Molecular characterisation of metanephric adenomas beyond BRAF: genetic evidence for potential malignant evolution.

Aims: Metanephric adenomas (MAs) are conventionally regarded as rare renal tumours with indolent behaviour; limited case reports have described MAs with aggressive features. Conventional MAs harbour hotspot BRAF V600E mutations. A BRAF V600E senescence pathway, mediated by cyclin-dependent kinase inhibitor 2A (CDKN2A)/p16, has been proposed to confer MA benignity. Aside from BRAF, the molecular landscape in both conventional MAs and those with aggressive features has not been fully characterised. The aim of this study was to molecularly profile a series of MAs to investigate the correlation between genomic findings and clinical outcome.

Methods And Results: We retrospectively examined the histomorphology and patient outcomes of 11 conventional MAs and one MA with aggressive features. Each was subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes and immunohistochemical profiling. All tumours were positive for WT1 immunostaining and BRAF V600E mutation. One conventional MA contained an additional somatic BRCA2 pathogenic mutation. The MA with aggressive features had a biphasic appearance: one component was epithelial, with areas morphologically consistent with conventional MA; the second component was sarcomatous, with areas of solid and angiosarcomatous growth. Differential profiling of the two populations revealed identical BRAF, EIF1AX and TERT promoter hotspot mutations in the epithelial and sarcomatous components. Deep deletion of CDKN2A and MYC amplification were identified only in the sarcomatous component.

Conclusions: Although the vast majority of MAs show indolent behaviour, rare pathogenic alterations can occur in conventional MAs in addition to BRAF. Molecular profiling of a case with aggressive clinical and pathological features shows genetic evidence for malignant evolution in MAs.