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.
Highlights
Papillary renal cell carcinoma is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour
We find driver mutations in BAP1, SETD2, ARID2 and Nrf[2] pathway genes that frequently occur within sub-clones, and recurrent, large-scale copy number changes that are usually present in major clones
For discovery of somatic Papillary renal cell carcinoma (pRCC) driver mutations, we examined somatic mutation calls from the 31 cancers with exome- and genome-sequence data, and restricted our analysis to proteincoding regions
Summary
Papillary renal cell carcinoma (pRCC) is an important subtype of kidney cancer with a problematic pathological classification and highly variable clinical behaviour. The most common type of RCC has a clear cell morphology (ccRCC) and usually arises owing to mutations in the VHL tumour suppressor gene[1]. In contrast to ccRCC18, relatively little is known about the mutations that drive pRCC growth and the clonality of copy number events and single-nucleotide variants (SNVs), apart from the small minority of cancers with changes in MET and FH. We aim to search for driver mutations and recurrent copy number events and decipher the evolutionary landscape of pRCC, by inferring clonality from both single- and multi-region sampling strategies. We find driver mutations in BAP1, SETD2, ARID2 and Nrf[2] pathway genes that frequently occur within sub-clones, and recurrent, large-scale copy number changes that are usually present in major clones
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