Deficiencia de reparación de apareamientos erróneos e inestabilidad de microsatélites en el carcinoma adrenocortical

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.

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.

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.

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.