Microsatellite instability and expression of MLH1 and MSH2 in carcinomas of the small intestine.
BACKGROUND
Carcinomas of the small intestine are rare, but the risk is greatly increased in patients with hereditary nonpolyposis colorectal cancer (HNPCC) due to an inherited mismatch repair (MMR) gene mutation, most commonly affecting the genes MLH1 or MSH2. Defective MMR is characterized by microsatellite instability (MSI) and loss of MMR protein expression in the tumor tissue. However, a subset of several sporadic tumor types, including about 15% of colon cancers, also evolve through defective MMR.


METHODS
The authors have assessed the frequency of MSI and analyzed the immunohistochemical expression of MLH1 and MSH2 in a population-based series of 89 adenocarcinomas of the small intestine. To study the contribution of MSI and defective MMR protein expression in young patients, 43 cancers of the small intestine from patients below age 60 years (including 24 tumors from the population-based series and an additional 19 tumors from young individuals) were also analyzed.


RESULTS
MSI was detected in 16/89 tumors (18%) in the population-based series, and immunohistochemistry revealed loss of expression for MLH1 in 7/16 MSI tumors and in 2/73 MSS tumors, whereas all tumors showed normal expression for MSH2. Among the young patients, the authors identified MSI in 10/43 tumors (23%), and 6 of these 10 MSI tumors showed immunohistochemical loss of MMR protein expression, which affected MLH1 in 3 cases and MSH2 in 3 cases.


CONCLUSIONS
The frequency of MSI (18%) in adenocarcinomas of the small intestine equals that of colon cancer. However, silencing of MLH1 seems to explain the MSI status in only about half of the MSI tumors. Among patients with cancer of the small intestine before age 60 years, MSI is found in 23% of the cases, with MLH1 and MSH2 being affected at equal frequencies, indicating that HNPCC may underly a subset of such cases.
Planck
Maria
M
Department of Oncology, University Hospital, Lund, Sweden.
Ericson
Kajsa
K
Piotrowska
Zofia
Z
Halvarsson
Britta
B
Rambech
Eva
E
Nilbert
Mef
M
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D000255:Adenosine Triphosphate; D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins
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; D000255:Adenosine Triphosphate; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein