Deficiency of PTEN and CDKN2A Tumor-Suppressor Genes in Conventional and Chondroid Chordomas: Molecular Characteristics and Clinical Relevance.
常规和软骨样脊索瘤中 PTEN 和 CDKN2A 肿瘤抑制基因的缺乏: 分子特征和临床相关性。
- 作者列表："Yang C","Sun J","Yong L","Liang C","Liu T","Xu Y","Yang J","Liu X
Introduction:Chordoma is a malignant tumor predominantly involving the skull base and vertebral column. This study aimed to investigate the molecular characteristics of PTEN and CDKN2A in conventional and chondroid chordomas and their correlation with clinical prognosis. Materials and Methods:A total of 42 patients were enrolled, including 26 patients with conventional chordoma and 16 patients with chondroid chordoma. Clinicopathological profiles and tissue specimens were collected. Gene sequencing and fluorescence in situ hybridization were performed to identify genetic alterations in the PTEN and CDKN2A genes. Immunohistochemical staining was used for semiquantitative evaluation of PTEN and CDKN2A expression. Results:Gene sequencing revealed an intron SNP (c.80-96A>G) and a missense mutation (c.10G>A; p.Gly4Arg) in the PTEN gene and a missense mutation (c.442G>A; p.Ala148Thr) in the CDKN2A gene. Loss of the PTEN locus was identified in 25 (59.5%) cases, and loss of the CDKN2A locus was found in 28 (66.7%) cases. There was no significant correlation between progression-free survival (PFS)/overall survival (OS) and loss of PTEN or CDKN2A. The patients with lower PTEN expression showed significantly shorter PFS and OS than those with higher expression, while there was no significant difference in PFS or OS between patients with lower CDKN2A expression and those with higher CDKN2A expression. Conclusion:Our findings delineated the genetic landscape and expression of PTEN and CDKN2A in chordomas. PTEN expression may serve as a prognostic and predictive biomarker for chordomas.
导读: 脊索瘤是一种主要累及颅底和脊柱的恶性肿瘤。本研究旨在探讨 PTEN 和 CDKN2A 在常规和软骨样脊索瘤中的分子特征及其与临床预后的相关性。 材料与方法: 共纳入 42 例患者，其中常规脊索瘤 26 例，软骨样脊索瘤 16 例。收集临床病理特征和组织标本。进行基因测序和荧光原位杂交，鉴定 PTEN 和 CDKN2A 基因的遗传改变。采用免疫组织化学染色半定量评价 PTEN 和 CDKN2A 的表达。 结果: 基因测序发现一个内含子 SNP (c.80-96A>G) 和一个错义突变 (c.10G> a; p。gly4Arg) 在 PTEN 基因和一个错义突变 (c.442G> a; p.CDKN2A 基因中的 Ala148Thr)。25 例 (59.5%) 发现 PTEN 位点缺失，28 例 (66.7%) 发现 CDKN2A 位点缺失。无进展生存期 (PFS)/总生存期 (OS) 与 PTEN 或 CDKN2A 缺失之间无显著相关性。PTEN 低表达的患者 PFS 和 OS 明显短于高表达的患者,而 CDKN2A 低表达患者与 CDKN2A 高表达患者的 PFS 或 OS 无显著差异。 结论: 我们的研究结果描绘了脊索瘤中 PTEN 和 CDKN2A 的遗传景观和表达。PTEN 表达可能作为脊索瘤的预后和预测生物标志物。
METHODS:BACKGROUND:Osteosarcoma is the most common primary bone malignancy in children and adolescents. In order to find factors related to its recurrence, and thus improve recovery prospects, a powerful clinical signature is needed. Long noncoding RNAs (lncRNAs) are essential in osteosarcoma processes and development, and here we report significant lncRNAs to aid in earlier diagnosis of osteosarcoma. METHODS:A univariate Cox proportional hazards regression analysis and a multivariate Cox regression analysis were used to analyze osteosarcoma patients' lncRNA expression data from the Therapeutically Applicable Research To Generate Effective Treatments (TARGET), a public database. RESULTS:A lncRNA signature consisting of three lncRNAs (RP1-261G23.7, RP11-69E11.4 and SATB2-AS1) was selected. The signature was used to sort patients into high-risk and low-risk groups with meaningful recurrence rates (median recurrence time 16.80 vs. >128.22 months, log-rank test, P143.80 months, log-rank test, P=0.006). A multivariate Cox regression analysis showed that the significant lncRNA was an independent prognostic factor for osteosarcoma patients. Functional analysis suggests that these lncRNAs were related to the PI3K-Akt signaling pathway, the Wnt signaling pathway, and the G-protein coupled receptor signaling pathway, all of which have various, important roles in osteosarcoma development. The significant 3-lncRNA set could be a novel prediction biomarker that could aid in treatment and also predict the likelihood of recurrence of osteosarcoma in patients.
