Mutational profiling of SMARCA4 and SMARCB1 in ampullary adenocarcinoma: a preliminary study

Dear Editor,

Ampullary adenocarcinoma (AAC) accounts for only 0.2% of gastrointestinal malignancies and, although a surgical approach is suitable in 80% of cases, the 5-year survival rate is 30-50% with a high recurrence rate (50%) ¹. The most frequent histological subtypes are mixed, pancreatobiliary (PB), and intestinal (INT) ¹. Therapeutic approaches are limited, with approved gemcitabine-based regimen in PB and 5-fluororacil in INT AAC patients, respectively ¹. AAC molecular profiling predominantly highlighted KRAS mutations followed by TP53, WNT/APC, PIK3CA, SMAD4 then BRAF, CDKN2A, FBXW7, ERBB2, PDFGRA, SMARCB1, RB1 ¹. Among them, only BRAF point mutations (detected in 9.3% of cases) and NTRK aberrant transcripts (2.0% of cases) make AAC patients eligible for Idabrafenib plus trametinib (MEK inhibitors) and anti NTRK inhibitors, respectively ¹. In this scenario, the identification of novel specific molecular hallmark able to optimize the clinical management of AAC patients is crucial.

SMARC proteins are core subunits of the SWI1/SNF1 complex and are involved in chromatin remodeling and DNA repair ². SMARCA4 (BRAHMA RELATED GENE, BRG1), involved in ERBB, GnRH, and PI-3K/AKT/mTOR signaling pathways, acts in transcriptional modulation, DNA repair, and cell cycle checkpoint ². A high expression level of SMARCA4 has been described as a negative prognostic factor across different solid tumors ².