Somatic mutations and increased lymphangiogenesis observed in a rare case of intramucosal gastric carcinoma with lymph node metastasis
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Naoki Ikari1,2,*, Shota Aoyama1,*, Akiyoshi Seshimo1, Yuji Suehiro3, Tomoko Motohashi3, Shohei Mitani3, Sawako Yoshina3, Etsuko Tanji2, Akiko Serizawa1, Takuji Yamada1, Kiyoaki Taniguchi1, Masakazu Yamamoto1 and Toru Furukawa2,4,5
1Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan
2Institute for Integrated Medical Sciences, Tokyo Women’s Medical University, Tokyo, Japan
3Department of Physiology, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan
4Department of Surgical Pathology, Tokyo Women’s Medical University Hospital, Tokyo, Japan
5Department of Histopathology, Tohoku University Graduate School of Medicine, Sendai, Japan
*These authors have contributed equally to this work
Toru Furukawa, email: [email protected]
Keywords: early gastric cancer; lymph node metastasis; lymphangiogenesis; NBN; PAX8
Received: May 18, 2017 Accepted: January 13, 2018 Published: January 22, 2018
Background and aim: Intramucosal gastric adenocarcinoma of the well-moderately differentiated type only exhibits lymph node metastasis in extremely rare cases. We encountered such case and investigated both the lymphangiogenic properties and somatic mutations in the cancer to understand the prometastatic features of early-stage gastric cancer.
Methods: We quantitatively measured the density of lymphatic vessels and identified mutations in 412 cancer-associated genes through next-generation target resequencing of DNA extracted from tumor cells in a formalin-fixed and paraffin-embedded tissue. Functional consequence of the identified mutation was examined in vitro by means of gene transfection, immunoblot, and the quantitative real-time polymerase chain reaction assay.
Results: The intramucosal carcinoma was accompanied by abundant lymphatic vessels. The metastatic tumor harbored somatic mutations in NBN, p.P6S, and PAX8, p.R49H. The PAX8R49H showed significantly higher transactivation activity toward E2F1 than the wild-type PAX8 (P< 0.001).
Conclusions: Our data suggest that increased lymphangiogenesis and somatic mutations of NBN and/or PAX8 could facilitate lymph node metastasis from an intramucosal gastric carcinoma. These findings may potentially inform evaluations of the risk of developing lymph node metastasis in patients with intramucosal gastric cancer.
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