Whole-genome landscape of pancreatic neuroendocrine tumours

Aldo Scarpa; David K. Chang; Katia Nones; Vincenzo Corbo; Ann-Marie Patch; Peter Bailey; Rita T. Lawlor; Amber L. Johns; David K. Miller; Andrea Mafficini; Borislav Rusev; Maria Scardoni; Davide Antonello; Stefano Barbi; Katarzyna O. Sikora; Sara Cingarlini; Caterina Vicentini; Skye Mckay; Michael C.J. Quinn; Timothy J.C. Bruxner; Angelika N. Christ; Ivon Harliwong; Senel Idrisoglu; Suzanne Mclean; Craig Nourse; Ehsan Nourbakhsh; Peter J. Wilson; Matthew J. Anderson; J. Lynn Fink; Felicity Newell; Nick Waddell; Oliver Holmes; Stephen H. Kazakoff; Conrad Leonard; Scott Wood; Qinying Xu; Shivashankar Hiriyur Nagaraj; Eliana Amato; Elena Amato; Irene Dalai; Samantha Bersani; Ivana Cataldo; Angelo P. Dei Tos; Paola Capelli; Maria Vittoria Davì; Luca Landoni; Anna Malpaga; Marco Miotto; Vicki L.J. Whitehall; Barbara A. Leggett; Janelle L. Harris; Jonathan Harris; Marc D. Jones; Jeremy Humphris; Lorraine A. Chantrill; Venessa Chin; Adnan M. Nagrial; Marina Pajic; Christopher J. Scarlett; Andreia Pinho; Ilse Rooman; Christopher Toon; Jianmin Wu; Mark Pinese; Mark Cowley; Andrew Barbour; Amanda Mawson; Emily S. Humphrey; Emily K. Colvin; Angela Chou; Jessica A. Lovell; Nigel B. Jamieson; Fraser Duthie; Marie-Claude Gingras; William E. Fisher; Rebecca A. Dagg; Loretta M.S. Lau; Michael Lee; Hilda A. Pickett; Roger R. Reddel; Jaswinder S. Samra; James G. Kench; Neil D. Merrett; Krishna Epari; Nam Q. Nguyen; Nikolajs Zeps; Massimo Falconi; Michele Simbolo; Giovanni Butturini; George Van Buren; Stefano Partelli; Matteo Fassan; Kum Kum Khanna; Anthony J. Gill; David A. Wheeler; Richard A. Gibbs; Elizabeth A. Musgrove; Claudio Bassi; Giampaolo Tortora; Paolo Pederzoli; Paola Pederzoli; John V. Pearson; Nicola Waddell; Andrew V. Biankin; Sean M. Grimmond

doi:10.1038/nature21063

Whole-genome landscape of pancreatic neuroendocrine tumours

Aldo Scarpa, David K. Chang, Katia Nones, Vincenzo Corbo, Ann-Marie Patch, Peter Bailey, Rita T. Lawlor, Amber L. Johns, David K. Miller, Andrea Mafficini, Borislav Rusev, Maria Scardoni, Davide Antonello, Stefano Barbi, Katarzyna O. Sikora, Sara Cingarlini, Caterina Vicentini, Skye Mckay, Michael C.J. Quinn, Timothy J.C. BruxnerAngelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Mclean, Craig Nourse, Ehsan Nourbakhsh, Peter J. Wilson, Matthew J. Anderson, J. Lynn Fink, Felicity Newell, Nick Waddell, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Scott Wood, Qinying Xu, Shivashankar Hiriyur Nagaraj, Eliana Amato, Elena Amato, Irene Dalai, Samantha Bersani, Ivana Cataldo, Angelo P. Dei Tos, Paola Capelli, Maria Vittoria Davì, Luca Landoni, Anna Malpaga, Marco Miotto, Vicki L.J. Whitehall, Barbara A. Leggett, Janelle L. Harris, Jonathan Harris, Marc D. Jones, Jeremy Humphris, Lorraine A. Chantrill, Venessa Chin, Adnan M. Nagrial, Marina Pajic, Christopher J. Scarlett, Andreia Pinho, Ilse Rooman, Christopher Toon, Jianmin Wu, Mark Pinese, Mark Cowley, Andrew Barbour, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Jessica A. Lovell, Nigel B. Jamieson, Fraser Duthie, Marie-Claude Gingras, William E. Fisher, Rebecca A. Dagg, Loretta M.S. Lau, Michael Lee, Hilda A. Pickett, Roger R. Reddel, Jaswinder S. Samra, James G. Kench, Neil D. Merrett, Krishna Epari, Nam Q. Nguyen, Nikolajs Zeps, Massimo Falconi, Michele Simbolo, Giovanni Butturini, George Van Buren, Stefano Partelli, Matteo Fassan, Kum Kum Khanna, Anthony J. Gill, David A. Wheeler, Richard A. Gibbs, Elizabeth A. Musgrove, Claudio Bassi, Giampaolo Tortora, Paolo Pederzoli, Paola Pederzoli, John V. Pearson, Nicola Waddell, Andrew V. Biankin, Sean M. Grimmond

