胃底腺型胃癌の発育進展様式と発癌機序

Histological Characteristics of Neoplastic Progression and Molecular Changes in Gastric Adenocarcinoma of Fundic Gland Type

要旨●胃底腺型胃癌のβ-catenin核内標識率は浸潤に伴い増加し，胃底腺ポリープ，通常型胃癌より高く，Wnt/β-cateninシグナル伝達系関連遺伝子の変異はAXIN2（27％），CTNNB1（15％），PPP2R1A（9％）と胃底腺ポリープや通常型胃癌より高率で，さらに同伝達系関連のSFRP1，APC，AXIN2遺伝子のメチル化率（67〜89％）も胃底腺ポリープより高い．また，胃底腺型胃癌（粘膜下層浸潤癌）ではGNAS遺伝子変異（19％），Kras遺伝子変異（8％）を認めるが，胃底腺ポリープや通常型胃癌ではほとんどみられない．以上から，胃底腺型胃癌の発育進展には胃底腺ポリープや通常型胃癌とは異なるWnt系およびGTP結合蛋白関連シグナル伝達系の活性化が関与すると考えられる．

　GA-FG（gastric adenocarcinoma of fundic gland type）is a newly described, rare variant of gastric carcinoma with less aggressive biological behavior, and it is predominantly composed of chief cells with anisonucleosis. Nuclear β-catenin immunolabeling in GA-FG showed a stepwise increment from intramucosal tumors to submucosal invasive carcinoma, and was higher than those seen in fundic gland polyps or conventional gastric carcinomas. Analysis of members of the Wnt/β-catenin signaling pathway indicated that AXIN2, CTNNB1（the gene that encodes for β-catenin）, or PPP2R1A（protein phosphatase 2 regulatory protein 1A, the gene that encodes for protein phosphatase 2）were mutated in 27%, 15%, and 9% of GA-FG cases, respectively ; these frequencies were higher than those seen in fundic gland polyps or conventional gastric carcinomas. SFRP1（another gene member of the Wnt/β-catenin signal pathway）, APC, and AXIN2 were methylated in 67-89% of GA-FGs, which was higher than that seen in fundic gland polyps. Activating mutations in GNAS and Kras were detected in 19% and 8% of GA-FGs, respectively, whereas these mutations were found very rarely in fundic gland polyps or conventional gastric carcinomas. In line with these facts, it is possible that activation of both the Wnt/β-catenin signaling pathway and the GTP-binding protein-mediated signaling pathway is associated with the development and progression of GA-FG. Further studies are needed to elucidate the histological characteristics of neoplastic progression and molecular changes in GA-FG.