Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Anne-Sophie van der Werf-'t Lam; Diantha Terlouw; Carli M Tops; Merel S van Kan; Liselotte P van Hest; Hans J P Gille; Floor A M Duijkers; Anja Wagner; Ellis L Eikenboom; Tom G W Letteboer; Mirjam M de Jong; Sanne W Bajwa-Ten Broeke; Fonnet E Bleeker; Encarna B Gomez Garcia; Niels de Wind; J Tom van Wezel; Hans Morreau; Manon Suerink; Maartje Nielsen

doi:10.1016/j.modpat.2023.100240

Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers

Mod Pathol. 2023 Sep;36(9):100240. doi: 10.1016/j.modpat.2023.100240. Epub 2023 Jun 10.

Authors

Anne-Sophie van der Werf-'t Lam¹, Diantha Terlouw², Carli M Tops¹, Merel S van Kan¹, Liselotte P van Hest³, Hans J P Gille³, Floor A M Duijkers⁴, Anja Wagner⁵, Ellis L Eikenboom⁶, Tom G W Letteboer⁷, Mirjam M de Jong⁸, Sanne W Bajwa-Ten Broeke⁸, Fonnet E Bleeker⁹, Encarna B Gomez Garcia¹⁰, Niels de Wind¹¹, J Tom van Wezel², Hans Morreau², Manon Suerink¹, Maartje Nielsen¹²

Affiliations

¹ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
² Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
⁴ Department of Clinical Genetics, Amsterdam Medical Center, Amsterdam, The Netherlands.
⁵ Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁶ Department of Clinical Genetics, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Gastroenterology and Hepatology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, The Netherlands.
⁷ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
⁸ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁹ Department of Clinical Genetics, Netherlands Cancer Institute, Amsterdam, The Netherlands.
¹⁰ Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands.
¹¹ Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹² Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: m.nielsen@lumc.nl.

PMID: 37307877
DOI: 10.1016/j.modpat.2023.100240

Abstract

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.

Keywords: Lynch Syndrome; immunohistochemistry; microsatellite instability; mismatch repair deficiency.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colonic Neoplasms* / genetics
Colorectal Neoplasms* / pathology
Colorectal Neoplasms, Hereditary Nonpolyposis* / diagnosis
Colorectal Neoplasms, Hereditary Nonpolyposis* / genetics
Colorectal Neoplasms, Hereditary Nonpolyposis* / pathology
DNA Mismatch Repair / genetics
DNA-Binding Proteins / genetics
Endometrial Neoplasms* / genetics
Female
Humans
Microsatellite Instability
Microsatellite Repeats

Substances

DNA-Binding Proteins