Open AccessMolecular and clinicopathological analysis of three cases of gastric juvenile polyposis
Author(s) -
Yamashiro Yuya,
Yanai Yuka,
Takeda Tsutomu,
Hayashi Takuo,
Akazawa Yoichi,
Yatagai Noboru,
Ueyama Hiroya,
Eguchi Hidetaka,
Nagahara Akihito,
Yao Takashi,
Saito Tsuyoshi
Publication year - 2022
Publication title -
jgh open
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.546
H-Index - 8
ISSN - 2397-9070
DOI - 10.1002/jgh3.12781
Subject(s) - loss of heterozygosity , sanger sequencing , germline mutation , biology , germline , carcinogenesis , pathology , malignant transformation , atypia , immunohistochemistry , phenotype , neoplastic transformation , lesion , mutation , cancer research , cancer , genetics , allele , medicine , immunology , gene
Background and Aim Juvenile polyposis (JP) is a rare disease known to be associated with mutations either in SMAD4 / BMPR1A . 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. Methods 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 SMAD4 , BMPR1A , and TP53.Results Two of the three cases were suspected of having germline SMAD4 mutations based on their familial medical histories; the remaining case was found to have a SMAD4 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 SMAD4 LOH status; however, we also noted paradoxical SMAD4 expression in the neoplastic lesions despite the biallelic inactivation of SMAD4 revealed in the genetic evaluation. Conclusions 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 SMAD4 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.