Gain of chromosome 1q and MYCN characterize unique subgroups of Asian Wilms tumor patients.
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Wilms tumors in Asian populations demonstrate uniquely favorable biological characteristics and are not appropriately stratified by current risk markers like loss of heterozygosity of 1p and 16q. We analyzed the prognostic associations of copy number changes at other genomic loci in a population-based cohort of Wilms tumor and explored genomic profiles of relapsed cases. Chromosomal aberrations of targeted loci were evaluated in 61 Wilms tumors treated with National Wilms Tumor Study regimens in Singapore hospitals from 2001-2022, and 26 tumors from a separate Asian validation set, and correlated with clinical variables. Mutational signatures of 6 relapsed patients' tumors were profiled using whole-exome sequencing. Clustering analysis identified a subgroup (65.6 %) of predominantly non-Asian patients with higher frequency of relapse, 1p and 16q loss and 1q gain. A smaller predominantly-Asian subgroup (34.4 %) with low stage and few relapses was characterized by gain of MYCN and minimal 1p, 1q and 16q aberrations. MYCN exon 2 gain was present in 9.8 % of the discovery set and 11.5 % of the validation set. Loss of IGF2 and 1p gene ABCA4, and gain of 1q genes, were associated with relapse. Notably, relapsed tumors demonstrated no recurrent somatic mutations; instead, in 2 patients with 1q gain clonal deconvolution showed persistence of chemo-refractory clones without metachronous pathogenic variants. Among Asian Wilms tumor patients, 1q gain is prognostic for relapse. Gain of MYCN features uniquely in Asian patients and may represent a favorable prognostic marker. These results identify distinct molecular subgroups associated with varying prognosis and relapse among Asian patients.