumor-associated genes accumulate. Defective mismatch repair (MMR) is the cause of microsatellite instability (MSI) pathway that characterizes a subset of gastrointestinal tumors and is specifically associated with tumor development within the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. The few studies that have assessed MMR defects in Barrett-associated adenocarcinomas have reached different results. We therefore assessed the expression of the MMR proteins MLH1 and MSH2 in a series of 59 Barrett adenocarcinomas and found a loss of MMR protein immunostaining in 2/59 (3%) tumors; one tumor showed a loss of MSH2 expression, the other tumor showed a loss of MLH1, and both tumors displayed an MSI-high phenotype. Our findings suggest that only a small subset of Barrett adenocarcinomas develop because of defective MMR, but demonstrate that MLH1 and MSH2 are the primary targets for defective MMR also in this tumor type.
Falkenback
Dan
D
Department of Surgery, University Hospital, S-221 85 Lund, Sweden. dan.falkenback@helsingborgslasarett.se
Johansson
Jan
J
Halvarsson
Britta
B
Nilbert
Mef
M
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000209:etiology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000235:genetics*; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000032:analysis; D004938:Esophageal Neoplasms / Q000209:etiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000032:analysis; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein