Human Cancer Genomic Research, Research Centre, King Faisal Specialist Hospital and Research Centre, MBC#98-16, P.O. Box 3354, 11211, Riyadh, Saudi Arabia.
Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Sci Rep. 2023 Oct 29;13(1):18559. doi: 10.1038/s41598-023-45882-x.
Papillary Thyroid Cancer (PTC) is the most common type of thyroid cancer. The membrane-associated glycoprotein cadherin-16 (CDH16) plays a significant role in the embryonal development of thyroid follicles and cell adhesion. Previous studies have indicated a substantial downregulation of CDH16 in PTC. However, its role in Middle Eastern PTC has not been elucidated. We analyzed a tissue microarray comprising 1606 PTC and 240 normal thyroid tissues using immunohistochemistry to assess CDH16 expression and determine its clinico-pathological associations. We also conducted BRAF and TERT mutations analyses through Sanger sequencing. Disease-free survival (DFS) was assessed using Kaplan-Meier curves. CDH16 immunostaining was seen in 100% of normal thyroid tissues but only in 9.4% of PTC tissues (p < 0.0001). The loss of CDH16 expression was associated with aggressive PTC characteristics including bilaterality, multifocality, extrathyroidal extension, tall cell variant, lymph node metastasis (LNM) and distant metastasis. Additionally a correlation between loss of CDH16 expression and BRAF and TERT mutations was identified. Intriguingly, upon conducting multivariate logistic regression analysis, CDH16 was determined to be an independent predictor for LNM (Odds ratio = 2.46; 95% confidence interval = 1.60-3.79; p < 0.0001). Furthermore, CDH16 loss was associated with a shorter DFS (p = 0.0015). However, when we further subdivided CDH16 negative patients based on the co-existence of TERT and/or BRAF mutations, we found that patients with both CDH16 negative expression and TERT mutation exhibited the shortest DFS (p < 0.0001). In conclusion, our results suggest that CDH16 protein expression could serve as a valuable diagnostic tool for PTC. Furthermore, these findings demonstrate that the loss of CDH16 expression is an independent predictor of LNM and may contribute to the aggressiveness of PTC. Therefore, downregulation of CDH16 in PTC might be a potential target for designing novel therapeutic strategies to treat PTC.
甲状腺乳头状癌（PTC）是最常见的甲状腺癌类型。膜相关糖蛋白钙黏蛋白-16（CDH16）在甲状腺滤泡的胚胎发育和细胞黏附中起着重要作用。先前的研究表明，CDH16 在 PTC 中显著下调。然而，其在中东 PTC 中的作用尚未阐明。我们使用免疫组织化学分析了包含 1606 例 PTC 和 240 例正常甲状腺组织的组织微阵列，以评估 CDH16 的表达并确定其与临床病理的关联。我们还通过 Sanger 测序进行了 BRAF 和 TERT 突变分析。通过 Kaplan-Meier 曲线评估无病生存（DFS）。CDH16 免疫染色在 100%的正常甲状腺组织中可见，但仅在 9.4%的 PTC 组织中可见（p<0.0001）。CDH16 表达缺失与侵袭性 PTC 特征相关，包括双侧性、多灶性、甲状腺外延伸、高细胞变体、淋巴结转移（LNM）和远处转移。此外，还发现 CDH16 表达缺失与 BRAF 和 TERT 突变之间存在相关性。有趣的是，进行多变量逻辑回归分析后，CDH16 被确定为 LNM 的独立预测因子（比值比=2.46；95%置信区间=1.60-3.79；p<0.0001）。此外，CDH16 缺失与较短的 DFS 相关（p=0.0015）。然而，当我们根据 TERT 和/或 BRAF 突变的共存进一步细分 CDH16 阴性患者时，我们发现同时存在 CDH16 阴性表达和 TERT 突变的患者DFS 最短（p<0.0001）。总之，我们的结果表明 CDH16 蛋白表达可作为 PTC 的有价值的诊断工具。此外，这些发现表明 CDH16 表达缺失是 LNM 的独立预测因子，并可能导致 PTC 的侵袭性。因此，PTC 中 CDH16 的下调可能是设计治疗 PTC 的新型治疗策略的潜在靶点。
