Whole-Exome and Whole-Genome Sequencing Identifies Driver CTNNB1 Mutations in Ossifying Renal Tumor of Infancy

Source abstract

Ossifying renal tumor of infancy (ORTI) is an exceedingly rare pediatric renal neoplasm with an inherently benign clinical course. Although histomorphologically well-described, its underlying molecular pathogenesis remains largely unknown, often posing diagnostic pitfalls when distinguishing it from malignant mimics such as Wilms tumor and cellular congenital mesoblastic nephroma. Here, we systematically evaluated the clinicopathologic, immunohistochemical, and genomic spectrum of 4 pediatric ORTI cases from male infants aged 0.5 to 10 months (median: 2.5 mo), all presenting with gross hematuria. Histologically, all tumors exhibited a characteristic biphasic architecture composed of an osteoid/osteoblast-rich component intermixed with a bland spindle cell component, accompanied by variable calcification, localized blastema-like foci, and a lobulated growth pattern. By immunohistochemistry, all cases (4/4, 100%) demonstrated strong, diffuse nuclear β-catenin accumulation in both components, alongside diffuse nuclear positivity for WT1 and SATB2, and focal cyclin D1 expression. The Ki-67 proliferation index revealed a distinct gradient, being consistently higher in the spindle cell component (5% to 30%) than in the osteoid areas (2% to 15%). All tumors were negative for pan-TRK, ALK, CD34, S100, and PAX8. Next-generation sequencing (NGS) (WGS/WES) identified a recurrent, somatic activating hotspot mutation in exon 3 of CTNNB1 (c.A121G, p.T41A) in 100% of cases (4/4), perfectly correlating with nuclear β-catenin localization. Secondary alterations in Wnt pathway regulators ( APC, AXIN1/AXIN2 ) and BMPR1A were also detected, while FISH confirmed the absence of ETV6::NTRK3 gene rearrangements. All patients achieved long-term disease-free survival following complete surgical resection (follow-up up to 10 y). In summary, ORTI is a distinct, CTNNB1 -driven pediatric renal neoplasm defined by recurrent exon 3 hotspot mutations and aberrant nuclear β-catenin expression. Recognition of these pathognomonic molecular and immunophenotypic hallmarks establishes robust diagnostic criteria to definitively distinguish ORTI from its malignant pediatric renal mimics.