High Throughput Mutational Profiling of Biliary Neuroendocrine Carcinomas

초록

Background: Biliary neuroendocrine carcinomas (NECs) are extremely rare with worse prognosis. Due to its rarity, no well-established therapeutic modality have been set up for treatment of biliary NECs. Comparing with neuroendocrine tumors from other organs, one of the characteristics of biliary NECs are mixed adenoendocrine carcinomas (MANECs) which consist of mixed neuroendocrine carcinomas with conventional cholangiocarcinomas. To the best of our knowledge, somatic mutational patterns of biliary NECs have not been well elucidated. Design: DNA was extracted from FFPE tissues from 14 (7 NECs and 5 MANECs) biliary NECs, and followed by preparation of library for targeted NGS with OncoPanel Version 2 probe set focused on cancer related 505 genes. Captured sequences were amplified then allowed to Massive Parallel Sequencing using MiSeq platform. Results: NEC component in pure NEC were classified as 6 small cell carcinomas and 1 large cell carcinoma. In MANECs, all 5 were small cell carcinomas. Commonly mutated genes included MUC2 (9/12, 75%), TP53 (8/12, 67%), RB (8/12, 67%), HLA-A (5/12, 42%), HLA-DRB1 (4/12, 33%), NOTCH2 (4/12, 33%), CREBBP (3/12, 25%), AFF (3/12, 25%). Other mutations, including ERBB3, KATA6, LAMA5, KMT2D, NOTCH4, SYNE1 (2 cases each, 17%), APC, GNAS, and MYCL (1 case each, 8%) were detected at lower frequencies. Conclusions: Mutational profiling of biliary NECs demonstrate combined mutational patterns of small cell carcinomas and cholangiocarcinomas. Understanding these unique mutational pattern may be helpful for proper treatment of biliary NEC patients.