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JMD 2005, Vol. 7, No. 2
Copyright © 2005 American Society for Investigative Pathology & Association for Molecular Pathology

Microsatellite Analysis of Hereditary Nonpolyposis Colorectal Cancer-Associated Colorectal Adenomas by Laser-Assisted Microdissection

Correlation with Mismatch Repair Protein Expression Provides New Insights in Early Steps of Tumorigenesis

Giuseppe Giuffrè^*, Annegret Müller, Thomas Brodegger, Tina Bocker-Edmonston, Johannes Gebert^¶, Matthias Kloor^¶, Wolfgang Dietmaier^||, Frank Kullmann^**, Reinhard Büttner, Giovanni Tuccari^*, Josef Rüschoff German HNPCC Consortium, German Cancer Aid, (Deutsche Krebshilfe)

From the Department of Human Pathology, * University of Messina, Messina, Italy; the Department of General Surgery, University of Göttingen, Göttingen, Germany; the Institute of Molecular Pathology, ^¶ University of Heidelberg, Heidelberg, Germany; the Institute of Pathology ^|| and the Department of Internal Medicine, ** University of Regensburg, Regensburg, Germany; the Institute of Pathology, University Hospital Bonn, Bonn, Germany; the Institute of Pathology, Klinikum Kassel, Kassel, Germany; and the Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania

Although microsatellite instability (MSI) testing is a useful tool for molecular screening of hereditary nonpolyposis colorectal cancer (HNPCC) carcinomas, conflicting results have been obtained in colorectal adenomas. This might result from different techniques of tissue sampling and MSI analysis. Alternatively, some HNPCC-associated adenomas may follow a molecular route that differs from the MSI pathway. In the present study we examined the MSI status of 18 adenomas from 17 HNPCC patients by comparing manual adenoma dissection under gross visual control with laser microdissection of single adenoma crypts. After manual gross dissection, 50% (9 of 18) and 11.1% (2 of 18) of the adenomas displayed high-level (MSI-H) and low-level (MSI-L) MSI, respectively. The same set of adenomas split into 83.3% (15 of 18) MSI-H and 5.6% (1 of 18) MSI-L after laser microdissection. The expression pattern of mismatch repair (MMR) proteins showed a higher concordance rate with the MSI status in laser-dissected (94%) than gross-dissected (47%) adenomas. Whereas two adenomas remained microsatellite stable (MSS) and MMR proficient even after laser-assisted dissection, two MSI-H cases showed either rare instabilities at coding microsatellites or intratumoral heterogeneity of MSI with and without MSH2 expression. This suggests that in some adenomas development of MMR dysfunction occurs stepwise with MSI, arising before complete loss of MMR gene expression, whereas other HNPCC-associated adenomas might develop independently of MMR deficiency.