Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution.

Nature Communications
Michal KovacI P M Tomlinson

Abstract

Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. Here we sequence the genomes or exomes of 31 pRCCs, and in four tumours, multi-region sequencing is undertaken. We identify BAP1, SETD2, ARID2 and Nrf2 pathway genes (KEAP1, NHE2L2 and CUL3) as probable drivers, together with at least eight other possible drivers. However, only ~10% of tumours harbour detectable pathogenic changes in any one driver gene, and where present, the mutations are often predicted to be present within cancer sub-clones. We specifically detect parallel evolution of multiple SETD2 mutations within different sub-regions of the same tumour. By contrast, large copy number gains of chromosomes 7, 12, 16 and 17 are usually early, monoclonal changes in pRCC evolution. The predominance of large copy number variants as the major drivers for pRCC highlights an unusual mode of tumorigenesis that may challenge precision medicine approaches.

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Datasets Mentioned

BETA
PRJEB7875
ERP008861

Methods Mentioned

BETA
PBAF
amplicon sequencing
exome sequencing
electrophoresis
PCR
PCRs

Software Mentioned

Torrent Server
ChAS
ABSOLUTE
Chemistry
Covaris
Intogen
Complete Genomics CGAtools
BWA
AmpliSeq Designer
Pyclone

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