Tumor Biology and Immunology PhD Program, Department of Basic Oncology, Hacettepe University Cancer Institute, Sıhhiye, 06100, Ankara, Turkey.
Stem Cell Sciences PhD Program, Department of Stem Cell, Hacettepe University Faculty of Sciences, Sıhhiye, 06100, Ankara, Turkey.
Virchows Arch. 2021 Oct;479(4):747-754. doi: 10.1007/s00428-021-03064-y. Epub 2021 Mar 1.
Sclerosing angiomatoid nodular transformation (SANT) is a rare vascular lesion of the spleen. Although several hypotheses have been suggested, the etiopathogenesis of SANT remains unknown. It is also unclear whether SANT is a reactive or a neoplastic lesion. Since CTNNB1 (β-catenin gene) exon 3 mutations were frequently detected in some rare fibrovascular lesions, we aimed to investigate the presence of oncogenic CTNNB1 mutations in SANT cases. For this purpose, 7 cases of SANT with typical histopathological features were retrieved. First, the presence of CTNNB1 exon 3 alterations was examined with a recently described immunohistochemistry-based method. Then, the findings were confirmed with polymerase chain reaction (PCR), reverse transcription PCR (RT-PCR), and Sanger sequencing. In all cases, immunochemistry of β-catenin gave a staining pattern that was suggestive of exon 3 alteration; however, no missense mutations were found in any case at the CTNNB1 exon 3 hotspot region. Subsequently, we screened for large interstitial deletions of CTNNB1 exon 3 which revealed short PCR products in three cases. Sequencing confirmed that these cases had large interstitial deletions, resulting in loss of the entire exon 3 of CTNNB1. In the remaining four cases, loss of exon 3 was documented at the cDNA level, although genomic deletion was not identified. These results demonstrate that loss of CTNNB1 exon 3 and stabilization of β-catenin with activation of Wnt signaling pathway might have a significant role in the pathogenesis of SANT. Through this study, we provided important evidence for the neoplastic nature and pathogenesis of this disorder.
硬化性血管样结节性转化（SANT）是一种罕见的脾脏血管病变。尽管已经提出了几种假说，但 SANT 的病因仍然未知。SANT 是否是反应性还是肿瘤性病变也不清楚。由于 CTNNB1（β-连环蛋白基因）外显子 3 突变在一些罕见的纤维血管病变中经常被检测到，我们旨在研究 SANT 病例中是否存在致癌 CTNNB1 突变。为此，我们检索了 7 例具有典型组织病理学特征的 SANT 病例。首先，使用最近描述的一种基于免疫组织化学的方法检查 CTNNB1 外显子 3 改变的存在。然后，通过聚合酶链反应（PCR）、逆转录 PCR（RT-PCR）和 Sanger 测序来确认结果。在所有病例中，β-连环蛋白免疫化学染色模式提示外显子 3 改变；然而，在 CTNNB1 外显子 3 热点区域的任何病例中均未发现错义突变。随后，我们筛选 CTNNB1 外显子 3 的大片段缺失，在 3 例中发现短 PCR 产物。测序证实这些病例存在大片段缺失，导致 CTNNB1 外显子 3 完全缺失。在其余 4 例中，虽然未检测到基因组缺失，但在 cDNA 水平上记录了外显子 3 的缺失。这些结果表明，CTNNB1 外显子 3 的缺失和 β-连环蛋白的稳定以及 Wnt 信号通路的激活可能在 SANT 的发病机制中起重要作用。通过这项研究，我们为该疾病的肿瘤性质和发病机制提供了重要证据。
