Minimal microsatellite shift in microsatellite instability high endometrial cancer: a significant pitfall in diagnostic interpretation.

Abstract

Mismatch-repair deficiency testing plays a critical role in the identification of proband in Lynch Syndrome families and triaging patients with high stage or recurrent solid malignancies for check point inhibitor (Pembrolizumab) immunotherapy. We compared microsatellite shift patterns of microsatellite instability PCR analysis at 5 NCI recommended loci between microsatellite instability high endometrial carcinoma (n = 50) and microsatellite instability high colorectal cancer (n = 19). The endometrial cancer cohort included 45 endometrioid, 1 serous, and 4 clear cell carcinomas. Overall, 52% (26/50) of microsatellite instability high endometrial cancers showed minimal microsatellite shift (defined as a one to three nucleotide repeat shift at an involved locus) observed at least at one locus. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, the frequencies at each involved locus were D2S123 (21/21, 100%), D17S250 (10/11, 89%), D5S346 (11/12, 92%), BAT25 (9/12, 80%), and BAT26 (8/21, 45%). Noticeably, 11 of the 26 cases (42%) showed only minimal shift. Among microsatellite instability high endometrial cancers with minimal microsatellite shift, 65% (17/26) had combined MLH1 and PMS2 loss, 8% (2/26) had combined MSH2 and MSH6 loss, 13% (3/26) had MSH6 loss and 15% (4/26) had loss of PMS2 by immunohistochemistry. In contrast, only 16% (3/19) had minimal microsatellite shift seen in colorectal cancer cohort with corresponding loss of MLH1/PMS2, MSH2/MSH6, or MSH6. Overall, 15% (7/50) of microsatellite instability high endometrial carcinomas showed isolated loss of MSH6 in contrast to 7% (1/15) seen in microsatellite instability high colorectal carcinomas. In conclusion, microsatellite instability high endometrial carcinomas have a significantly higher frequency of minimal microsatellite shift that coincides with a high percentage of combined loss of MLH1/PMS2. Microsatellite instability high endometrial cancers also have more frequent loss of MSH-6. Diagnostically, recognition of minimal microsatellite shift is crucial for accurate interpretation of microsatellite instability PCR data of endometrial carcinoma.

• Authors: Xinyu Wu, Olivia Snir, Douglas Rottmann, Serena Wong, Natalia Buza, Pei Hui
• Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc (Mod Pathol) Vol. 32 Issue 5 Pg. 650-658 (05 2019) ISSN: 1530-0285 [Electronic] United States
• PMID: 30443012 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Biomarkers, Tumor
• DNA-Binding Proteins
• G-T mismatch-binding protein
• MLH1 protein, human
• PMS2 protein, human
• MSH2 protein, human
• Mismatch Repair Endonuclease PMS2
• MutL Protein Homolog 1
• MutS Homolog 2 Protein

Topics

• Aged
• Aged, 80 and over
• Biomarkers, Tumor (analysis, genetics)
• Colorectal Neoplasms, Hereditary Nonpolyposis (chemistry, genetics, pathology)
• DNA-Binding Proteins (analysis)
• Endometrial Neoplasms (chemistry, genetics, pathology)
• Female
• Genetic Loci
• Genetic Predisposition to Disease
• Humans
• Immunohistochemistry
• Microsatellite Instability
• Middle Aged
• Mismatch Repair Endonuclease PMS2 (analysis)
• MutL Protein Homolog 1 (analysis)
• MutS Homolog 2 Protein (analysis)
• Phenotype
• Polymerase Chain Reaction
• Predictive Value of Tests
• Reproducibility of Results