METHODS::Long non-coding RNAs (lncRNAs) regulates the initiation and progression of osteosarcoma (OS), specifically lncRNA RP11-361F15.2 has been shown to play prominent roles in tumorigenesis. Previously, M2-Like polarization of tumor-associated macrophages (TAMs) has been identified to play a key role in cancer migration/invasion. Hence, it is essential to understand the role of RP11-361F15.2 in tumorigenesis and its association with M2-Like polarization of TAMs. The results indicate that RP11-361F15.2 is significantly increased in OS tissues, and its expression is positively correlated with cytoplasmic polyadenylation element binding protein 4 (CPEB4) expression and negatively associated with miR-30c-5p expression. Further, overexpression of RP11-361F15.2 increased OS cell migration/invasion and M2-Like polarization of TAMs in vitro, as well as promoted xenograft tumor growth in vivo. Mechanistically, luciferase reporter assays indicated that RP11-361F15.2 upregulated CPEB4 expression by competitively binding to miR-30c-5p. Further, we have identified that RP11-361F15.2 promotes CPEB4-mediated tumorigenesis and M2-Like polarization of TAMs through miR-30c-5p in OS. We also identified that RP11-361F15.2 acts as competitive endogenous RNA (ceRNA) against miR-30c-5p thereby binding and activating CPEB4. This RP11-361F15.2/miR-30c-5p/CPEB4 loop could be used as a potential therapeutic strategy for the treatment of OS.
METHODS:PURPOSE:The objective of this study was to investigate potential correlations between pathologic fractures (PFs) and prognosis of patients with primary central high-grade osteosarcoma of the extremities. METHODS:We retrospectively analyzed 2,847 patients registered in the Consecutive Cooperative Osteosarcoma Study Group database with primary central high-grade osteosarcoma of the extremities, treated between 1980 and 2010. Intended treatment included pre- and postoperative chemotherapy and surgery. Univariable and multivariable survival analyses were performed for all patients and then differentiated for adult and pediatric (≤ 18 years at time of diagnosis) patients. RESULTS:A total of 2,193 patients were ≤ 18 years of age; 11.3% of all patients had PFs. In the overall cohort, presence of PF correlated significantly with tumor site, histologic subtype, relative tumor size, and primary metastases, but not with body mass index or local surgical remission. In univariable analysis, 5-year overall survival (OAS) of patients with and without PF was 63% versus 71%, respectively (P = .007), and 5-year event-free survival (EFS) was 51% versus 58% (P = .026). In pediatric patients, OAS and EFS did not differ significantly between patients with and without PF. In adults, 5-year OAS in patients with and without PF was 46% versus 69% (P < .001), and 5-year EFS was 36% versus 56% (P < .001). In multivariable analysis, PF was not a statistically significant factor for OAS or EFS in the total cohort or in pediatric patients. In adult patients, PF remained an independent prognostic factor for OAS (P = .013; hazard ratio [HR], 1.893). It was not a significant prognostic factor for EFS (P = .263; HR, 1.312). CONCLUSION:In this largest study to date with extremity osteosarcomas, we observed the occurrence of PF to correlate with inferior OAS expectancies in adult but not in pediatric patients.