Race Disparities in Peptide Profiles of North American and Kenyan Wilms Tumor Specimens

Abstract

Background Wilms tumor (WT) is the most common childhood kidney cancer worldwide and arises in children of black African ancestry with greater frequency and severity than other race groups. A biologic basis for this pediatric cancer disparity has not been previously determined. We hypothesized that unique molecular fingerprints might underlie the variable incidence and distinct disease characteristics of WT observed between race groups. Study Design To evaluate molecular disparities between WTs of different race groups, the Children’s Oncology Group provided 80 favorable histology specimens divided evenly between black and white patients and matched for disease characteristics. As a surrogate of sub-Saharan African patients, we also analyzed 18 Kenyan WT specimens. Tissues were probed for peptide profiles using MALDI-TOF imaging mass spectrometry. To control for histologic variability within and between specimens, cellular regions were analyzed separately as triphasic (containing blastema, epithelia, and stroma), blastema-only, and stroma-only. Data were queried using ClinProTools and statistically analyzed. Results Peptide profiles, detected in triphasic WT regions, recognized race with good accuracy, which increased for blastema- or stroma-only regions. Peptide profiles from North American WTs differed between black and white race groups but were far more similar in composition than Kenyan specimens. Individual peptides were identified that also associated with WT patient and disease characteristics (eg, treatment failure and stage). Statistically significant peptide fragments were used to sequence proteins, revealing specific cellular signaling pathways and candidate drug targets. Conclusions WT specimens arising among different race groups show unique molecular fingerprints that could explain disparate incidences and biological behavior and that could reveal novel therapeutic targets.

Resolving the etiology of atopic disorders by using genetic analysis of racial ancestry

“…256 While we are not aware of any studies exploring the use of proteomics to characterize the relationship between race and allergic disease, peptide profiles and protein signatures that are specifically associated with several different cancer forms in patients of African ancestry have been identified. 257,258 Similarly, we can expect proteomics to play a future role in explaining racial disparities and identifying race-specific biomarkers associated with allergic disease. MicroRNAs (miRNAs) are small noncoding RNAs that act mainly as suppressors of gene expression at the posttranscriptional level, 259–261 which may act as key regulators of the development and activity of innate and adaptive immune systems and control inflammatory processes.…”

Genetic and chromosomal alterations in Kenyan Wilms Tumor

“…The combined frequency of three genetic alterations fundamental to Wilms tumorigenesis, specifically WT1, CTNNB1, and WTX (i.e., AMER1 or FAM123B), has been estimated to occur in roughly one-third of WT, whereas aberrant expression of IGF2 has been shown to occur in 70% of WT specimens (Huff, 2011;Gadd et al, 2012). Furthermore, WT maintenance and disease progression are associated with the altered expression of multiple other genes, such as TP53, MYCN, CITED1, SIX2, TOP2A, and CRABP2 (Lovvorn et al, 2007;Schaub et al, 2007;Williams et al, 2011Williams et al, , 2015Murphy et al, 2012bMurphy et al, , 2014Libes et al, 2014a;Pierce et al, 2014). Specifically, mutations in TP53 and accumulation of its protein product, TP53, are a common finding in unfavorable histology (UH) WT and a notorious marker of treatment resistance (Lahoti et al, 1996;Sredni et al, 2001;Natrajan et al, 2007;Maschietto et al, 2014).…”

Peptide spectra in Wilms tumor that associate with adverse outcomes

“…Peptides used to create these models can then be sequenced, their parent proteins identified, and queried for targetable moieties. (7) Once validated by an external tumor set, these data could be used to not only identify tumors with known outcomes, but also to potentially predict the likelihood of treatment failure or metastasis and thereby identify patients that would benefit from more intensive chemotherapy at the time of diagnosis.…”

“…(8, 9) Prior work from our laboratory has delineated proteomic, tumor-specific differences between tumors from race groups that may explain the increased incidence and adverse WT behavior observed in minority groups. (7, 10, 11)…”