Distinct genomic, microenvironmental, and nephron signatures in VHL kidney cysts and tumors

Patients with von Hippel-Lindau (VHL) disease develop multiple distinct kidney cysts and clear cell renal cell carcinomas (ccRCCs) throughout their lifetime. Although cysts are typically considered precursors of ccRCC, no molecular evidence of cysts to tumor progression was provided to date, due to the lack of an accurate molecular characterization of these lesions. We performed a comprehensive molecular characterization of four kidney cysts and six ccRCCs obtained from the same VHL-disease patient, thus all sharing the same genetic germline and host environment. We combined whole genome sequencing (WGS) and RNA sequencing (RNA-seq) profiling with pathological examinations. Cysts and tumors exhibited distinct transcriptomic profiles. Tumors showed increased glycolysis and response to hypoxia, while cysts were associated with enrichment in extracellular matrix organization and inflammation and displayed elevated expression of nephron distal portion markers. Deconvolution analysis further revealed different stromal and immune microenvironments with cysts enriched in myofibroblasts and plasma cells signatures whereas tumors were associated with tumor-associated macrophages (TAMs) and tumor vasculature signatures. Genomically, most cysts and tumors were clonally independent, harboring distinct somatic single-nucleotide variants. Despite sharing some somatic mutational signatures, tumors and cysts exhibited divergent somatic copy number alterations. Only tumors displayed chromosome 3p loss, resulting in VHL loss of heterozygosity, without other driver mutations. VHL patients develop multiple kidney cysts and solid tumors throughout their lifetime and their clinical management is challenging. This study presents the first in-depth molecular analysis of kidney cysts and ccRCC in a single VHL patient. We observed distinct molecular profiles between cysts and tumors, suggesting independent origins. While preliminary, these findings challenge the assumption that cysts always serve as precursors of ccRCC in VHL disease and underscore the need for larger studies to improve surveillance and management of renal lesions in patients with VHL disease.