ECE2024 Rapid Communications Rapid Communications 3: Adrenal and Cardiovascular Endocrinology | Part I (7 abstracts)
Mismatch repair deficiency and microsatellite instability in adrenocortical carcinoma: Diagnosis, prevalence, and clinical impact
Barbara Altieri 1 , Sabine Herterich 2 , Stefan Kircher 3 , Arne Jahn 4 , Maria-Veronica Teleanu 5 , Juliane Lippert 1 , Laura-Sophie Landwehr 1 , Otilia Kimpel 1 , Miriam Reuter 1 , Hanna Remde 1 , Albrecht Stenzinger 6 , Hanno Glimm 7 , Ralf Bargou 8 , Stefan Froehling 5 , Cristina L Ronchi 1,9 , Silke Appenzeller 8 , Martin Fassnacht 1,2,8 & Kroiss Matthias 1,10
1Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany; 2Clinical Chemistry and Laboratory Medicine, University Hospital, University of Würzburg, Würzburg, Germany; 3Institute of Pathology, University of Würzburg, Würzburg, Germany; 4Institut für Klinische Genetik, Dresden, Germany; 5National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; 6Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany; 7National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany; 8Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Würzburg, Germany; 9College of Medical and Dental Sciences, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom, 10Department of Internal Medicine IV, University Hospital Munich, Ludwig-Maximilians-Universität München, Munich, Germany
Background: DNA mismatch repair (MMR) maintains genomic integrity and stability. Inactivation of the MMR genes MLH1, PMS2, MSH2, and MSH6 by somatic or germline variants or gene methylation causes MMR deficiency (dMMR) leading to microsatellite instability (MSI) and high tumour mutational burden. In many tumour entities, patients with dMMR/MSI respond well to immune checkpoint inhibitor (ICI) therapy. The clinical relevance of dMMR and MSI in adrenocortical carcinoma (ACC) remains uncertain.
Objective: To systematically investigate MMR gene variants and methylation, MMR protein expression, and MSI in patients with ACC and to test for their association with clinical variables including response to ICI.
Methods: Immunohistochemistry of MLH1, PMS2, MSH2, and MSH6 was performed in 109 ACC tissues with available germline and somatic MMR gene variants by whole-genome (n=14), exome (n=7) or targeted-panel sequencing (n=88). Pathogenic/likely pathogenic MMR variants were confirmed by Sanger-sequencing. Methylation status was evaluated by multiplex ligation-dependent probe amplification in patients with dMMR tumours. Microsatellite analysis of dinucleotide and mononucleotide microsatellite loci NR21, NR27, BAT40, and KCNJ5 were analysed by plex PCR in 99 patients. Clinicopathological data were analysed retrospectively.
Results: Immunohistochemistry showed dMMR in 15/109 cases (13.8%) with prevalence of MSH6-loss either alone (n=3) or associated with MSH2-loss (n=4), MLH1/PMS2-loss (n=1), or as tetra-loss (n=1). Hormone secretion (P=0.31), ENSAT stage (P=0.53), Ki67% (P=0.12), S-GRAS score (P=0.23), history of other malignancy (P=0.19), progression-free (HR=1.21, 95%CI=0.63-2.31, P=0.57) and disease-specific survival (HR=1.26, 95%CI=0.58-2.71, P=0.56) did not differ between patients with and without dMMR. Weiss score was significantly higher in dMMR tumours (P=0.008). Ten patients with dMMR tumours had pathogenic/likely pathogenic germline (n=4) or somatic (n=5) MMR variants or MLH1 hypermethylation (n=1), but plex PCR showed MSI only in 3 cases. Among patients without dMMR, few cases had germline (n=1) or somatic (n=1) MMR variants or MSI (n=1). 4/5 patients with dMMR and/or MMR variants who received ICI did not respond. A single patient with germline MSH6 variant, tumoural dMMR, but lack of MSI, was stable on immunotherapy for 12 months.
Conclusion: This is the first large systematic multiparameter study of dMMR/MSI in ACC. Loss of MMR protein expression is rare in ACC. MSI is infrequent even in patients with dMMR at immunohistochemistry. Germline variants in MMR genes (Lynch syndrome) are found in 4.5% of ACC and not always associated with dMMR/MSI. Different from other cancers, dMMR in ACC is not associated with histopathological and clinical characteristics or prognosis, including response to immunotherapy.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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