Multiregion sequencing of sarcomatoid renal cell carcinoma arising from autosomal dominant polycystic kidney disease

Abstract

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) is an inherited cystic kidney disease associated with a spectrum of various renal and extrarenal manifestations, including increased risk of kidney cancers. Here, we present the initial molecular description of sarcomatoid renal cell carcinoma (sRCC) arising in the setting of ADPKD. Methods Multiregion whole‐exome sequencing and whole transcriptomic sequencing were used to examine intratumoral molecular heterogeneity among histologically‐distinct spindle (sarcomatoid), epithelioid, or biphasic compartments within the tumor and compared with the non‐malignant ADPKD component. Results Spindle and biphasic components harbored several overlapping driver gene mutations, but do not share any with the epithelioid component. Mutations in ATM, CTNNB1, and NF2 were present only in the biphasic and spindle components, while mutations in BID, FLT3, ARID1B, and SMARCA2 were present only in the epithelioid component. We observed dichotomous evolutionary pathways in the development of epithelioid and spindle compartments, involving early mutations in TP53 and ATM/CTNNB1/NF2 respectively. Wnt, PI3K‐mTOR, and MAPK signaling pathways, known key mechanisms involved in ADPKD development, featured prominently in the sarcomatoid component. Conclusion This highlights that common pro‐oncogenic signals are present between ADPKD and sRCC providing insights into their shared pathobiology.

Keywords

• genetics
• hereditary
• phylogeny
• tumor evolution