Yamashiro Yuya, Yanai Yuka, Takeda Tsutomu, Hayashi Takuo, Akazawa Yoichi, Yatagai Noboru, Ueyama Hiroya, Eguchi Hidetaka, Nagahara Akihito, Yao Takashi, Saito Tsuyoshi
Department of Human Pathology Juntendo University School of Medicine Tokyo Japan.
Department of Gastroenterology Juntendo University School of Medicine Tokyo Japan.
JGH Open. 2022 Jun 28;6(8):531-538. doi: 10.1002/jgh3.12781. eCollection 2022 Aug.
Juvenile polyposis (JP) is a rare disease known to be associated with mutations either in /. JP is known to often develop into malignant tumors, with a reported probability of 9-50%. However, the mechanisms of its carcinogenesis are not fully understood. We tried to elucidate the mechanisms of malignant transformation underlying this condition in three cases of gastric JP.
We selected polyps from each patient displaying varying degrees of atypia and their nearby normal polyps and compared them using immunohistochemistry, Sanger sequencing, and loss of heterozygosity (LOH) analysis of , , and
Two of the three cases were suspected of having germline mutations based on their familial medical histories; the remaining case was found to have a germline mutation following preoperative genetic testing. All three cases were shown to present with both SMAD4 positive and negative areas across each lesion, with the neoplastic lesions tending to show stronger nuclear SMAD4 expression. This expression was closely associated with the LOH status; however, we also noted paradoxical SMAD4 expression in the neoplastic lesions despite the biallelic inactivation of revealed in the genetic evaluation.
These data suggest that strong nuclear expression of SMAD4, even when seemingly paradoxical, seems to be closely associated with dysplastic polyps in JP. Complete inactivation of was not shown to be essential for the development of dysplastic polyps in gastric JP, and other pathways seemed to be involved in the acquisition of the malignant phenotype.
青少年息肉病（JP）是一种罕见疾病，已知与/中的突变相关。JP常发展为恶性肿瘤，报道的概率为9% - 50%。然而，其致癌机制尚未完全明确。我们试图在3例胃JP病例中阐明这种情况潜在的恶性转化机制。
我们从每位患者中选取显示不同程度异型性的息肉及其附近的正常息肉，并使用免疫组织化学、桑格测序以及对、和进行杂合性缺失（LOH）分析来进行比较。
根据家族病史，3例中有2例怀疑存在种系突变；术前基因检测发现其余1例存在种系突变。所有3例病变在每个病灶中均显示出SMAD4阳性和阴性区域，肿瘤性病变往往显示出更强的核SMAD4表达。这种表达与LOH状态密切相关；然而，尽管基因评估显示双等位基因失活，但我们在肿瘤性病变中也注意到了矛盾的SMAD4表达。
这些数据表明，即使看似矛盾，SMAD4的强核表达似乎与JP中的发育异常息肉密切相关。在胃JP中，完全失活对于发育异常息肉的发生并非必不可少，其他途径似乎也参与了恶性表型的获得。
