Wang Yu, Garabedian Michael J, Logan Susan K
Department of Urology, New York University School of Medicine 550 First Avenue, MSB235, New York, NY 10016, USA ; Department of Microbiology, New York University School of Medicine 550 First Avenue, MSB235, New York, NY 10016, USA.
Department of Microbiology, New York University School of Medicine 550 First Avenue, MSB235, New York, NY 10016, USA.
Am J Cancer Res. 2015 Jun 15;5(7):2320-9. eCollection 2015.
Uterine carcinosarcoma (UCS) is a rare type of cancer and accounts for 5% of uterine malignancies. However, UCS patients suffer a high prevalence of chemo-resistance and a very poor prognosis compared to uterine cancer patients. URI is a chaperone with functions in transcription. We analyzed the somatic URI1 copy number variation in 57 post-menopausal non-metastatic UCS patients in comparison to 363 uterine corpus endometrial carcinomas. URI1 amplification was detected in 40% (23/57) of primary UCS and 5.5% (20/363) of uterine carcinomas. UCS patients with URI1 amplification exhibited 13% (3/23) tumor-free survival compared to 41% (14/34) in the absence of URI amplification (P=0.023). URI1 amplification (OR=6.54, P=0.027), weight (OR=1.068, P=0.024), hypertension (OR=3.35, P=0.044), and tumor stage (OR=2.358, P=0.018) associated with poor survival. Patients treated with hormone replacement therapy (OR=15.87, P=0.011) displayed enhanced overall survival. Combined radiation and chemotherapy improved patient survival (median survival=2043 days) compared to single (median survival=597 days) or no treatment (median survival=317 days, P=0.0016). Importantly, patients with URI1 amplification had poor response to adjuvant treatment compared to control group (P=0.013). Tumors with URI1 amplification displayed decreased transcription of genes encoding tumor suppressor and apoptotic regulators and increased expression of genes regulating oncogenesis, survival and metastasis. Overexpression of URI1 in a cultured cell model induced ATM expression and resistance to cisplatin. Our findings suggest that high prevalence in UCS may associate with poor prognosis and worse response to adjuvant treatment.
子宫癌肉瘤（UCS）是一种罕见的癌症类型，占子宫恶性肿瘤的5%。然而，与子宫癌患者相比，UCS患者化疗耐药的发生率很高，预后很差。URI是一种在转录过程中发挥作用的伴侣蛋白。我们分析了57例绝经后非转移性UCS患者与363例子宫体子宫内膜癌患者的体细胞URI1拷贝数变异情况。在40%（23/57）的原发性UCS患者和5.5%（20/363）的子宫癌患者中检测到URI1扩增。与未发生URI扩增的患者相比，发生URI1扩增的UCS患者无瘤生存率为13%（3/23），而未扩增患者为41%（14/34）（P=0.023）。URI1扩增（OR=6.54，P=0.027）、体重（OR=1.068，P=0.024）、高血压（OR=3.35，P=0.044）和肿瘤分期（OR=2.358，P=0.018）与生存不良相关。接受激素替代治疗的患者（OR=15.87，P=0.011）总体生存率提高。与单一治疗（中位生存期=597天）或未治疗（中位生存期=317天，P=0.0016）相比，联合放疗和化疗可提高患者生存率（中位生存期=2043天）。重要的是，与对照组相比，发生URI1扩增的患者对辅助治疗反应较差（P=0.013）。发生URI1扩增的肿瘤显示编码肿瘤抑制因子和凋亡调节因子的基因转录减少，而调节肿瘤发生、生存和转移的基因表达增加。在培养细胞模型中过表达URI1可诱导ATM表达并产生顺铂耐药性。我们的研究结果表明，UCS中URI1的高发生率可能与预后不良及辅助治疗反应较差有关。
