Intra and Inter Tumoral Heterogeneity In Von Hippel-Lindau related Renal Cancer

Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome caused by germline pathogenic variants in the VHL gene. Affected individuals develop multiple primary tumours in several organs, but the determinant of their life expectancy is clear cell renal cell carcinoma (ccRCC). The current standard of care is based on arbitrary decisions. Due to the lack of biological or molecular markers assisting clinical decision-making, patients undergo multiple surgical interventions with an incremental risk of complications and morbidity. The most important clinical need in those individuals is to overcome intra/intertumoral heterogeneity in VHL-associated ccRCC to allow tailored decisions and treatments. Therefore, we set up a methodology aiming at creating the first integrated map of intra- and inter-tumour heterogeneity in VHL-associated ccRCC by overlaying imaging, histology, multiplex immunohistochemistry, and multi-omics data from multi-region tumour biopsies. This, combined with the establishment of patient derived organoids cultures, can provide innovative tools to guide clinical management. Overall design: Three tumors from the same VHL patient were used for the analysis: two lesions retrieved from the left kidney (L1 and L3) and one lesion from the right kidney (R1). Each tumor was divided into four distinct areas (labeled as "black," "blue," "brown," and "green"). RNA was extracted from biopsies taken from each area, and the four areas were considered replicates of the same tumor.