Mismatch repair deficiency and microsatellite instability in adrenocortical carcinoma
Background - Genetic and epigenetic alterations can cause mismatch repair (MMR) deficiency (dMMR) leading to microsatellite instability (MSI). Although dMMR/MSI predicts response to immune checkpoint inhibitors (ICIs) in several cancers, their relevance in adrenocortical carcinoma (ACC) remains uncl...
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| Autori principali: | , , , , , , , , , , , , , , , , , |
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| Natura: | Article (Journal) |
| Lingua: | inglese |
| Pubblicazione: |
5 February 2026
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| In: |
ESMO open
Year: 2026, Volume: 11, Fascicolo: 2, Pages: 1-12 |
| ISSN: | 2059-7029 |
| DOI: | 10.1016/j.esmoop.2025.106030 |
| Accesso online: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.esmoop.2025.106030 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2059702925019003 
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| Note sull'autore: | B. Altieri, S. Kircher, S. Herterich, A. Jahn, M.-V. Teleanu, J. Lippert, L.-S. Landwehr, O. Kimpel, M. Reuter, H. Remde, A. Stenzinger, H. Glimm, R.C. Bargou, S. Fröhling, C.L. Ronchi, S. Appenzeller, M. Fassnacht, and M. Kroiss |
| Riassunto: | Background - Genetic and epigenetic alterations can cause mismatch repair (MMR) deficiency (dMMR) leading to microsatellite instability (MSI). Although dMMR/MSI predicts response to immune checkpoint inhibitors (ICIs) in several cancers, their relevance in adrenocortical carcinoma (ACC) remains unclear. - Patients and methods - We investigated the MMR system and MSI in patients with apparently sporadic ACC and explored associations with clinical characteristics and outcomes. In a subgroup, correlation between dMMR/MSI and response to ICI was evaluated. Immunohistochemistry for MLH1, PMS2, MSH2, and MSH6 was carried out in 109 ACC tissues with molecular data. Germline pathogenic/likely pathogenic (P/LP) and somatic oncogenic/likely oncogenic (O/LO) MMR variants were validated by Sanger sequencing. MLH1 methylation and EPCAM deletions were assessed via multiplex ligation-dependent probe amplification. MSI was analysed using plex PCR. - Results - dMMR was identified in 15 (14%) cases, mainly involving MSH6 loss (n = 9, 8.3%) either with MSH2 or alone. No significant differences were observed in hormone secretion, European Network for the Study of Adrenal Tumors (ENSAT) stage, proliferation index (Ki67%), S-GRAS (Stage, Grade, Resection status, Age, Symptoms) score, progression-free survival (8 versus 14 months) and overall survival (72 versus 80 months) between patients with and without dMMR. A slightly higher frequency of other malignancies was observed in dMMR cases (27% versus 11%, P = 0.09). Ten dMMR tumours were linked to P/LP germline (n = 4, 26.7%) or O/LO somatic (n = 5, 33.6%) MMR variants or MLH1 hypermethylation (n = 1, 6.7%), but only three (20%) showed MSI. Lynch syndrome was identified in 5% of patients. Among 12 patients treated with ICIs, time to progression was similar between those with and without defective MMR (4 versus 5 months, P = 0.21). Only one of five ICI responders had a confirmed MSH6 variant. - Conclusion - DMMR occurs in a minority of ACC, often without MSI. Although Lynch syndrome accounts for a subset of cases, dMMR is not predictive of clinical features or ICI response. Nonetheless, MMR testing remains important for identifying individuals at hereditary cancer risk. |
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| Descrizione del documento: | Gesehen am 18.05.2026 |
| Descrizione fisica: | Online Resource |
| ISSN: | 2059-7029 |
| DOI: | 10.1016/j.esmoop.2025.106030 |