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

Abstract

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.

Metanephric adenoma: molecular study and review of the literature

“…Caliò [ 14 ] et al identified the V600E mutation in 41 out of 48 MA patients (85%) with a mean age of 54, while Choueiri et al [ 11 ] reported it in 26/29 patients (89%) also with a mean age of 54, and Ding et al [ 17 ] described 27 MA patients with mean age of 39 years and 22 (81%) with BRAF mutation. Other authors have reported the V600E mutation in smaller series [ 18 – 21 ]. In our research, as shown in Table 1 , the mutation was identified in three of the four patients studied (75%), aged between 19 and 65 (mean 47.5).…”

Molecular Characterization of Metanephric Adenoma, Epithelial Wilms Tumor, and Overlap Lesions: An Integrated Whole-exome and Transcriptome Sequencing Analysis

“…22 BRAF mutation has been identified as a genetic hallmark of MA. [4][5][6] However, differential diagnoses are more challenging when the tumors show overlapping features such as atypical features existing in a tumor with background morphology reminiscent of MA or a monophasic WT composed predominantly of epithelial elements and occurring in older patients. Herein, we collected a few such cases and performed integrated WES and WTS for better characterization of these tumors.…”

“…Others that are monophasically epithelial and occur in adults are currently designated epithelial WTs. BRAF mutation, most commonly V600E, has been detected in over 90% of MA4–6 but not in 2 large unselected series of pediatric WT 7,8. The status of BRAF and the usefulness of the assays (sequencing or immunohistochemistry) have also been evaluated in overlap lesions.…”

KANK1-NTRK3 fusions define a subset of BRAF mutation negative renal metanephric adenomas

“…Recent studies of MA have emphasized the importance of advanced molecular testing. Previous studies have demonstrated that the vast majority of MAs harbor BRAF V600E mutations, and that epithelial WTs lack BRAF V600E mutations [19,20,35]. Choueiri et al published the largest series of MA demonstrating that 90% of MAs harbor a BRAF V600E mutation [14].…”

“…Overall, 90% of all published MA cases evaluated for BRAF mutations harbor BRAF exon 15 mutations. Most recent published study by Chan et al examined the genetic profiles using next-generation sequencing on eleven conventional MAs and revelated all eleven cases harboring BRAF V600E mutations [35].…”