Pancreatic acinar cell carcinoma (PACC): A comparative genomic landscape study.

Abstract

746 Background: PACC is a rare subtype accounting for ~1% of all exocrine pancreatic neoplasms and remains understudied compared to conventional pancreatic ductal adenocarcinoma (PDAC). Here, we performed a comparative analysis of the genomic landscapes of PACC versus PDAC using the FoundationCORE dataset to identify potential therapeutic vulnerabilities. Methods: Comprehensive genomic profiling using hybrid capture-based next-generation sequencing (NGS) was performed on 196 PACC and 29,493 PDAC tumors to identify pathogenic genomic alterations (GAs). All patients (pts) had stage III/IV disease at the time of profiling. Genomic ancestry, microsatellite instability (MSI), tumor mutational burden (TMB), and homologous recombination deficiency signature (HRDsig) were assessed. Statistical analysis was performed using Fisher’s exact test, with false discovery rate correction applied via the Benjamini-Hochberg method for independent variables or the Benjamini–Yekutieli method for dependent variables. Results: PACC was more common in males than PDAC (67.9% vs 52.7%, p<0.0001) with similar age (median 66 yrs, IQR 58-74 vs 67 yrs, IQR 60-74) and genomic ancestry distributions. A median of 4 GAs/tumor (IQR 2.25-5.75) were identified in PACC. MSI-high status was rare in both cohorts (1.0% vs 0.5%, p=1.0). TMB was higher in PACC than PDAC, driven by greater enrichment of cases in the 10-20 mut/Mb (5.1% vs 0.7%, p<0.0001) and ≥20 mut/Mb (2.0% vs 0.5%, p=0.039) ranges. HRDsig positivity was also enriched in PACC (20.9% vs 4.6%, p<0.0001), consistent with prior reports indicating strong association with germline DNA damage repair mutations. Alterations in canonical PDAC driver genes were significantly less frequent in PACC, including KRAS (6.1% vs 93.6%, p<0.0001), TP53 (17.4% vs 78.9%, p<0.0001), CDKN2A (31.6% vs 58.6, p<0.0001), and SMAD4 (19.9% vs 29.1%; p=0.0054). MTAP loss was also less frequent in PACC (15.8% vs 23.8%; p=0.0097). Conversely, PACC was enriched for mutations in BRAF (11.2% vs 2.0, p<0.0001), BRCA2 (14.3% vs 2.9%, p<0.0001), APC (10.2% vs 1.1%, p<0.0001), CTNNB1 (12.2% vs 0.7%, p<0.0001), and GNAS (12.2% vs 3.2%, p<0.0001). Conclusions: PACC exhibits a distinct genomic profile from PDAC, characterized by fewer canonical drivers and frequent KRAS wild-type status. Enrichment for BRAF mutations highlights opportunities for MAPK- targeted therapies, while increased TMB and HRD signatures suggest potential sensitivity to immunotherapy and DNA repair-directed strategies, respectively.