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, Sara Cingarlini, Caterina Vicentini, Katarzyna O. Sikora, Skye McKay, Michael C.J. Quinn, Timothy J.C. Bruxner & 85 others 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, 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, Australian Pancreatic Cancer Genome Initiative, Kum Kum Khanna, Anthony J. Gill, David A. Wheeler, Richard A. Gibbs, Elizabeth A. Musgrove, Claudio Bassi, Giampaolo Tortora, Paolo Pederzoli, John V. Pearson, Nicola Waddell, Andrew V. Biankin, Sean M. Grimmond, Vincent Lam

Research output: Contribution to journalArticleResearchpeer-review

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.

LanguageEnglish
Pages65-71
Number of pages7
JournalNature
Volume543
Issue number7643
DOIs
Publication statusPublished - 2 Mar 2017
Externally publishedYes

Fingerprint

Neuroendocrine Tumors
DNA Repair
Genome
Mutation
Gene Fusion
DNA Glycosylases
Multiple Endocrine Neoplasia Type 1
Chromatin Assembly and Disassembly
Germ-Line Mutation
Telomere
Point Mutation
Genes
DNA Damage
Maintenance
Gene Expression
Neoplasms

Cite this

Scarpa, A., Chang, D. K., Nones, K., Corbo, V., Patch, A. M., Bailey, P., ... Grimmond, S. M. (2017). Whole-genome landscape of pancreatic neuroendocrine tumours. Nature, 543(7643), 65-71. https://doi.org/10.1038/nature21063
Scarpa, Aldo ; Chang, David K. ; Nones, Katia ; Corbo, Vincenzo ; Patch, Ann Marie ; Bailey, Peter ; Lawlor, Rita T. ; Johns, Amber L. ; Miller, David K. ; Mafficini, Andrea ; Rusev, Borislav ; Scardoni, Maria ; Antonello, Davide ; Barbi, Stefano ; Cingarlini, Sara ; Vicentini, Caterina ; Sikora, Katarzyna O. ; McKay, Skye ; Quinn, Michael C.J. ; Bruxner, Timothy J.C. ; Christ, Angelika N. ; Harliwong, Ivon ; Idrisoglu, Senel ; McLean, Suzanne ; Nourse, Craig ; Nourbakhsh, Ehsan ; Wilson, Peter J. ; Anderson, Matthew J. ; Fink, J. Lynn ; Newell, Felicity ; Waddell, Nick ; Holmes, Oliver ; Kazakoff, Stephen H. ; Leonard, Conrad ; Wood, Scott ; Xu, Qinying ; Nagaraj, Shivashankar Hiriyur ; Amato, Eliana ; Dalai, Irene ; Bersani, Samantha ; Cataldo, Ivana ; Dei Tos, Angelo P. ; Capelli, Paola ; Davì, Maria Vittoria ; Landoni, Luca ; Malpaga, Anna ; Miotto, Marco ; Whitehall, Vicki L.J. ; Leggett, Barbara A. ; Harris, Janelle L. ; Harris, Jonathan ; Jones, Marc D. ; Humphris, Jeremy ; Chantrill, Lorraine A. ; Chin, Venessa ; Nagrial, Adnan M. ; Pajic, Marina ; Scarlett, Christopher J. ; Pinho, Andreia ; Rooman, Ilse ; Toon, Christopher ; Wu, Jianmin ; Pinese, Mark ; Cowley, Mark ; Barbour, Andrew ; Mawson, Amanda ; Humphrey, Emily S. ; Colvin, Emily K. ; Chou, Angela ; Lovell, Jessica A. ; Jamieson, Nigel B. ; Duthie, Fraser ; Gingras, Marie Claude ; Fisher, William E. ; Dagg, Rebecca A. ; Lau, Loretta M.S. ; Lee, Michael ; Pickett, Hilda A. ; Reddel, Roger R. ; Samra, Jaswinder S. ; Kench, James G. ; Merrett, Neil D. ; Epari, Krishna ; Nguyen, Nam Q. ; Zeps, Nikolajs ; Falconi, Massimo ; Simbolo, Michele ; Butturini, Giovanni ; Van Buren, George ; Partelli, Stefano ; Fassan, Matteo ; Australian Pancreatic Cancer Genome Initiative ; Khanna, Kum Kum ; Gill, Anthony J. ; Wheeler, David A. ; Gibbs, Richard A. ; Musgrove, Elizabeth A. ; Bassi, Claudio ; Tortora, Giampaolo ; Pederzoli, Paolo ; Pearson, John V. ; Waddell, Nicola ; Biankin, Andrew V. ; Grimmond, Sean M. / Whole-genome landscape of pancreatic neuroendocrine tumours. In: Nature. 2017 ; Vol. 543, No. 7643. pp. 65-71.
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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.",
author = "Aldo Scarpa and Chang, {David K.} and Katia Nones and Vincenzo Corbo and Patch, {Ann Marie} 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 Sara Cingarlini and Caterina Vicentini and Sikora, {Katarzyna O.} 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 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 Gingras, {Marie Claude} 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 {Australian Pancreatic Cancer Genome Initiative} 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 Pearson, {John V.} and Nicola Waddell and Biankin, {Andrew V.} and Grimmond, {Sean M.} and Vincent Lam",
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Scarpa, A, Chang, DK, Nones, K, Corbo, V, Patch, AM, Bailey, P, Lawlor, RT, Johns, AL, Miller, DK, Mafficini, A, Rusev, B, Scardoni, M, Antonello, D, Barbi, S, Cingarlini, S, Vicentini, C, Sikora, KO, 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, 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, MC, 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, Australian Pancreatic Cancer Genome Initiative, Khanna, KK, Gill, AJ, Wheeler, DA, Gibbs, RA, Musgrove, EA, Bassi, C, Tortora, G, Pederzoli, P, Pearson, JV, Waddell, N, Biankin, AV & Grimmond, SM 2017, 'Whole-genome landscape of pancreatic neuroendocrine tumours', Nature, vol. 543, no. 7643, pp. 65-71. https://doi.org/10.1038/nature21063

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

In: Nature, Vol. 543, No. 7643, 02.03.2017, p. 65-71.

Research output: Contribution to journalArticleResearchpeer-review

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 - Cingarlini, Sara

AU - Vicentini, Caterina

AU - Sikora, Katarzyna O.

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 - 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 - Australian Pancreatic Cancer Genome Initiative

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 - Pearson, John V.

AU - Waddell, Nicola

AU - Biankin, Andrew V.

AU - Grimmond, Sean M.

AU - Lam, Vincent

PY - 2017/3/2

Y1 - 2017/3/2

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.

UR - http://www.scopus.com/inward/record.url?scp=85014580625&partnerID=8YFLogxK

U2 - 10.1038/nature21063

DO - 10.1038/nature21063

M3 - Article

VL - 543

SP - 65

EP - 71

JO - Nature

T2 - Nature

JF - Nature

SN - 1476-4687

IS - 7643

ER -

Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature. 2017 Mar 2;543(7643):65-71. https://doi.org/10.1038/nature21063