Department of Biopathology, Institut Bergonié, Comprehensive Cancer Center, Bordeaux, France.
Comprehensive Cancer Center, INSERM U1218, Institut Bergonié, Bordeaux, France.
Genes Chromosomes Cancer. 2019 Mar;58(3):155-163. doi: 10.1002/gcc.22694. Epub 2019 Jan 7.
Mutations of CTNNB1 have been implicated in tumorigenesis in many organs. However, tumors harboring a CTNNB1 translocation are extremely rare and this translocation has never been reported in a uterine mesenchymal neoplasm. We report a novel translocation t(2;3)(p25;p22) involving the GREB1 (intron 8) and CTNNB1 (exon 3) in a uterine tumor resembling ovarian sex cord tumor (UTROSCT), which exhibited extrauterine metastasis. The translocation detected by RNA-sequencing was validated by RT-PCR, and resulted in nuclear expression of β-catenin. Juxtapositioning with GREB1, which is overexpressed in response to estrogens, resulted in overexpression of a truncated and hypophosphorylated nuclear β-catenin in the primary and recurrent tumors. This accumulation of nuclear β-catenin results in a constitutive activation of the Wnt/β-catenin signaling pathway with a major oncogenic effect. The CTNNB1 gene fusion, promoted by an estrogen-responsive gene (GREB1), could be a potential driver of tumorigenesis in this case and a therapeutic target with adapted inhibitors. RT-PCR and immunohistochemistry performed on 11 additional UTROSCTs showed no CTNNB1 fusion transcript or nuclear β-catenin immunoreactivity.
CTNNB1 基因突变与许多器官的肿瘤发生有关。然而，携带 CTNNB1 易位的肿瘤极为罕见，这种易位从未在子宫间质肿瘤中报道过。我们报道了一种新的易位 t(2;3)(p25;p22)，涉及 GREB1（内含子 8）和 CTNNB1（外显子 3），发生在类似于卵巢性索肿瘤的子宫肿瘤（UTROSCT）中，该肿瘤表现出宫外转移。通过 RNA 测序检测到的易位通过 RT-PCR 得到了验证，并导致 β-连环蛋白的核表达。与 GREB1 并列，GREB1 受雌激素的过度表达，导致原发性和复发性肿瘤中截短和低磷酸化的核 β-连环蛋白过度表达。这种核 β-连环蛋白的积累导致 Wnt/β-连环蛋白信号通路的持续激活，具有主要的致癌作用。在这种情况下，由雌激素反应基因（GREB1）促进的 CTNNB1 基因融合可能是肿瘤发生的潜在驱动因素，也是一种具有适应性抑制剂的治疗靶点。对另外 11 例 UTROSCT 进行的 RT-PCR 和免疫组织化学分析显示，没有 CTNNB1 融合转录本或核 β-连环蛋白免疫反应性。
