Mismatch-repair deficiency testing is crucial for the identification of probands in Lynch Syndrome families and triaging patients with recurrent or high stage solid malignancies for checkpoint inhibitor (Pembrolizumab) immunotherapy. Researchers investigated the microsatellite shift patterns of microsatellite instability PCR analysis at 5 NCI recommended loci in microsatellite instability-high endometrial carcinoma (n = 50) and microsatellite instability-high colorectal cancer (n = 19).
About 45 endometrioid, 1 serous, and 4 clear cell carcinomas were included in the endometrial cancer cohort. Overall, 52% (26/50) of microsatellite instability-high endometrial cancers showed minimal microsatellite shift. D2S123 (21/21, 100%), D17S250 (10/11, 89%), D5S346 (11/12, 92%), BAT25 (9/12, 80%), and BAT26 (8/21, 45%) were the frequencies at each implicated locus in microsatellite instability-high endometrial malignancies with limited microsatellite shift.
Notably, 11 of the 26 instances (42%) exhibited just a little change. By immunohistochemistry, 65% (17/26) of microsatellite instability-high endometrial malignancies with limited microsatellite shift 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 PMS2 loss. In comparison, only 16% (3/19) of the colorectal cancer cohort exhibited a minor microsatellite shift with associated loss of MLH1/PMS2, MSH2/MSH6, or MSH6. In total, 15% (7/50) of microsatellite instability-high endometrial carcinomas had isolated deletion of MSH6, compared to 7% (1/15) of microsatellite instability-high colorectal carcinomas. In conclusion, high endometrial carcinomas with microsatellite instability have a much greater frequency of minimum microsatellite shift, which aligns with a high percentage of combined loss of MLH1/PMS2. MSH-6 deletion is more common in high endometrial malignancies with microsatellite instability. Recognizing minor microsatellite shifts is critical for the correct interpretation of endometrial cancer microsatellite instability PCR results.