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

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.

Testicular germ cell tumors type 2 have high RNA expression of LDHB,the gene for lactate dehydrogenase subunit B

This study analyzed RNA expression of genes for three serum tumor markers,alpha fetoprotein(AFP),human chorionic gonadotropin(hCG),and lactate dehydrogenase(LDH),in patients with testicular germ cell tumors(TGCT)type 2.The gene AFP encodes AFP,the gene for chorionic gonadotropin beta polypeptide 5(CGB5)encodes a major part of the specific beta subunit of hCG,and the genes for LDH subunit A(LDHA),LDH subunit B(LDHB),and LDH subunit C(LDHC)encode three different subunits of LDH.LDHB encodes the LDHB subunit present as a tetramer in LDH isoenzyme 1(LDH-1).We examined three datasets with 203 samples of normal testis tissue(NT)and TGCT type 2.Yolk sac tumor(YST)expressed RNA of AFP fourteen thousand times higher than seminoma(SE),embryonal carcinoma(EC),and teratoma(TER)combined(P=0.00015).In the second microarray,choriocarcinoma(CC)expressed RNA of CGB5 ten times higher than other histologic types of TGCT combined.EC expressed RNA of LDHB twice higher than SE,YST and TER combined(P=0.000041).EC expressed RNA of LDHB higher than that YST expressed RNA of AFP and that CC expressed RNA of CGB5.In conclusion,TGCT type 2 expressed RNA of LDHB markedly higher than the RNA of 23 other candidate genes for TGCT type 2.

Mechanisms of cisplatin sensitivity and resistance in testicular germ cell tumors

Testicular germ cell tumors(TGCTs)are a cancer pharmacology success story with a majority of patients cured even in the highly advanced and metastatic setting.Successful treatment of TGCTs is primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy.However,a significant percentage of patients are,or become,refractory to cisplatin and die from progressive disease.Mechanisms for both clinical hypersensitivity and resistance have largely remained a mystery despite the promise of applying lessons to the majority of solid tumors that are not curable in the metastatic setting.Recently,this promise has been heightened by the realization that distinct(and perhaps pharmacologically replicable)epigenetic states,rather than fixed genetic alterations,may play dominant roles in not only TGCT etiology and progression but also their curability with conventional chemotherapies.In this review,it discusses potential mechanisms of TGCT cisplatin sensitivity and resistance to conventional chemotherapeutics.

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

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.