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KIT, PDGFRalpha and EGFR analysis in nephroblastoma
Sylvia C Wetli1, Ivo Leuschner, Dieter Harms
1Institute for Pathology, Basel University Hospital, Schoenbeinstrasse 40, CH-4031 Basel, Switzerland.
Abstract:
Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel therapeutic strategies. Selective KIT, PDGFRalpha and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRalpha exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively. KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours (26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression in one of four. There were no KIT, PDGFRalpha or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRalpha mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup. Therefore, it remains open if KIT, PDGFRalpha or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma in the absence of KIT, PDGFRalpha or EGFR mutations.
Insights
This study found no mutations in KIT, PDGFRalpha, or epidermal growth factor receptor (EGFR) in nephroblastoma. While KIT and EGFR expression showed a trend with poor outcomes in high-risk tumors, tyrosine kinase inhibitors may not be effective without these specific mutations.
Area of Science:
- Pediatric Oncology
- Molecular Pathology
- Cancer Therapeutics
Background:
- Nephroblastoma prognosis has improved, yet a high-risk subgroup requires novel therapeutic strategies.
- Tyrosine kinase inhibitors targeting KIT, PDGFRalpha, and EGFR are effective in other cancers.
- Investigating these targets in nephroblastoma could reveal new treatment avenues.
Purpose of the Study:
- To analyze KIT, PDGFRalpha, and EGFR expression and mutations in nephroblastoma.
- To determine if tyrosine kinase inhibition is a viable therapeutic strategy for nephroblastoma.
- To correlate expression/mutation status with patient prognosis.
Main Methods:
- Immunohistochemistry was used to analyze KIT and EGFR expression in 209 nephroblastomas.
- Mutation analysis of KIT, PDGFRalpha, and EGFR genes was performed on 63 and 209 samples.
- Correlation of molecular findings with clinical data and patient outcomes was assessed.
Main Results:
- No mutations were detected in KIT, PDGFRalpha, or EGFR genes.
- KIT and EGFR expression was observed in 10.5% and 14.8% of tumors, respectively.
- KIT expression was more frequent in high-risk tumors (22.3%) compared to low-/intermediate-risk tumors (14.4%).
- A trend suggested an association between KIT/EGFR expression and poor outcomes in high-risk nephroblastomas, but it was not statistically significant.
Conclusions:
- KIT, PDGFRalpha, and EGFR mutations do not appear to play a significant role in nephroblastoma pathogenesis.
- The absence of targetable mutations suggests that tyrosine kinase inhibitors may not be effective therapies for nephroblastoma.
- Further research is needed to explore alternative therapeutic targets for high-risk nephroblastoma subgroups.
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