Mitsuhiro Nikaido1, Nobuyuki Kakiuchi1,2,3, Shin'ichi Miyamoto4,5, Tomonori Hirano1,2,3, Yasuhide Takeuchi2,6, Taro Funakoshi7, Akira Yokoyama7, Tatsuki Ogasawara2,3, Yoshihiro Yamamoto7, Atsushi Yamada7, Takeshi Setoyama1,8, Takahiro Shimizu1, Yukari Kato9, Suguru Uose9, Takaki Sakurai6,10, Sachiko Minamiguchi6, Kazutaka Obama11, Yoshiharu Sakai11,12, Manabu Muto7, Tsutomu Chiba1,9, Seishi Ogawa2,3,13, Hiroshi Seno1. 1. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 2. Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 3. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan. 4. Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan. shmiyamo@kuhp.kyoto-u.ac.jp. 5. Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, 1-1 Fukakusa-Mukaihata-Cho, Fushimi, Kyoto, 612-8555, Japan. shmiyamo@kuhp.kyoto-u.ac.jp. 6. Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 7. Department of Therapeutic Oncology, Kyoto University Graduate School of Medicine, Kyoto, Japan. 8. Department of Gastroenterology, Osaka Red Cross Hospital, Osaka, Japan. 9. Department of Gastroenterology and Hepatology, Kansai Electric Power Hospital, Osaka, Japan. 10. Department of Pathology, Kansai Electric Power Hospital, Osaka, Japan. 11. Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. 12. Department of Surgery, Osaka Red Cross Hospital, Osaka, Japan. 13. Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
Abstract
BACKGROUND: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.
BACKGROUND: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.
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