title: Molecular characterization of Wilms' tumor from a resource-constrained region of sub-Saharan Africa.
abstract: Sub-Saharan African children have an increased incidence of Wilms' tumor (WT) and experience alarmingly poor outcomes. Although these outcomes are largely due to inadequate therapy, we hypothesized that WT from this region exhibits features of biological aggressiveness that may warrant broader implementation of high-risk therapeutic protocols. We evaluated 15 Kenyan WT (KWT) for features of aggressive disease (blastemal predominance and Ki67/cellular proliferation) and treatment resistance (anaplasia and p53 immunopositivity). To explore the additional biological features of KWT, we determined the mutational status of the CTNNB1/β-catenin and WT1 genes and performed immunostaining for markers of Wnt pathway activation (β-catenin) and nephronic progenitor cell self-renewal (WT1, CITED1 and SIX2). We characterized the proteome of KWT using imaging mass spectrometry (IMS). The results were compared to histology- and age-matched North American WT (NAWT) controls. For patients with KWT, blastemal predominance was noted in 53.3% and anaplasia in 13%. We detected increased loss to follow-up (p = 0.028), disease relapse (p = 0.044), mortality (p = 0.001) and nuclear unrest (p = 0.001) in patients with KWT compared to controls. KWT and NAWT showed similar Ki67/cellular proliferation. We detected an increased proportion of epithelial nuclear β-catenin in KWT (p = 0.013). All 15 KWT specimens were found to harbor wild-type CTNNB1/β-catenin, and one contained a WT1 nonsense mutation. WT1 was detected by immunostaining in 100% of KWT, CITED1 in 80% and SIX2 in 80%. IMS revealed a molecular signature unique to KWT that was distinct from NAWT. The African WT specimens appear to express markers of adverse clinical behavior and treatment resistance and may require alternative therapies or implementation of high-risk treatment protocols.
authors.affiliation: Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. andrew.j.murphy@vanderbilt.edu
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Murphy
authors.forename: Jason R
authors.initials: JR
authors.lastname: Axt
authors.forename: Christian
authors.initials: C
authors.lastname: de Caestecker
authors.forename: Janene
authors.initials: J
authors.lastname: Pierce
authors.forename: Hernan
authors.initials: H
authors.lastname: Correa
authors.forename: Erin H
authors.initials: EH
authors.lastname: Seeley
authors.forename: Richard M
authors.initials: RM
authors.lastname: Caprioli
authors.forename: Mark W
authors.initials: MW
authors.lastname: Newton
authors.forename: Mark P
authors.initials: MP
authors.lastname: de Caestecker
authors.forename: Harold N
authors.initials: HN
authors.lastname: Lovvorn
mesh_terms: D017954:Africa South of the Sahara; D051017:Apoptosis Regulatory Proteins; D002675:Child, Preschool; D005260:Female; D016162:Genes, Wilms Tumor; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D009154:Mutation; D009687:Nuclear Proteins / Q000032:analysis; D011379:Prognosis; D015534:Trans-Activators; D014157:Transcription Factors / Q000032:analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D009396:Wilms Tumor / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051176:beta Catenin / Q000032:analysis / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C512688:CITED1 protein, human; C495270:CTNNB1 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin