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Peptide spectra in Wilms tumor that associate with adverse outcomes
Andrew Jackson Murphy1, Janene Pierce1, Erin H Seeley2
1Department of Pediatric Surgery, Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee.
Background:
The 2013 Children's Oncology Group (COG) blueprint for renal tumor research challenges investigators to develop new, risk-specific biological therapies for unfavorable histology and higher-risk Wilms tumor (WT) in an effort to close a persistent survival gap and to reduce treatment toxicities. As an initial response to this call from the COG, we used imaging mass spectrometry to determine peptide profiles of WT associated with adverse outcomes.
Materials And Methods:
We created a WT tissue microarray containing 2-mm punches of formalin-fixed, paraffin-embedded specimens archived from 48 sequentially treated WT patients at our institutions. Imaging mass spectrometry was performed to compare peptide spectra between three patient groups as follows: unfavorable versus favorable histology, treatment success versus failure, and COG higher- versus lower-risk disease. Statistically significant peptide peaks differentiating groups were identified and incorporated into a predictive model using a genetic algorithm.
Results:
One hundred thirty-one peptide peaks were differentially expressed in unfavorable versus favorable histology WT (P < 0.05). Two hundred three peaks differentiated treatment failure from success (P < 0.05). Seventy-one peaks differentiated COG higher-risk disease from the very-low, low, and standard-risk groups (P < 0.05). These peaks were used to develop predictive models that could differentiate among patient groups 98.49%, 94.46%, and 98.55% of the time, respectively. Spectral patterns were internally cross-validated using a leave-20% out model.
Conclusions:
Peptide spectra can discriminate adverse behavior of WT. After future external validation and refinement, these models could be used to predict WT behavior and to stratify intensity of chemotherapy regimens. Furthermore, peptides discovered in the model could be sequenced to identify potential risk-specific drug targets.
Insights
Imaging mass spectrometry identified distinct peptide profiles in Wilms tumor (WT) associated with adverse outcomes. These findings could lead to better risk stratification and targeted therapies for pediatric kidney cancer.
Area of Science:
- Oncology
- Proteomics
- Biomarker Discovery
Background:
- Wilms tumor (WT) research aims to reduce survival gaps and treatment toxicities for high-risk patients.
- Imaging mass spectrometry (IMS) was employed to analyze peptide profiles in WT.
- This study addresses the Children's Oncology Group (COG) call for novel, risk-specific therapies.
Purpose of the Study:
- To identify peptide profiles in WT that correlate with adverse outcomes.
- To develop predictive models for WT behavior based on peptide spectra.
- To discover potential therapeutic targets for risk-stratified treatment.
Main Methods:
- A WT tissue microarray from 48 patients was analyzed using IMS.
- Peptide spectra were compared between groups: histology, treatment outcome, and COG risk.
- A genetic algorithm was used to build predictive models from significant peptide peaks.
Main Results:
- 131 peptide peaks differentiated unfavorable from favorable WT histology (P < 0.05).
- 203 peaks distinguished treatment failure from success (P < 0.05).
- 71 peaks identified higher-risk WT, with predictive models achieving >94% accuracy.
Conclusions:
- Peptide spectra effectively discriminate adverse WT behavior.
- Validated models may predict WT behavior and guide chemotherapy intensity.
- Discovered peptides could serve as targets for novel, risk-specific drugs.
