Jiang Yunyun, Janku Filip, Subbiah Vivek, Angelo Laura S, Naing Aung, Anderson Peter M, Herzog Cynthia E, Fu Siqing, Benjamin Robert S, Kurzrock Razelle
Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Oncotarget. 2013 Jun;4(6):884-9. doi: 10.18632/oncotarget.1021.
Ewing sarcoma occurs in children, adolescents and young adults. High STAT3 levels have been reported in approximately 50% of patients with Ewing sarcoma, and may be important in tumorigenesis. Protein tyrosine phosphatase delta (PTPRD) is a tumor suppressor that inhibits STAT3 activation. To date, while somatic mutations in PTPRD have been reported in diverse tumors, germline mutations of PTPRD have not been investigated in Ewing sarcoma or other cancers. We identified a novel germline mutation in the PTPRD gene in three of eight patients (37.5%) with metastatic Ewing sarcoma. Although the functional impact in two of the patients is unclear, in one of them the aberration was annotated as a W775stop germline mutation, and would be expected to lead to gene truncation and, hence, loss of the STAT3 dephosphorylation function of PTPRD. Since STAT3 is phosphorylated after being recruited to the insulin growth factor receptor (IGF-1R), suppression of IGF-1R could attenuate the enhanced STAT3 activation expected in the presence of PTPRD mutations. Of interest, two of three patients with germline PTPRD mutations achieved durable complete responses following treatment with IGF-1R monoclonal antibody-based therapies. Our pilot data suggest that PTPRD germline mutations may play a role in the development of Ewing sarcoma, a disease of young people, and their presence may have implications for therapy.
尤因肉瘤发生于儿童、青少年和青年成人。据报道，约50%的尤因肉瘤患者STAT3水平较高，其可能在肿瘤发生过程中起重要作用。蛋白酪氨酸磷酸酶δ（PTPRD）是一种抑制STAT3激活的肿瘤抑制因子。迄今为止，虽然在多种肿瘤中已报道了PTPRD的体细胞突变，但尚未在尤因肉瘤或其他癌症中研究PTPRD的种系突变。我们在8例转移性尤因肉瘤患者中的3例（37.5%）中鉴定出PTPRD基因的一种新的种系突变。虽然其中2例患者的功能影响尚不清楚，但其中1例的畸变被注释为W775stop种系突变，预计会导致基因截短，从而导致PTPRD的STAT3去磷酸化功能丧失。由于STAT3在被招募到胰岛素生长因子受体（IGF-1R）后被磷酸化，抑制IGF-1R可减弱在存在PTPRD突变时预期的增强的STAT3激活。有趣的是，3例种系PTPRD突变患者中有2例在接受基于IGF-1R单克隆抗体的治疗后实现了持久的完全缓解。我们的初步数据表明，PTPRD种系突变可能在尤因肉瘤（一种年轻人的疾病）的发生发展中起作用，其存在可能对治疗有影响。
