We investigated intratumor heterogeneity and clonal evolution of papillary renal cell carcinoma (pRCC) and rarer kidney cancer subtypes, integrating whole-genome sequencing and DNA methylation data. In 29 tumors, up to 10 samples from the center to the periphery of each tumor, and metastatic samples in 2 cases, enabled phylogenetic analysis of spatial features of clonal expansion, which showed congruent patterns of genomic and epigenomic evolution. In contrast to previous studies of clear cell renal cell carcinoma, in pRCC driver gene mutations and most arm-level somatic copy number alterations (SCNAs) were clonal. These findings suggest that a single biopsy would be sufficient to identify the important genetic drivers and targeting large-scale SCNAs may improve pRCC treatment, which is currently poor. While type 1 pRCC displayed near absence of structural variants (SVs), the more aggressive type 2 pRCC and the rarer subtypes had numerous SVs, which should be pursued for prognostic significance.

The genomic and epigenomic evolutionary history of papillary renal cell carcinomas