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Von Hippel–Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80–90% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one novel variant). The deleterious variants were significantly enriched in VHL disease Type 1. Interestingly, five synonymous or non-synonymous variants within exon 2 caused exon 2 skipping, which is the first report of exon 2 skipping caused by several missense variants. Whole genome and target deep sequencing analysis were performed for 22 unsolved cases with no variant identified and found three cases with VHL mosaicism (variant allele frequency: 2.5–22%), one with mobile element insertion in the VHL promoter region, and two with a pathogenic variant of BAP1 or SDHB. The variants associated with VHL disease are heterogeneous, and for more accuracy of the genetic diagnosis of VHL disease, comprehensive genome and DNA/RNA analyses are required to detect VHL mosaicism, complicated structure variants and other related gene variants.

Patients with end-stage renal disease (ESRD) or receiving dialysis have a much higher risk for renal cell carcinoma (RCC), but carcinogenic mechanisms and genomic features remain little explored and undefined. This study’s goal was to identify the genomic features of ESRD RCC and characterize them for associations with tumor histology and dialysis exposure. In this study, we obtained 33 RCCs, with various histological subtypes, that developed in ESRD patients receiving dialysis and performed whole-genome sequencing and transcriptome analyses. Driver events, copy-number alteration (CNA) analysis and mutational signature profiling were performed using an analysis pipeline that integrated data from germline and somatic SNVs, Indels and structural variants as well as CNAs, while transcriptome data were analyzed for differentially expressed genes and through gene set enrichment analysis. ESRD related clear cell RCCs’ driver genes and mutations mirrored those in sporadic ccRCCs. Longer dialysis periods significantly correlated with a rare mutational signature SBS23, whose etiology is unknown, and increased mitochondrial copy number. All acquired cystic disease (ACD)-RCCs, which developed specifically in ESRD patients, showed chromosome 16q amplification. Gene expression analysis suggests similarity between certain ACD-RCCs and papillary RCCs and in TCGA papillary RCCs with chromosome 16 gain identified enrichment for genes related to DNA repair, as well as pathways related to reactive oxygen species, oxidative phosphorylation and targets of Myc. This analysis suggests that ESRD or dialysis could induce types of cellular stress that impact some specific types of genomic damage leading to oncogenesis.