TY - JOUR
T1 - Genetic and chromosomal alterations in Kenyan Wilms Tumor
AU - on behalf of the Kenyan Wilms Tumor Consortium
AU - Lovvorn, Harold N.
AU - Pierce, Janene
AU - Libes, Jaime
AU - Li, Bingshan
AU - Wei, Qiang
AU - Correa, Hernan
AU - Gouffon, Julia
AU - Clark, Peter E.
AU - Axt, Jason R.
AU - Hansen, Erik
AU - Newton, Mark
AU - O'Neill, James A.
AU - N'Dungu, James
AU - Oruko, Oliver
AU - Githanga, Jessie
AU - Abdullah, Fatmah
AU - Musimbi, Joyce
AU - Njuguna, Festus
AU - Patel, Kirtika
AU - Ellsworth, Gabriel
AU - Mwachiro, Michael
AU - White, Russell
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/11/1
Y1 - 2015/11/1
N2 - 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.
AB - 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.
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U2 - 10.1002/gcc.22281
DO - 10.1002/gcc.22281
M3 - Article
C2 - 26274016
AN - SCOPUS:84941258860
SN - 1045-2257
VL - 54
SP - 702
EP - 715
JO - Genes Chromosomes and Cancer
JF - Genes Chromosomes and Cancer
IS - 11
ER -