Copy Number Analysis of 24 Oncogenes: MDM4 Identified as  a Putative Marker for Low Recurrence Risk in Non Muscle Invasive Bladder Cancer

Salvi, Samanta; Calistri, Daniele; Gurioli, Giorgia; Carretta, Elisa; Serra, Luigi; Gunelli, Roberta; Zoli, Wainer; Casadio, Valentina

doi:10.3390/ijms150712458

Cited by 13 publications

(11 citation statements)

References 23 publications

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“…Recently, molecular classifications have emerged from high-throughput analyses (7)(8)(9)(10)(11). Specific molecular pathways and potential new target genes not previously described in bladder carcinogenesis have been identified (12)(13)(14)(15). Alterations in coding regions are now being described in bladder cancer as in various other tumor types (16,17).…”

Section: Introductionmentioning

confidence: 99%

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer

Garinet

Pignot

Vacher

et al. 2019

Molecular Cancer Research

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Numerous pangenomic studies identified protein-coding genes and signaling pathways involved in bladder carcinogenesis. However, noncoding somatic alterations remain unexplored. A recent study revealed a mutational hotspot in intron 6 of GPR126 gene in 2.7% of a large breast cancer series. As GPR126 is highly expressed in bladder tissues, we investigated here the prevalence and the prognostic significance of these mutations in bladder cancer. We analyzed a cohort of 103 bladder cancers including 44 nonmuscle-invasive bladder cancers (NMIBC) and 59 muscle-invasive bladder cancers (MIBC). GPR126 mutations were analyzed by high-resolution melting and Sanger sequencing, and GPR126 expression levels were assessed using real-time quantitative RT-PCR. In NMIBC, somatic GPR126 noncoding mutations occurred in 47.7% of samples and were negatively associated with GPR126 mRNA levels. GPR126 mutations had higher frequencies in nonsmok-er patients and were associated with a prior history of NMIBC. GPR126 overexpression was detected in 70.5% of samples. GPR126 mutation and overexpression status were not associated with outcome. In MIBC, somatic GPR126 mutations occurred in 44.1% of samples. Mutations were more frequent in females. GPR126 overexpression was detected in 27.1% of the sample. A trend toward significance was observed between GPR126 overexpression and better outcome. We identified the second most frequent mutational hotspot after TERT promoter ($70%) in bladder cancer, with a mutation rate of approximately 50%.Implications: The GPR126 intronic mutational hotspot could be a promising clinical biomarker candidate to monitor tumor burden using circulating tumor DNA in bladder cancer.

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Section: Introductionmentioning

confidence: 99%

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer

Garinet

Pignot

Vacher

et al. 2019

Molecular Cancer Research

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“…In addition to TCGA data, recent articles have highlighted previously unknown genetic alterations in bladder cancer. MDM4 was described as a prognostic marker of recurrence in NMIBC 5 . TACC3 and FGFR3 can form a fusion gene, described in some cancers 1 , 4 , 6 .…”

Section: Methodsmentioning

confidence: 99%

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

Goux

Vacher

Schnitzler

et al. 2020

Sci Rep

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This study evaluated the prognostic value of a panel of 29 oncogenes derived from the analysis of The Cancer Genome Atlas (TCGA data) or from the recent literature on bladder tumors on a well-characterized series of muscle-invasive bladder cancer (MIBC) and non-MIBC (NMIBC) samples and tried to identify molecular prognostic markers. Mutations of HRAS, FGFR3, PIK3CA and TERT were found in 2.9%, 27.2%, 14.9% and 76.7% of tumor samples, respectively. Concerning NMIBC, on multivariate analysis, RXRA and FGFR3 levels were associated with recurrence-free survival (RFS) (p = 0.0022 and p = 0.0069) and RXRA level was associated with progression to muscle-invasive disease (p = 0.0068). We identified a 3-gene molecular signature associated with NMIBC prognosis. FGFR3 overexpression was associated with reduced response to Bacillus Calmette–Guerin treatment (p = 0.037). As regards MIBC, on multivariate analysis, ERCC2 overexpression was associated with RFS (p = 0.0011) and E2F3 and EGFR overexpression were associated with overall survival (p = 0.014 and p = 0.035). RT-PCR findings were confirmed by IHC for FGFR3. Genomic alterations in MIBC revealed in TCGA data also concern NMIBC and seem to be associated with prognosis in terms of recurrence and progression. Correcting these alterations by targeted therapies seems a promising pharmacological approach.

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“…The amplification and overexpression of MDMX have also been observed in bladder cancer and has been implicated in high-grade and invasive disease ( 70 ). Interestingly, MDMX amplification is significantly associated with low recurrence risk in bladder cancer and predicts better recurrence-free survival of patients with this disease ( 71 ). Besides, the amplification and high-level expression of MDMX has been reported in subtypes of liver cancer, i.e., hepatoblastoma and fibrolamellar hepatocellular carcinoma, but the clinical relevance of these findings in liver cancer is not yet clear ( 72 , 73 ).…”

Section: Amplification and Overexpression Of Mdmx In Human Cancer Andmentioning

confidence: 99%

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

et al. 2020

Front. Oncol.

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The oncogene MDMX, also known as MDM4 is a critical negative regulator of the tumor suppressor p53 and has been implicated in the initiation and progression of human cancers. Increasing evidence indicates that MDMX is often amplified and highly expressed in human cancers, promotes cancer cell growth, and inhibits apoptosis by dampening p53-mediated transcription of its target genes. Inhibiting MDMX-p53 interaction has been found to be effective for restoring the tumor suppressor activity of p53. Therefore, MDMX is becoming one of the most promising molecular targets for developing anticancer therapeutics. In the present review, we mainly focus on the current MDMX-targeting strategies and known MDMX inhibitors, as well as their mechanisms of action and in vitro and in vivo anticancer activities. We also propose other potential targeting strategies for developing more specific and effective MDMX inhibitors for cancer therapy.

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Copy Number Analysis of 24 Oncogenes: MDM4 Identified as a Putative Marker for Low Recurrence Risk in Non Muscle Invasive Bladder Cancer

Cited by 13 publications

References 23 publications

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer

High Prevalence of a Hotspot of Noncoding Somatic Mutations in Intron 6 of GPR126 in Bladder Cancer

Assessment of prognostic implication of a panel of oncogenes in bladder cancer and identification of a 3-gene signature associated with recurrence and progression risk in non-muscle-invasive bladder cancer

Targeting MDMX for Cancer Therapy: Rationale, Strategies, and Challenges

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