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362 Citations (Scopus)

Abstract

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

Original language	English
Pages (from-to)	65-71
Number of pages	7
Journal	Nature
Volume	543
DOIs	https://doi.org/10.1038/nature21063
Publication status	Published - 2017

Keywords

Base Sequence
Calmodulin-Binding Proteins
Carcinoma, Neuroendocrine
Chromatin Assembly and Disassembly
Chromosome Aberrations
DNA Copy Number Variations
DNA Glycosylases
DNA Mutational Analysis
DNA Repair
Female
Genome, Human
Genomics
Germ-Line Mutation
Humans
Male
Pancreatic Neoplasms
RNA-Binding Protein EWS
RNA-Binding Proteins
TOR Serine-Threonine Kinases
Telomere

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10.1038/nature21063

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Scarpa, A., Chang, D. K., Nones, K., Corbo, V., Patch, A.-M., Bailey, P., Lawlor, R. T., Johns, A. L., Miller, D. K., Mafficini, A., Rusev, B., Scardoni, M., Antonello, D., Barbi, S., Sikora, K. O., Cingarlini, S., Vicentini, C., Mckay, S., Quinn, M. C. J., ... Grimmond, S. M. (2017). Whole-genome landscape of pancreatic neuroendocrine tumours. Nature, 543, 65-71. https://doi.org/10.1038/nature21063

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title = "Whole-genome landscape of pancreatic neuroendocrine tumours",

abstract = "The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.",

keywords = "Base Sequence, Calmodulin-Binding Proteins, Carcinoma, Neuroendocrine, Chromatin Assembly and Disassembly, Chromosome Aberrations, DNA Copy Number Variations, DNA Glycosylases, DNA Mutational Analysis, DNA Repair, Female, Genome, Human, Genomics, Germ-Line Mutation, Humans, Male, Pancreatic Neoplasms, RNA-Binding Protein EWS, RNA-Binding Proteins, TOR Serine-Threonine Kinases, Telomere, Base Sequence, Calmodulin-Binding Proteins, Carcinoma, Neuroendocrine, Chromatin Assembly and Disassembly, Chromosome Aberrations, DNA Copy Number Variations, DNA Glycosylases, DNA Mutational Analysis, DNA Repair, Female, Genome, Human, Genomics, Germ-Line Mutation, Humans, Male, Pancreatic Neoplasms, RNA-Binding Protein EWS, RNA-Binding Proteins, TOR Serine-Threonine Kinases, Telomere",

