Genetic and chromosomal alterations in Kenyan Wilms Tumor.
Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub-Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub-Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment-resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT-associated genes and evaluated whole-genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow-up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment-resistant.
Department of Pediatric Surgery, Vanderbilt University School of Medicine, Nashville, TN.
Harold N
HN
Lovvorn
Department of Pediatric Surgery, Vanderbilt University School of Medicine, Nashville, TN.
Janene
J
Pierce
Department of Pediatrics, University of Illinois College of Medicine, Peoria, IL.|Division of Hematology/Oncology, University of Illinois College of Medicine, Peoria, IL.
Jaime
J
Libes
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
Bingshan
B
Li
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN.
Qiang
Q
Wei
Division of Pediatric Pathology, Vanderbilt University School of Medicine, Nashville, TN.
Hernan
H
Correa
Affymetrix, Santa Clara, CA.
Julia
J
Gouffon
Department of Urologic Surgery, Vanderbilt University School of Medicine, Nashville, TN.
Peter E
PE
Clark
Department of Pediatric Surgery, Vanderbilt University School of Medicine, Nashville, TN.
Jason R
JR
Axt
Department of Pediatric Surgery, Vanderbilt University School of Medicine, Nashville, TN.
Erik
E
Hansen
Division of Pediatric Anesthesia, Vanderbilt University School of Medicine, Nashville, TN.
Mark
M
Newton
Department of Pediatric Surgery, Vanderbilt University School of Medicine, Nashville, TN.
James A
JA
O'Neill
D002675:Child, Preschool; D002869:Chromosome Aberrations; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D016162:Genes, Wilms Tumor; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007630:Kenya; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics*
C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)