Convergent evolution of 11p allelic loss in multifocal Wilms tumors arising in WT1 mutation carriers

Abstract

Wilms tumors in patients with constitutional WT1 mutations are examples of Knudson's tumor suppressor paradigm, with somatic inactivation of the second allele occurring through 11p loss of heterozygosity. The time point of this second hit has remained unknown. We analyzed seven Wilms tumors from two patients with constitutional WT1 mutations by whole exome sequencing and genomic array. All tumors exhibited wild type WT1 loss through uniparental isodisomy. Each tumor had a unique genomic breakpoint in 11p, typically accompanied by a private activating mutation of CTNNB1. Hence, convergent evolution rather than field carcinogenesis underlies multifocal tumors in WT1 mutation carriers.

The Genetic and Epigenetic Features of Bilateral Wilms Tumor Predisposition: A Report from the Children's Oncology Group AREN18B5-Q Study

“…al. 51 This sequence is often followed by development of activating somatic CTNNB1 variants, which were the most common somatic variants found in the current study. Our results are consistent with the temporal sequence rst reported by Fukuzawa et.…”

Molecular insight into multiple Wilms tumors arising in germline WT1‐mutated/11p13‐deleted patients

“…In the two patients described by Valind et al 1 with germline WT1 mutation, the path to tumor formation was similar (11p CNNI and CTNNB1 mutation), whereas in the two patients carrying the 11p13 deletion it appeared to be different.…”

“…In this issue of Pediatric Blood and Cancer , Valind and colleagues present a very detailed investigation of multiple Wilms tumors (WTs) arising in two patients carrying constitutional WT1 mutations . Both patients presented with bilateral disease: in the first case, three tumor samples were investigated, one from the left (T1) and two from the right side WT (T2A,B); in the second case, five different tumors were studied, one from the right (T1) and four from the left side (T2–5).…”

The pathophysiology of bilateral and multifocal Wilms tumors: What we can learn from the study of predisposition syndromes

“…[30][31][32]39 In fact, Scott et al 6 found only germline and no somatic WT1 variants in patients a unique 11p breakpoint on the second allele, suggesting that the "second hit" occurred as an independent genetic event. [42][43][44] Furthermore, unique CTNNB1 variants in each tumor usually follow WT1 variants. 37 A summary of the molecular mechanisms leading to BWT in children with germline WT1 aberrations is shown in Figure 2.…”

“…A substantial proportion of WT with WT1 pathogenic variants are associated with pUPD on 11p, encompassing both 11p13 and 11p15.5, which results in biallelic inactivation of WT1 and biallelic expression of IGF2 . Recent studies of BWT and multifocal WT with WT1 pathogenic germline variants, including patients with WAGR, show that each tumor from the same patient has a unique 11p breakpoint on the second allele, suggesting that the “second hit” occurred as an independent genetic event 42–44 . Furthermore, unique CTNNB1 variants in each tumor usually follow WT1 variants 37 .…”