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

Michal B. Kovac; Carolina Navas; Stuart Horswell; Max Salm; Chiara Bardella; Andrew Rowan; Mark Stares; Francesc Castro Giner; Rosalie Fisher; Elza C. de Bruin; Monika Kovacova; Maggie Gorman; Seiko Makino; Jennet Williams; Emma Jaeger; Angela Jones; Kimberley Howarth; James Larkin; Lisa Pickering; Martin Gore; David L. Nicol; Steven Hazell; Gordon Stamp; Tim O'Brien; Ben Challacombe; Nik Matthews; Benjamin Phillimore; Sharmin Begum; Adam Rabinowitz; Ignacio Varela; Ashish Chandra; Catherine Horsfield; Alexander Polson; Maxine Tran; Rupesh Bhatt; Luigi M. Terracciano; Serenella Eppenberger-Castori; Andrew Protheroe; Eamonn Maher; Mona A. El Bahrawy; Stewart Fleming; Peter Ratcliffe; Karl Heinimann; Charles Swanton; Ian Tomlinson

doi:10.1038/ncomms7336

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

Michal B. Kovac, Carolina Navas, Stuart Horswell, Max Salm, Chiara Bardella, Andrew Rowan, Mark Stares, Francesc Castro Giner, Rosalie Fisher, Elza C. de Bruin, Monika Kovacova, Maggie Gorman, Seiko Makino, Jennet Williams, Emma Jaeger, Angela Jones, Kimberley Howarth, James Larkin, Lisa Pickering, Martin GoreDavid L. Nicol, Steven Hazell, Gordon Stamp, Tim O'Brien, Ben Challacombe, Nik Matthews, Benjamin Phillimore, Sharmin Begum, Adam Rabinowitz, Ignacio Varela, Ashish Chandra, Catherine Horsfield, Alexander Polson, Maxine Tran, Rupesh Bhatt, Luigi M. Terracciano, Serenella Eppenberger-Castori, Andrew Protheroe, Eamonn Maher, Mona A. El Bahrawy, Stewart Fleming, Peter Ratcliffe, Karl Heinimann, Charles Swanton, Ian Tomlinson

Research output: Contribution to journal › Article › peer-review

73 Citations (Scopus)

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.

Original language	English
Article number	6336
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7336
Publication status	Published - 19 Mar 2015

Keywords

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal/chemistry
Carcinoma, Renal Cell/genetics
Chromosome Mapping
Chromosomes/ultrastructure
DNA Copy Number Variations
Exome
Exons
Female
Gene Expression Regulation, Neoplastic
Histone-Lysine N-Methyltransferase/genetics
Humans
Kidney Neoplasms/genetics
Loss of Heterozygosity
Male
Middle Aged
Mutation
Phylogeny
Polymorphism, Single Nucleotide
Sequence Analysis, DNA

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ncomms7336Licence: Creative Commons: Attribution (CC BY)

https://www.nature.com/articles/ncomms7336Licence: Creative Commons: Attribution (CC BY)

Cite this

Kovac, M. B., Navas, C., Horswell, S., Salm, M., Bardella, C., Rowan, A., Stares, M., Castro Giner, F., Fisher, R., de Bruin, E. C., Kovacova, M., Gorman, M., Makino, S., Williams, J., Jaeger, E., Jones, A., Howarth, K., Larkin, J., Pickering, L., ... Tomlinson, I. (2015). Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nature Communications, 6, Article 6336. https://doi.org/10.1038/ncomms7336

@article{a852f71aafbc47ac9ef4cb67c2ff1dbf,

title = "Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution",

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. ",

keywords = "Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal/chemistry, Carcinoma, Renal Cell/genetics, Chromosome Mapping, Chromosomes/ultrastructure, DNA Copy Number Variations, Exome, Exons, Female, Gene Expression Regulation, Neoplastic, Histone-Lysine N-Methyltransferase/genetics, Humans, Kidney Neoplasms/genetics, Loss of Heterozygosity, Male, Middle Aged, Mutation, Phylogeny, Polymorphism, Single Nucleotide, Sequence Analysis, DNA",

