# Intra- and inter-tumoural heterogeneity in von Hippel–Lindau disease-related renal cancer: a multimodal data study protocol

## TL;DR

This study aims to improve treatment decisions for VHL disease patients by analyzing tumor heterogeneity using multiple data types.

## Contribution

A multimodal data protocol is proposed to map tumor heterogeneity in VHL-related kidney cancer for personalized treatment.

## Key findings

- Multiregional biopsies allow analysis of small tumors and reveal intra- and inter-tumor heterogeneity.
- Tumors show clonal independence and distinct chromosome 3p loss events.
- Patient-derived organoids are easier to grow from low-density tumor areas.

## Abstract

von Hippel–Lindau (VHL) disease is a rare hereditary cancer syndrome caused by germline pathogenic variants in the VHL gene. The current standard of care primarily involves surgical resection, which is arbitrarily recommended for renal tumours ≥ 3 cm to reduce the risk of metastasis. However, this approach often leads to repeated surgeries and increased patient morbidity. The key unmet clinical need for VHL patients is the ability to predict the most appropriate therapeutic strategy and the optimal timing for surgical intervention on an individualised basis. Here, we describe a methodology designed to create an integrated map of intra- and inter-tumour heterogeneity in VHL-associated clear cell renal cell carcinoma by combining radiomics, histology, RNA sequencing, whole genome sequencing, and patient-derived organoid cultures from multi-regional tumour biopsies. We hypothesise that decoding this heterogeneity through an integrated analysis of imaging, histopathology, and molecular profiling will enhance diagnostic accuracy and enable more informed and personalised therapeutic decisions for VHL patients.

Due to the current lack of biological or molecular markers assisting clinical decision-making, VHL patients undergo multiple surgical interventions with an incremental risk of complications and morbidity. We expect that our multimodal data study protocol will give tools to guide clinical management.

Multiregional needle biopsies enable comprehensive analysis even in small ccRCC.Imaging characteristics suggest the presence of intra- and inter-lesion heterogeneity.Tumours are clonally independent and harbour distinct chromosome 3p loss events.Tumours display both intra- and inter-tumour transcriptomics heterogeneity.Patient-derived organoids grow more easily from areas of low tumour density.

Multiregional needle biopsies enable comprehensive analysis even in small ccRCC.

Imaging characteristics suggest the presence of intra- and inter-lesion heterogeneity.

Tumours are clonally independent and harbour distinct chromosome 3p loss events.

Tumours display both intra- and inter-tumour transcriptomics heterogeneity.

Patient-derived organoids grow more easily from areas of low tumour density.