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Therapy-relevant MDM2 amplification in cholangiocarcinomas in Caucasian patients
Su Ir Lyu1, Patrick Sven Plum2, Caroline Fretter3
1Faculty of Medicine and University Hospital of Cologne, Institute of Pathology, University of Cologne, Kerpener Str. 62, Cologne 50937, Germany.
Background:
Cholangiocarcinomas (CCA) are a group of aggressive malignancies with poor prognosis. The distinct subtypes are related to different etiologies and genetic aberrations that are subject to targeted therapies. Mouse double minute 2 homolog (MDM2) is a potent inhibitor of tumor suppressor p53 and is proven to be altered in certain carcinomas. Novel targeted drugs, such as the MDM2-p53 antagonist Brigimadlin, have shown promising results for therapeutic efficacy in patients with MDM2 amplification and wild-type TP53.
Objectives:
This study therefore aimed to characterize CCAs regarding their MDM2 status, compare the concordance between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods, and elucidate the role of MDM2 amplification in prognosis and other clinicopathological characteristics.
Design:
Retrospective cohort study.
Methods:
All patients (n = 52) were diagnosed with CCA and received surgical resection with curative intention at the University Hospital of Cologne. Samples were analyzed retrospectively for MDM2 amplification with FISH and IHC. We correlated results with pre-existing molecular as well as clinical data.
Results:
We included 52 patients with primary CCA, three of which showed positive MDM2 amplification (5.8%). MDM2 amplification was present only in the intrahepatic CCA type and all patients with positive MDM2 amplification exhibited normal p53 status. Among the large-duct subtypes of intrahepatic CCAs, patients with positive MDM2 amplification demonstrated better survival than patients with negative MDM2 amplification (p = 0.041). Of the patients with MDM2 amplification, two underwent adjuvant therapy post-surgery (66.7%). There was a strong correlation between MDM2 amplification and positive protein expression in IHC. There were no identifiable molecular co-alterations of MDM2 with FGFR2 or SWI/SNF complex alterations.
Conclusion:
Real-world evidence in our Caucasian patient population confirmed that a significant number of intrahepatic CCAs showcase MDM2 amplification, qualifying for a personalized therapy option with Brigimadlin. MDM2 amplification must therefore be considered in the context of personalized molecular testing in CCA.
Insights
Intrahepatic cholangiocarcinomas (CCA) with MDM2 amplification show better survival and may benefit from targeted therapy. MDM2 amplification status is a key factor in personalized treatment strategies for CCA patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cholangiocarcinomas (CCA) are aggressive cancers with poor prognosis.
- Mouse double minute 2 homolog (MDM2) inhibits tumor suppressor p53 and is altered in some carcinomas.
- MDM2-p53 antagonists like Brigimadlin show therapeutic promise.
Purpose of the Study:
- Characterize MDM2 status in CCA.
- Compare fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for MDM2 detection.
- Investigate MDM2 amplification's role in CCA prognosis and clinicopathological features.
Main Methods:
- Retrospective cohort study of 52 CCA patients.
- Analysis of MDM2 amplification using FISH and IHC.
- Correlation of MDM2 status with molecular and clinical data.
Main Results:
- MDM2 amplification found in 5.8% of CCAs, exclusively in intrahepatic types.
- All MDM2-amplified cases had wild-type p53.
- Positive MDM2 amplification correlated with better survival in large-duct intrahepatic CCA.
- Strong concordance between MDM2 amplification (FISH) and protein expression (IHC).
Conclusions:
- MDM2 amplification is a relevant biomarker in Caucasian intrahepatic CCA patients.
- MDM2 amplification identifies patients eligible for targeted therapies like Brigimadlin.
- MDM2 status should be included in personalized molecular testing for CCA.
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