author = "Kovac, {Michal B.} and Carolina Navas and Stuart Horswell and Max Salm and Chiara Bardella and Andrew Rowan and Mark Stares and {Castro Giner}, Francesc and Rosalie Fisher and {de Bruin}, {Elza C.} and Monika Kovacova and Maggie Gorman and Seiko Makino and Jennet Williams and Emma Jaeger and Angela Jones and Kimberley Howarth and James Larkin and Lisa Pickering and Martin Gore and Nicol, {David L.} and Steven Hazell and Gordon Stamp and Tim O'Brien and Ben Challacombe and Nik Matthews and Benjamin Phillimore and Sharmin Begum and Adam Rabinowitz and Ignacio Varela and Ashish Chandra and Catherine Horsfield and Alexander Polson and Maxine Tran and Rupesh Bhatt and Terracciano, {Luigi M.} and Serenella Eppenberger-Castori and Andrew Protheroe and Eamonn Maher and {El Bahrawy}, {Mona A.} and Stewart Fleming and Peter Ratcliffe and Karl Heinimann and Charles Swanton and Ian Tomlinson",

year = "2015",

month = mar,

day = "19",

doi = "10.1038/ncomms7336",

language = "English",

volume = "6",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer",

}

Kovac, MB, Navas, C, Horswell, S, Salm, M, Bardella, C, Rowan, A, Stares, M, Castro Giner, F, Fisher, R, de Bruin, EC, Kovacova, M, Gorman, M, Makino, S, Williams, J, Jaeger, E, Jones, A, Howarth, K, Larkin, J, Pickering, L, Gore, M, Nicol, DL, Hazell, S, Stamp, G, O'Brien, T, Challacombe, B, Matthews, N, Phillimore, B, Begum, S, Rabinowitz, A, Varela, I, Chandra, A, Horsfield, C, Polson, A, Tran, M, Bhatt, R, Terracciano, LM, Eppenberger-Castori, S, Protheroe, A, Maher, E, El Bahrawy, MA, Fleming, S, Ratcliffe, P, Heinimann, K, Swanton, C & Tomlinson, I 2015, 'Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution', Nature Communications, vol. 6, 6336. https://doi.org/10.1038/ncomms7336

TY - JOUR

T1 - Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution

AU - Kovac, Michal B.

AU - Navas, Carolina

AU - Horswell, Stuart

AU - Salm, Max

AU - Bardella, Chiara

AU - Rowan, Andrew

AU - Stares, Mark

AU - Castro Giner, Francesc

AU - Fisher, Rosalie

AU - de Bruin, Elza C.

AU - Kovacova, Monika

AU - Gorman, Maggie

AU - Makino, Seiko

AU - Williams, Jennet

AU - Jaeger, Emma

AU - Jones, Angela

AU - Howarth, Kimberley

AU - Larkin, James

AU - Pickering, Lisa

AU - Gore, Martin

AU - Nicol, David L.

AU - Hazell, Steven

AU - Stamp, Gordon

AU - O'Brien, Tim

AU - Challacombe, Ben

AU - Matthews, Nik

AU - Phillimore, Benjamin

AU - Begum, Sharmin

AU - Rabinowitz, Adam

AU - Varela, Ignacio

AU - Chandra, Ashish

AU - Horsfield, Catherine

AU - Polson, Alexander

AU - Tran, Maxine

AU - Bhatt, Rupesh

AU - Terracciano, Luigi M.

AU - Eppenberger-Castori, Serenella

AU - Protheroe, Andrew

AU - Maher, Eamonn

AU - El Bahrawy, Mona A.

AU - Fleming, Stewart

AU - Ratcliffe, Peter

AU - Heinimann, Karl

AU - Swanton, Charles

AU - Tomlinson, Ian

PY - 2015/3/19

Y1 - 2015/3/19

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal/chemistry

KW - Carcinoma, Renal Cell/genetics

KW - Chromosome Mapping

KW - Chromosomes/ultrastructure

KW - DNA Copy Number Variations

KW - Exome

KW - Exons

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Histone-Lysine N-Methyltransferase/genetics

KW - Humans

KW - Kidney Neoplasms/genetics

KW - Loss of Heterozygosity

KW - Male

KW - Middle Aged

KW - Mutation

KW - Phylogeny

KW - Polymorphism, Single Nucleotide

KW - Sequence Analysis, DNA

U2 - 10.1038/ncomms7336

DO - 10.1038/ncomms7336

M3 - Article

C2 - 25790038

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 6336

ER -

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

Abstract

Keywords

UN SDGs

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