Molecular profiling of pancreatic acinar cell carcinoma and amphicrine-like carcinoma: high frequency of homologous recombination deficiency and molecular heterogeneity.

BACKGROUND: The 6th edition of the WHO Classification of Digestive System Tumours distinguishes amphicrine-like carcinomas (ALCs) from mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Acinar cell carcinomas (ACCs) with an intimately admixed and not separated neuroendocrine component comprising >30% of the tumour are classified as amphicrine-like ACCs (AL-ACCs). We characterised the genomic landscape of pancreatic ACCs and AL-ACCs to validate current classification and identify therapeutic targets. METHODS: Among 2,151 pancreatic biopsy and resection cases that underwent targeted next-generation sequencing using the OncoPanel AMC v4.3 or v4.5 (DNA-based hybrid capture, targeting 323 genes (v4.3) or 343 genes (v4.5)), eight ACCs, seven AL-ACCs originally diagnosed as MiNENs under the 5th edition of the WHO classification scheme, and four neuroendocrine tumours (NETs) were identified, diagnosed between 2020 and 2026. RESULTS: Homologous recombination deficiency (HRD)-associated alterations, involving BRCA1/2, ATM and FANCD2, were identified in 87.5% (7/8) of ACCs and 29% of AL-ACCs. One ACC had an ATRX nonsense mutation. Genomic heterogeneity was observed in molecular profiling of AL-ACCs; two demonstrated a 'true hybrid' signature with co-occurrence of lineage-specific drivers: MEN1 deletion and splice site mutation (neuroendocrine-associated), APC, SMAD4 and CTNNB1 alterations (exocrine-associated). Two others exhibited 'ACC-like' signatures, including missense BRCA1 and nonsense TP53 mutations and MDM4 and AKT3 amplifications, located on chromosome 1q, despite their neuroendocrine differentiation. CONCLUSIONS: Pancreatic ACCs frequently harbour HRD-related alterations, suggesting potential for PARP-inhibitor therapy. AL-ACCs comprise molecularly heterogeneous groups, including true hybrid and ACC-like patterns. Larger studies are required to elucidate the molecular distinction between true hybrid AL-ACCs and those with single-lineage alterations to refine their classification.