The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Abstract

Summary We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations.

Clock-like mutational processes in human somatic cells

“…However, in addition, the T>C mutations exhibit transcriptional strand bias, potentially indicating that some of these mutations arise from adducts subject to transcription coupled repair 9 . The signature 5 mutation rate is high in kidney clear cell and papillary cancers, which are thought to originate from kidney proximal tubular epithelium which absorbs metabolites, but low in kidney chromophobe tumours, which may arise from cells of the cortical collecting duct 10 . This raises the possibility that continuous exposure to a ubiquitous metabolic mutagen, which is actively reabsorbed in the kidney proximal tubule resulting in an elevated exposure in these cells, may underlie signature 5.…”

Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma

“…1B). These tumors were considered to have hypermutation based on prior definitions (31,32) and evidence of mismatch repair deficiency. Consistent with this classification, one hypermutated tumor had a heterozygous somatic truncating mutation at R389 in mutS homolog 2 (MSH2) in both carcinomatous and sarcomatoid elements with sarcomatoidspecific LOH at this locus and a sarcomatoid-specific heterozygous E1085K mutation in polymerase e (POLE).…”

The epigenetic landscape of renal cancer

“…The most frequently mutated genes in somatic chRCC are TP53 (32% of tumours) and PTEN (9% of tumours) 28,35 . Wilms tumours are often associated with developmental syndromes such as Wilms tumour, aniridia, genitourinary abnormalities, mental retardation (WAGR) syndrome, and with deletions of chromosome 11 36 .…”