Abstract
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.