A novel GLCC1::BRAF fusion with independent MYCN and MYC amplifications in primary tumor and metastasis in pediatric pancreatic acinar carcinoma

Abstract

Abstract Introduction/Objective Pediatric pancreatic acinar cell carcinoma (PACC) is a rare malignancy, comprising 5-15% of pediatric pancreatic tumors. BRAF rearrangement is found in 20-30% of PACC cases, most commonly an inversion in chromosome 7. We report a case of PACC with GLCC1::BRAF fusion. Methods/Case Report A 10-year-old male presented with six months of weight loss, back pain, and loose stools. Imaging demonstrated concentric soft tissue thickening around the celiac axis and superior mesenteric artery, clinically interpreted as vasculitis. Follow-up imaging showed extension of the soft tissue thickening, prompting biopsy of a periaortic lymph node showing metastatic PACC. Pancreaticduodenectomy revealed a 3.8 cm pancreatic neck mass with perineural invasion and metastatic deposits in multiple lymph nodes and retroperitoneal soft tissue. Fluorescence in situ hybridization of both specimens demonstrated BRAF gene rearrangement, with the partner identified as GLCC1 by next generation sequencing and fusion assays. Microarray on the lymph node demonstrated amplification of MYC on chromosome 8, but not in the resection specimen, which showed gain of chromosome 2 and amplification of MYCN. Results (if a Case Study enter NA) NA Conclusion The GLCC1::BRAF fusion has previously been reported once in a case of pheochromocytoma with peritoneal seeding. The MYC gene family members, c-MYC and MYCN, are involved many cancer types; amplifications are often associated with unfavorable prognosis in tumors such as neuroblastoma. However, the amplification of both genes in the same tumor at different loci has not been reported. The combination of the primary GLCC1::BRAF fusion with secondary amplification of MYC and MYCN is likely to drive the aggressive behavior and metastasis in this case of PACC. Treatment for PACC includes chemoradiation and BRAF inhibition. However, BRAF rearrangements without the V600E mutation show variable response to BRAF inhibitors. Potential alternatives include inhibitors to other targets within the BRAF signaling pathway. Further investigation is needed to determine the clinicopathologic impact of these novel genetic aberrancies.