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

Michal 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 Terracciano; Serenella Eppenberger-Castori; Andrew Protheroe; Eamonn  Maher; Mona 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 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 Terracciano, Serenella Eppenberger-Castori, Andrew Protheroe, Eamonn Maher, Mona El Bahrawy, Stewart Fleming, Peter Ratcliffe, Karl Heinimann, Charles Swanton (Lead / Corresponding author), Ian Tomlinson (Lead / Corresponding author)

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

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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
Number of pages	11
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms7336
Publication status	Published - 19 Mar 2015

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Fleming, Stewart
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Kovac, M., 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{c66efedcd6534fca89288bbe4e35bd5b,

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.",

author = "Michal Kovac and Carolina Navas and Stuart Horswell and Max Salm and Chiara Bardella and Andrew Rowan and Mark Stares and Francesc Castro-Giner 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 Luigi Terracciano and Serenella Eppenberger-Castori and Andrew Protheroe and Eamonn Maher and {El Bahrawy}, Mona 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",

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Kovac, M, 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, L, Eppenberger-Castori, S, Protheroe, A, Maher, E, El Bahrawy, M, 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

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

AU - Eppenberger-Castori, Serenella

AU - Protheroe, Andrew

AU - Maher, Eamonn

AU - El Bahrawy, Mona

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.

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

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