MCL1 as putative target in pancreatoblastoma
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Timm M Reissig1,2,3,4, Sebastian Uhrig5,6,7, Philipp J Jost8,9
1Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Hufelandstrasse 55, 45147, Essen, Germany.
Abstract:
Pancreatoblastoma (PB) is a rare tumor of the pancreas. In case of metastases, the treatment options are sparse and targeted approaches are not developed. We here evaluate MCL1 amplification as a putative target in PB.Thirteen samples from adult (10/13) and pediatric patients (3/13) were collected. Three of these samples had been previously subjected to whole-exome sequencing (2 cases) or whole-genome sequencing (1 case) within a precision oncology program (NCT/DKTK MASTER), and this analysis had shown copy number gains of MCL1 gene. We established a fluorescence in situ hybridization (FISH) test to assess the copy number alterations of MCL1 gene in 13 formalin-fixed paraffin-embedded PBs, including the 3 cases assessed by genome sequencing. FISH analysis showed the amplification of MCL1 in 2 cases (both were adult PB), one of which was a case with the highest copy number gain at genomic analysis. In both cases, the average gene copy number per cell was ≥ 5.7 and the MCL1/1p12 ratio was ≥ 2.4. Our data support MCL1 as a putative target in PB. Patients with MCL1-amplified PB might benefit from MCL1 inhibition. Sequencing data is useful to screen for amplification; however, the established FISH for MCL1 can help to determine the level and cellular heterogeneity of MCL1 amplification more accurately.
Insights
MCL1 amplification is identified as a potential therapeutic target in pancreatoblastoma (PB). This finding suggests that patients with MCL1-amplified PB may benefit from targeted MCL1 inhibition therapies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Pancreatoblastoma (PB) is a rare pancreatic tumor with limited treatment options for metastatic disease.
- Targeted therapies for PB are underdeveloped, necessitating the identification of novel therapeutic targets.
Purpose of the Study:
- To evaluate MCL1 gene amplification as a potential therapeutic target in pancreatoblastoma.
- To assess the prevalence and characteristics of MCL1 amplification in PB patient samples.
Main Methods:
- Analysis of 13 formalin-fixed paraffin-embedded pancreatoblastoma samples from adult and pediatric patients.
- Utilized whole-exome and whole-genome sequencing data from three samples showing previous copy number gains of MCL1.
- Developed and applied a fluorescence in situ hybridization (FISH) test to accurately assess MCL1 gene copy number alterations.
Main Results:
- MCL1 amplification was detected in two adult PB cases using FISH analysis.
- One of these cases exhibited the highest copy number gain identified through prior genomic analysis.
- FISH confirmed average gene copy numbers per cell ≥5.7 and MCL1/1p12 ratios ≥2.4 in amplified cases.
Conclusions:
- MCL1 is supported as a putative therapeutic target in pancreatoblastoma.
- Patients with MCL1-amplified PB may respond to MCL1 inhibition therapies.
- FISH provides a more accurate assessment of MCL1 amplification levels and cellular heterogeneity compared to sequencing alone.
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