Novel gene mutations in well-differentiated fetal adenocarcinoma of the lung in the next generation sequencing era

Objectives: Since well-differentiated fetal adenocarcinoma of lung (WDFA) is an extremely rare subtype of invasive lung adenocarcinoma, histologic features, biomarkers and molecular aberrant of it are not fully determined. This article aims to investigate the clinic-pathologic details and potential driver genes of WDFA. Materials and methods: Two cases of WDFA were selected from a large cohort of 730 cases of primary adenocarcinoma of the lung resected in West China Hospital of Sichuan University between January 2016 and June 2017, retrospectively. Both of them were conducted to immunohistochemical profile and gene mutation analysis by using 56-parelle-NGS. Results: Microscopically, besides conventional histologic characteristics of WDFA, such as well-differentiated glands composed of obvious glycogen-rich cells and squamoid morules formation, remarkable proliferation of benign fibrous tissue, focal necrosis and mitoses were found. Unlike the common adenocarcinomas of the lung, WDFAs showed nuclear/cytoplasmic expression of beta-catenin, diffuse expression for TTF-1, and focal for Napsin A. Furthermore, molecular analysis demonstrated two novel missense gene mutations of BRCA2 and TSC2, as well as the classical CTNNB1 gene mutation and silent mutation of DDR2 gene. Conclusions: This report presents the first case with two novel gene mutations of the WDFA, suggesting that in addition to beta-catenin, BRCA2 and TSC2 might play some important roles in up-regulation of Wnt signaling pathway. Moreover, use of NGS technique is helpful to understand the biology of this rare neoplasm and provide the potential gene for targeted therapy.