Microsatellite Instability (MSI) in Gastrointestinal Adenomas: Does It Answer the Germline Versus Sporadic Cancer Question?
DS Allende, C Fraser, D Patil, B Leach, MP Bronner, TP Plesec. Cleveland Clinic, Cleveland, OH
Background: High microsatellite instability (MSI-H) is present in ∼90% of hereditary non-polyposis colorectal cancers (HNPCC) and ∼10-15% of sporadic-type colorectal cancers. The MSI status in adenomas may be helpful in differentiating germline versus sporadic cancers.
Design: MSI status was determined by PCR and capillary gel electrophoresis of five mononucleotide repeats (BAT25, BAT26, NR21, NR24 and MONO27) from formalin-fixed paraffin-embedded tumor and paired normal samples. MSI-H was defined as instability in 2 or more markers. Immunohistochemistry (IHC) for MLH-1, MSH-2, MSH-6 and PMS-2 was performed on MSI-H cases. Clinical information, results of germline mutation testing (GT) and genetic history were assessed. Features at least suggestive of HNPCC included confirmed deleterious mutation in a DNA mismatch repair gene, multiple family members and generations with HNPCC-related cancers, or loss of MSH-2, or isolated loss of PMS-2 or MSH-6 by IHC.
Results: Of the 217 adenomas, 155 were accompanied by adenocarcinoma. Of these, 140 (90%) had concordant MSI status, and 26/140 (18%) were MSI-H. IHC was performed on 25 of the 26 concordant cases and showed matching protein loss in all cases with MLH-1 loss in 18; MSH-2 loss in 5; and isolated MSH-6 loss in 2. All 14 discordant cases showed MSI-H in the cancer, but not in the adenoma; IHC on the discordant cancers revealed MLH-1 loss in 11/13 cases and MSH-2 loss in 1/13 cases. One of 62 (1.6%) adenomas not associated with adenocarcinoma was MSI-H. No adenomas were MSI-low. Correlation between MSI status in adenomas associated with MSI-H carcinomas, results of GT, family history, and IHC analysis is summarized below.
|Adenoma Phenotype||Deleterious Mutation||Family History Suggestive of HNPCC||MSH-2 + isolated MSH-6 IHC Loss||Total Independent Features of HNPCC|