Unexpected Expression of Mismatch Repair Protein Is More Commonly Seen with Pathogenic Missense than Other Mutations in Lynch Syndrome.

Abstract It has been observed that some colorectal cancer patients with Lynch syndrome (LS) due to germline or double somatic pathogenic variants in the mismatch repair (MMR) genes may have intact protein expression observed in their tumors by immunohistochemistry (IHC). This has been speculated to occur more frequently in LS cases due to pathogenic missense mutations leading to expression of a full-length but nonfunctional protein with retained antigenicity. Our goals were to study the frequency of unexpected MMR expression in colorectal cancers among LS patients with missense mutations, LS patients with truncating mutations, as well as cases with double somatic MMR mutations, and evaluate if the unexpected MMR expression is more common in certain categories. IHC slides were available on 82 patients with MMR deficiency without methylation, including 56 LS cases and 26 double somatic MMR mutation cases. 16 of 82 MMR-defective cases showed unexpected MMR expression, with 10 cases showing tumor staining weaker than control and 6 cases (7%) with intact staining. Unexpected MMR expression was most commonly seen with LS cases with missense mutations (4 of 9, 44%), followed by MMR double somatic mutation cases (7 of 26, 27%), and lastly by LS cases with truncating mutations (5 of 47, 11%). Cautious interpretation of MMR IHC is advised when dealing with tumor staining that is weaker than control regardless of percentage of tumor staining, as these cases may harbor pathogenic MMR gene mutations. Missense mutations may account for some LS cases that may be missed by IHC alone. Strict adherence to proper interpretation of IHC with attention to staining intensity and the status of heterodimer partner protein will prevent many potential misses.