N. Corbitt2, J. Pierce1, B. Li3, Q. Wei3, R. Flores1, H. Correa1, S. Uccini4, H. Frangoul1, A. Alsaadawi5, S. F. Al-Badri5, A. F. Al-Darraji5, R. M. Al-Saeed5, M. F. Al-Jadiry5, S. A. Al-Hadad5, H. N. Lovvorn1 1Monroe Carell, Jr Childrens Hospital,Department Of Pediatric Surgery,Nashville, TENNESEE, USA 2Vanderbilt University Medical Center,Department Of General Surgery,Nashville, TENNESSEE, USA 3Vanderbilt University School Of Medicine,Department Of Molecular Physiology And Biophysics,Nashville, TENNESSEE, USA 4Sapienza University,Department Of Clinical And Molecular Medicine,Rome, , Italy 5Childrens Welfare Teaching Hospital,Department Of Pathology And Oncology,Baghdad, , Iraq 6Wasit University College Of Medicine,Oncology Department,Wasit, , Iraq
Introduction: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its survival rate varies drastically between developed and developing countries. Affected children of non-Caucasian ethnicities residing in resource-challenged countries often demonstrate advanced stage disease at presentation and experience dismal survival from WT. However, poverty and limited access to healthcare may not entirely explain these disparate findings, as ethnic variations in the genetic profile of WT could too contribute to its tumorigenesis, disease progression, treatment resistance, and overall poor survival. Interestingly, the survival rate from WT in the impoverished nation of Iraq was a mere 51% at last report in 2008, but no genetic or epidemiologic explanation for this unacceptably low survival was provided. The aim of this study was to characterize the genetic profile of WT in Iraqi children as a foundation to identify novel therapeutic targets.
Methods: WT patients (n=154) who were treated at the Children’s Welfare Teaching Hospital in Baghdad, Iraq between June 2008 and March 2014 were selected for potential molecular evaluation. Tissue samples from 35 patients could be located given the political challenges in that region during this time. Genomic DNA from formalin-fixed, paraffin-embedded tissue samples was analyzed using next generation sequencing (NGS) to identify single nucleotide variations, insertions, and deletions in ten target genes documented to promote Wilms tumorigenesis (WT1, CTNNB1, WTX, and IGF2) or disease maintenance (TP53, MYC-N, CITED1, SIX2, CRABP2, and TOP2A). Immunohistochemical analysis was performed to evaluate expression of proteins (WT1, CTNNB1, NCAM, CITED1, SIX2, and TP53) fundamental to WT biology.
Results: Using NGS, we detected mutations in previously identified loci of WT1 and CTNNB1 as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry for 6 marker proteins (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53) of WT showed expression patterns typical of blastemal-predominant specimens, a poor prognostic feature in certain regions of the world. The median clinical follow up was 40.5 months (range, 6-78 months). Only one child, whose WT contained mutations in both WT1 and CTNNB1, was confirmed dead from disease among this cohort despite the healthcare and socioeconomic challenges unique to the Iraqi population.
Conclusion: This study is the first to report the molecular characterization of WT in Iraqi children. Although limited by small sample size due to regional challenges, our analysis suggests that WT obtained from this Iraqi cohort shares some biological features of specimens observed in other nations but also exhibits potentially distinguishing genetic features. Once validated in a larger series, these findings will direct the future development of targeted molecular therapies that may improve WT survival in Iraq and other impoverished nations in the Middle East.