Mismatch Repair Protein and Microsatellite Instability Analysis in Pancreatic Ductal Adenocarcinoma

TL;DR

This study examines mismatch repair proteins in pancreatic cancer to identify patterns linked to prognosis and tumor characteristics.

Contribution

The study identifies MMR deficiency and MSI-H status as novel prognostic biomarkers in pancreatic ductal adenocarcinoma.

Findings

MMR deficiency and MSI-H status were found in 6.6% of PDAC patients, associated with younger age and distinct tumor features.

Isolated MutS and MutL complex losses were observed in 12.3% and 15.1% of cases, respectively.

HER3 positivity was more common in intermediate MutL cases compared to HER2 positivity.

Abstract

Introduction: Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive, heterogeneous, and lethal malignancies in humans. Mismatch repair (MMR) proteins constitute a fundamental component of the DNA mismatch repair pathway, which is responsible for correcting replication-associated errors, including incorrect base pairings and small insertions or deletions. This study aims to evaluate the immunohistochemical expression of MSH2, MSH6, MLH1, and PMS2 in resected PDAC and to analyze their association with pTNM stage, perineural and lymphovascular invasion, HER2 and HER3 expression, and tumor volume. Methods: A cohort of 106 patients with currative intent Whipple procedure was evaluated, their corresponding paraffin blocks and slides were analyzed using tissue microarray. Immunohistochemical analysis of MLH1, PMS2, MSH2, and MSH6 was performed. Patients were grouped based on MMR expression profiles: isolated MutS loss (MSH2/MSH6), and isolated MutL loss (MLH1/PMS2). Results: Among the 106 subjects evaluated, 13 (12.3%) exhibited isolated MutS complex loss and 16 (15.1%) showed MutL complex loss. A total of 7 patients (6.6%) demonstrated concurrent loss of all four MMR proteins, representing a pattern suggestive of MMR deficiency MSI-H. These ones were significantly younger (median 56 vs. 64 years, p = 0.0492) and had distinct T-stage distribution (p = 0.0237). Two intermediate subgroups were identified: five patients with isolated MutL loss and one patient with isolated MutS loss. HER3 positivity was observed in 3/5 of the intermediate MutL cases and HER2 positivity in only one. Conclusions: MMR deficiency and potential MSI-H status were identified to be relevant prognostic biomarkers for pancreatic cancer patients, with MSI-H patients displaying a younger age and distinct tumor features.

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