URI1 amplification in uterine carcinosarcoma associates with chemo-resistance and poor prognosis.
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.
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.
Yu
Y
Wang
Department of Microbiology, New York University School of Medicine 550 First Avenue, MSB235, New York, NY 10016, USA.
Michael J
MJ
Garabedian
Department of Urology, New York University School of Medicine 550 First Avenue, MSB235, New York, NY 10016, USA ; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine 550 First Avenue, MSB235, New York, NY 10016, USA.
Susan K
SK
Logan
URI1; prognosis; survival; uterine carcinosarcoma