Inter- and intra-tumor heterogeneity of genetic and immune profiles in inherited renal cell carcinoma

Patients with von Hippel-Lindau disease (vHL) are at risk of developing spatially and temporally multiple clear cell renal cell carcinomas (ccRCCs), which offers a valuable opportunity to analyze inter- and intra-tumor heterogeneity of genetic and immune profiles within the same patient. Here, we perform whole-exome and RNA sequencing, digital gene expression, and immunohistochemical analyses for 81 samples from 51 ccRCCs of 10 patients with vHL. Inherited ccRCCs are clonally independent and have less genomic alterations than sporadic ccRCCs. Hierarchical clustering of transcriptome profiles shows two clusters with distinct immune signatures: immune hot and cold clusters. Interestingly, not only samples from the same tumors but also different tumors from the same patients tend to show a similar immune signature, whereas samples from different patients frequently exhibit different signatures. Our findings reveal the genetic and immune landscape of inherited ccRCCs, demonstrating the relevance of host factors in shaping anti-tumor immunity. [Display omitted] •Inherited ccRCCs have a lower number of somatic alterations than sporadic ccRCCs•Inherited ccRCCs are classified into immune hot and cold clusters•Different tumors from the same patients tend to show a similar immune signature•Not only tumor but also host factors influence the immune microenvironment Through integrated immunogenomic analysis of 51 inherited clear cell renal cell carcinomas from 10 patients with vHL, Tabata et al. demonstrate that inter-patient heterogeneity is more profound than inter-tumor heterogeneity within the same patients with respect to immune profile, suggesting the relevance of host factors in shaping anti-tumor immunity.