Target sequencing of cancer-related genes in early esophageal squamous neoplasia resected by endoscopic resection in Japanese patients
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Shoji Kobayashi1, Tatsuya Yamaguchi1, Shinya Maekawa1, Shinichi Takano1, Toru Kuno1, Keisuke Tanaka1, Yuya Tsukui1, Fumihiko Iwamoto1, Takashi Yoshida1, Yukiko Asakawa1, Mitsuharu Fukasawa1, Yasuhiro Nakayama1, Taisuke Inoue1, Tomoyoshi Uetake1, Minoru Sakamoto1, Masahiko Ohtaka1, Tadashi Sato1 and Nobuyuki Enomoto1
1First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Chuo, Yamanashi 409-3898, Japan
Shinya Maekawa, email: [email protected]
Keywords: next generation sequencing; early esophageal squamous neoplasia; cancer-related gene mutation; copy number variation
Received: March 26, 2018 Accepted: October 24, 2018 Published: December 04, 2018
Background and Aims: Next generation sequencing (NGS) has revealed a great deal about cancer-related somatic changes in esophageal squamous cell neoplasia; however, the changes in the very early stages remain unclear.
Results: TP53 (87%) and CDKN2A (20%) hot spot mutations were frequently found in early lesions. TP53 was the most common mutation (LGIN/HGIN, 86%; EP, 83%; LPM, 95%; MM/SM1, 80%), followed by CDKN2A (29%, 28%, 16% and 10%, respectively); the frequency of other mutations increased as the disease advanced (p < 0.01). Copy number variation analysis revealed copy number aberrations in multiple genes, including PIK3CA amplification (48%). NGS was superior to p53 immunostaining for detecting TP53 mutations (74% vs. 87%); in combination, the two tests improved detectability to 94%. Clinically, smoking was associated with the occurrence of TP53 mutations in these early lesions (p = 0.049).
Materials and Methods: Fifty-four early esophageal neoplasia lesions from 47 patients treated by endoscopic resection (low-grade intraepithelial neoplasia [LGIN], n = 1; high-grade intraepithelial neoplasia [HGIN] n = 7; invasion limited to epithelium [EP/M1], n = 18; lamina propria mucosae [LPM/M2], n = 19; muscularis mucosae [MM/M3], n = 8; and upper third of the SM [SM1], n = 2) were isolated from formalin-fixed paraffin-embedded tissue specimens by laser-capture microdissection. Target sequencing of 50 cancer-related genes was performed with an Ion Proton sequencer; their association with the clinical characteristics was investigated.
Conclusions: Mutations of TP53 and CDKN2A, and PIK3CA amplification were common in early esophageal squamous neoplasia, while other mutations accumulated with disease progression. An understanding of these molecular events might provide a molecular basis for early lesion treatment.
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