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.