author = "Aldo Scarpa and Chang, {David K.} and Katia Nones and Vincenzo Corbo and Ann-Marie Patch and Peter Bailey and Lawlor, {Rita T.} and Johns, {Amber L.} and Miller, {David K.} and Andrea Mafficini and Borislav Rusev and Maria Scardoni and Davide Antonello and Stefano Barbi and Sikora, {Katarzyna O.} and Sara Cingarlini and Caterina Vicentini and Skye Mckay and Quinn, {Michael C.J.} and Bruxner, {Timothy J.C.} and Christ, {Angelika N.} and Ivon Harliwong and Senel Idrisoglu and Suzanne Mclean and Craig Nourse and Ehsan Nourbakhsh and Wilson, {Peter J.} and Anderson, {Matthew J.} and Fink, {J. Lynn} and Felicity Newell and Nick Waddell and Oliver Holmes and Kazakoff, {Stephen H.} and Conrad Leonard and Scott Wood and Qinying Xu and Nagaraj, {Shivashankar Hiriyur} and Eliana Amato and Elena Amato and Irene Dalai and Samantha Bersani and Ivana Cataldo and {Dei Tos}, {Angelo P.} and Paola Capelli and Dav{\`i}, {Maria Vittoria} and Luca Landoni and Anna Malpaga and Marco Miotto and Whitehall, {Vicki L.J.} and Leggett, {Barbara A.} and Harris, {Janelle L.} and Jonathan Harris and Jones, {Marc D.} and Jeremy Humphris and Chantrill, {Lorraine A.} and Venessa Chin and Nagrial, {Adnan M.} and Marina Pajic and Scarlett, {Christopher J.} and Andreia Pinho and Ilse Rooman and Christopher Toon and Jianmin Wu and Mark Pinese and Mark Cowley and Andrew Barbour and Amanda Mawson and Humphrey, {Emily S.} and Colvin, {Emily K.} and Angela Chou and Lovell, {Jessica A.} and Jamieson, {Nigel B.} and Fraser Duthie and Marie-Claude Gingras and Fisher, {William E.} and Dagg, {Rebecca A.} and Lau, {Loretta M.S.} and Michael Lee and Pickett, {Hilda A.} and Reddel, {Roger R.} and Samra, {Jaswinder S.} and Kench, {James G.} and Merrett, {Neil D.} and Krishna Epari and Nguyen, {Nam Q.} and Nikolajs Zeps and Massimo Falconi and Michele Simbolo and Giovanni Butturini and {Van Buren}, George and Stefano Partelli and Matteo Fassan and Khanna, {Kum Kum} and Gill, {Anthony J.} and Wheeler, {David A.} and Gibbs, {Richard A.} and Musgrove, {Elizabeth A.} and Claudio Bassi and Giampaolo Tortora and Paolo Pederzoli and Paola Pederzoli and Pearson, {John V.} and Nicola Waddell and Biankin, {Andrew V.} and Grimmond, {Sean M.}",

year = "2017",

doi = "10.1038/nature21063",

language = "English",

volume = "543",

pages = "65--71",

journal = "Nature",

issn = "0028-0836",

publisher = "-London : Macmillan, 1869- -New York, NY; Nature America Incorporated",

}

Scarpa, A, Chang, DK, Nones, K, Corbo, V, Patch, A-M, Bailey, P, Lawlor, RT, Johns, AL, Miller, DK, Mafficini, A, Rusev, B, Scardoni, M, Antonello, D, Barbi, S, Sikora, KO, Cingarlini, S, Vicentini, C, Mckay, S, Quinn, MCJ, Bruxner, TJC, Christ, AN, Harliwong, I, Idrisoglu, S, Mclean, S, Nourse, C, Nourbakhsh, E, Wilson, PJ, Anderson, MJ, Fink, JL, Newell, F, Waddell, N, Holmes, O, Kazakoff, SH, Leonard, C, Wood, S, Xu, Q, Nagaraj, SH, Amato, E, Amato, E, Dalai, I, Bersani, S, Cataldo, I, Dei Tos, AP, Capelli, P, Davì, MV, Landoni, L, Malpaga, A, Miotto, M, Whitehall, VLJ, Leggett, BA, Harris, JL, Harris, J, Jones, MD, Humphris, J, Chantrill, LA, Chin, V, Nagrial, AM, Pajic, M, Scarlett, CJ, Pinho, A, Rooman, I, Toon, C, Wu, J, Pinese, M, Cowley, M, Barbour, A, Mawson, A, Humphrey, ES, Colvin, EK, Chou, A, Lovell, JA, Jamieson, NB, Duthie, F, Gingras, M-C, Fisher, WE, Dagg, RA, Lau, LMS, Lee, M, Pickett, HA, Reddel, RR, Samra, JS, Kench, JG, Merrett, ND, Epari, K, Nguyen, NQ, Zeps, N, Falconi, M, Simbolo, M, Butturini, G, Van Buren, G, Partelli, S, Fassan, M, Khanna, KK, Gill, AJ, Wheeler, DA, Gibbs, RA, Musgrove, EA, Bassi, C, Tortora, G, Pederzoli, P, Pederzoli, P, Pearson, JV, Waddell, N, Biankin, AV & Grimmond, SM 2017, 'Whole-genome landscape of pancreatic neuroendocrine tumours', Nature, vol. 543, pp. 65-71. https://doi.org/10.1038/nature21063

TY - JOUR

T1 - Whole-genome landscape of pancreatic neuroendocrine tumours

AU - Scarpa, Aldo

AU - Chang, David K.

AU - Nones, Katia

AU - Corbo, Vincenzo

AU - Patch, Ann-Marie

AU - Bailey, Peter

AU - Lawlor, Rita T.

AU - Johns, Amber L.

AU - Miller, David K.

AU - Mafficini, Andrea

AU - Rusev, Borislav

AU - Scardoni, Maria

AU - Antonello, Davide

AU - Barbi, Stefano

AU - Sikora, Katarzyna O.

