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Characterization of progression-related alternative splicing events in testicular germ cell tumors

Asian Journal of Andrology 2021年第3期23卷 259-265页

作者： Chuan-Jie Zhang Zong-Tai Li Kan-Jie Shen Lu Chen Dan-Feng Xu Yi Gao Department of Urinary Surgery Ruijin HospitalShanghai Jiaotong University School of MedicineShanghai 200025China Department of Medical Oncology Gaozhou People's HospitalGaozhou 525200China First Clinical Medical College of Nanjing Medical University Nanjing 210000China

Accumulating evidence supports the significance of aberrant alternative splicing(AS)events in cancer;however,genome-wide profiling of progression-free survival(PFS)-related AS events in testicular germ cell tumors(TGCT)has not been reported.Here,we analyzed high-throughput RNA-sequencing data and percent-spliced-in values for 150 patients with TGCT.Using univariate and multivariate Cox regression analysis and a least absolute shrinkage and selection operator method,we identified the top 15 AS events most closely associated with disease progression.A risk-associated AS score(ASS)for the 15 AS events was calculated for each patient.ASS,pathological stage,and T stage were significantly associated with disease progression by univariate analysis,but only ASS and pathological stage remained significant by multivariate analysis.The ability of these variables to predict 5-year progression was assessed using receiver operating characteristic curve analysis.ASS had stronger predictive value than a combination of age,pathological stage,and T stage(area under the curve=0.899 and 0.715,respectively).Furthermore,Kaplan—Meier analysis of patients with low and high ASS demonstrated that high ASS was associated with significantly worse PFS than low ASS(P=1.46 × 10^(-7)).We also analyzed the biological functions of the PFS-related AS-related genes and found enrichment in pathways associated with DNA repair and modification.Finally,we identified a regulatory network of splicing factors with expression levels that correlated significantly with AS events in TGCT.Collectively,this study identifies a novel method for risk stratification of patients and provides insight into the molecular events underlying TGCT.

关键词： alternative splicing events network progression-free survival-related model testicular germ cell tumor

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Low hypoxia inducible factor-1α(HIF-1α)expression in testicular germ cell tumors--a major reason for enhanced chemosensitivity?

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Chinese Journal of Cancer Research 2017年第4期29卷 374-378页

作者： niraj shenoy roxana dronca fernando quevedo stephen a boorjian john cheville brian costello manish kohli thomas witzig lance pagliaro division of oncology mayo clinicRochesterMN 55905usa department of urology mayo clinicRochesterMN 55905usa division of clinical pathology mayo clinicRochesterMN 55905usa

The molecular basis for enhanced chemosensitivity of testicular germ cell tumors （GCT） has been an area of great interest, as it could potentially give us therapeutic leads in other resistant malignancies. Thus far, however, the increased sensitivity of C＆T has been variously attributed to multiple factors -- an inability to detoxify cisplatin, a lack of export pumps, an inability to repair the DNA damage, an intact apoptotic cascade and lack of p53 mutation; but a unifying underlying etiology leading to the aforementioned processes and having a translational implication has so far been elusive. Herein, we offer evidence to support a potential significant role for the previously demonstrated low hypoxia inducible factor-la （HIF-la） expression in mediating the general exquisite chemosensitivity of testicular GCT, through the aforementioned processes. This molecular mechanism based hypothesis could have a significant translational implication in platinum refractory GCT as well as other platinum resistant malignancies.

关键词： Hypoxia inducible factor-la （HIF-la） testicular germ cell tumor chemosensitivity

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