N53: Discordant IHC MMR Staining And MSI Results In Tumors Of MSH6 Mutation Carriers

A. S. van der Werf – ’t Lam1, M. S. Kan1, M. Suerink1, L. P. van Hest2, H. J. P. Gille2, A. Wagner3, C. Tops1, T. van Wezel4, H. Morreau4, S.ten Broeke1, M. Nielsen1

1 – Department of Clinical Genetics, Leiden University Medical Centre, The Netherlands. 2 – Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands. 3 – Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, The Netherlands. 4 – Department of Pathology, Leiden University Medical Centre, The Netherlands.


Aim: Diagnosing Lynch Syndrome caused by a MSH6 mutation can be challenging due to the relatively frequent occurrence of discordant immunohistochemistry staining  (i.e. MSH6 positive staining) and microsatellite stable phenotype. The aim of this study is to describe to what extent discordant phenotypes occur in colorectal and endometrial carcinomas (CRC/EC) in MSH6 families.

Method: Data were collected from 192 MSH6 families  with a confirmed segregating pathogenic germline variant ascertained from Dutch family cancer clinics.

Results: The data consists of 9719 family members and 838 proven mutation carriers. MSH6-mutation carriers with CRC or EC (n=306) were included in the study, accounting for 219 CRCs and 122 ECs. Of the tested tumors, discordant staining for MSH6 was reported in 10 out of 68 CRCs (14.7%) and 3 out of 26 ECs (11,5%). Six out of 62 CRCs (9.7%) and 5 out of 25 (20.0%) ECs appeared to be microsatellite stable. Fifteen germline MSH6 mutation carriers also displayed negative staining for MSH2 in addition to negative MSH6 staining, but did not harbor a germline MSH2 mutation.

Conclusion: Germline MSH6 mutation carriers can be missed using reflex  IHC MMR testing as is currently standard in most western countries. MSH6 germline or tumor DNA analysis – preferably as part of a larger gene panel – should therefore be considered, especially in patients fulfilling the Bethesda criteria.