AU - Cingarlini, Sara

AU - Vicentini, Caterina

AU - Mckay, Skye

AU - Quinn, Michael C.J.

AU - Bruxner, Timothy J.C.

AU - Christ, Angelika N.

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Mclean, Suzanne

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Wilson, Peter J.

AU - Anderson, Matthew J.

AU - Fink, J. Lynn

AU - Newell, Felicity

AU - Waddell, Nick

AU - Holmes, Oliver

AU - Kazakoff, Stephen H.

AU - Leonard, Conrad

AU - Wood, Scott

AU - Xu, Qinying

AU - Nagaraj, Shivashankar Hiriyur

AU - Amato, Eliana

AU - Amato, Elena

AU - Dalai, Irene

AU - Bersani, Samantha

AU - Cataldo, Ivana

AU - Dei Tos, Angelo P.

AU - Capelli, Paola

AU - Davì, Maria Vittoria

AU - Landoni, Luca

AU - Malpaga, Anna

AU - Miotto, Marco

AU - Whitehall, Vicki L.J.

AU - Leggett, Barbara A.

AU - Harris, Janelle L.

AU - Harris, Jonathan

AU - Jones, Marc D.

AU - Humphris, Jeremy

AU - Chantrill, Lorraine A.

AU - Chin, Venessa

AU - Nagrial, Adnan M.

AU - Pajic, Marina

AU - Scarlett, Christopher J.

AU - Pinho, Andreia

AU - Rooman, Ilse

AU - Toon, Christopher

AU - Wu, Jianmin

AU - Pinese, Mark

AU - Cowley, Mark

AU - Barbour, Andrew

AU - Mawson, Amanda

AU - Humphrey, Emily S.

AU - Colvin, Emily K.

AU - Chou, Angela

AU - Lovell, Jessica A.

AU - Jamieson, Nigel B.

AU - Duthie, Fraser

AU - Gingras, Marie-Claude

AU - Fisher, William E.

AU - Dagg, Rebecca A.

AU - Lau, Loretta M.S.

AU - Lee, Michael

AU - Pickett, Hilda A.

AU - Reddel, Roger R.

AU - Samra, Jaswinder S.

AU - Kench, James G.

AU - Merrett, Neil D.

AU - Epari, Krishna

AU - Nguyen, Nam Q.

AU - Zeps, Nikolajs

AU - Falconi, Massimo

AU - Simbolo, Michele

AU - Butturini, Giovanni

AU - Van Buren, George

AU - Partelli, Stefano

AU - Fassan, Matteo

AU - Khanna, Kum Kum

AU - Gill, Anthony J.

AU - Wheeler, David A.

AU - Gibbs, Richard A.

AU - Musgrove, Elizabeth A.

AU - Bassi, Claudio

AU - Tortora, Giampaolo

AU - Pederzoli, Paolo

AU - Pederzoli, Paola

AU - Pearson, John V.

AU - Waddell, Nicola

AU - Biankin, Andrew V.

AU - Grimmond, Sean M.

PY - 2017

Y1 - 2017

N2 - The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

AB - The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

KW - Base Sequence

KW - Calmodulin-Binding Proteins

KW - Carcinoma, Neuroendocrine

KW - Chromatin Assembly and Disassembly

KW - Chromosome Aberrations

KW - DNA Copy Number Variations

KW - DNA Glycosylases

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Female

KW - Genome, Human

KW - Genomics

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Pancreatic Neoplasms

KW - RNA-Binding Protein EWS

KW - RNA-Binding Proteins

KW - TOR Serine-Threonine Kinases

KW - Telomere

KW - Base Sequence

KW - Calmodulin-Binding Proteins

KW - Carcinoma, Neuroendocrine

KW - Chromatin Assembly and Disassembly

KW - Chromosome Aberrations

KW - DNA Copy Number Variations

KW - DNA Glycosylases

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Female

KW - Genome, Human

KW - Genomics

KW - Germ-Line Mutation

KW - Humans

KW - Male

KW - Pancreatic Neoplasms

KW - RNA-Binding Protein EWS

KW - RNA-Binding Proteins

KW - TOR Serine-Threonine Kinases

KW - Telomere

UR - http://hdl.handle.net/10807/172588

U2 - 10.1038/nature21063

DO - 10.1038/nature21063

M3 - Article

SN - 0028-0836

VL - 543

SP - 65

EP - 71

JO - Nature

JF - Nature

ER -

Whole-genome landscape of pancreatic neuroendocrine tumours

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Keywords

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