Whole genomes redefine the mutational landscape of pancreatic cancer

Nicola Waddell; Marina Pajic; Ann-Marie Patch; David K. Chang; Karin S. Kassahn; Peter Bailey; Amber L. Johns; David Miller; Katia Nones; Kelly Quek; Michael C. J. Quinn; Alan J. Robertson; Muhammad Z. H. Fadlullah; Tim J. C. Bruxner; Angelika N. Christ; Ivon Harliwong; Senel Idrisoglu; Suzanne Manning; Craig Nourse; Ehsan Nourbakhsh; Shivangi Wani; Peter J. Wilson; Emma Markham; Nicole Cloonan; Matthew J. Anderson; J. Lynn Fink; Oliver Holmes; Stephen H. Kazakoff; Conrad Leonard; Felicity Newell; Barsha Poudel; Sarah Song; Darrin Taylor; Nick Waddell; Scott Wood; Qinying Xu; Jianmin Wu; Mark Pinese; Mark J. Cowley; Hong C. Lee; Marc D. Jones; Adnan M. Nagrial; Jeremy Humphris; Lorraine A. Chantrill; Venessa Chin; Angela M. Steinmann; Amanda Mawson; Emily S. Humphrey; Emily K. Colvin; Angela Chou; Christopher J. Scarlett; Andreia V. Pinho; Marc Giry-Laterriere; Ilse Rooman; Jaswinder S. Samra; James G. Kench; Jessica A. Pettitt; Neil D. Merrett; Christopher Toon; Krishna Epari; Nam Q. Nguyen; Andrew Barbour; Nikolajs Zeps; Nigel B. Jamieson; Janet S. Graham; Simone P. Niclou; Rolf Bjerkvig; Robert Grützmann; Daniela Aust; Ralph H. Hruban; Anirban Maitra; Christine A. Iacobuzio-Donahue; Christopher L. Wolfgang; Richard A. Morgan; Rita T. Lawlor; Vincenzo Corbo; Claudio Bassi; Massimo Falconi; Giuseppe Zamboni; Giampaolo Tortora; Margaret A. Tempero; Anthony J. Gill; James R. Eshleman; Christian Pilarsky; Aldo Scarpa; Elizabeth A. Musgrove; John V. Pearson; Andrew V. Biankin; Sean M. Grimmond

doi:10.1038/nature14169

Whole genomes redefine the mutational landscape of pancreatic cancer

Nicola Waddell, Marina Pajic, Ann-Marie Patch, David K. Chang, Karin S. Kassahn, Peter Bailey, Amber L. Johns, David Miller, Katia Nones, Kelly Quek, Michael C. J. Quinn, Alan J. Robertson, Muhammad Z. H. Fadlullah, Tim J. C. Bruxner, Angelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan NourbakhshShivangi Wani, Peter J. Wilson, Emma Markham, Nicole Cloonan, Matthew J. Anderson, J. Lynn Fink, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, Jianmin Wu, Mark Pinese, Mark J. Cowley, Hong C. Lee, Marc D. Jones, Adnan M. Nagrial, Jeremy Humphris, Lorraine A. Chantrill, Venessa Chin, Angela M. Steinmann, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Christopher J. Scarlett, Andreia V. Pinho, Marc Giry-Laterriere, Ilse Rooman, Jaswinder S. Samra, James G. Kench, Jessica A. Pettitt, Neil D. Merrett, Christopher Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Nigel B. Jamieson, Janet S. Graham, Simone P. Niclou, Rolf Bjerkvig, Robert Grützmann, Daniela Aust, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Vincenzo Corbo, Claudio Bassi, Massimo Falconi, Giuseppe Zamboni, Giampaolo Tortora, Margaret A. Tempero, Anthony J. Gill, James R. Eshleman, Christian Pilarsky, Aldo Scarpa, Elizabeth A. Musgrove, John V. Pearson, Andrew V. Biankin, Sean M. Grimmond

Risultato della ricerca: Contributo in rivista › Articolo in rivista

1296 Citazioni (Scopus)

Abstract

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Lingua originale	English
pagine (da-a)	495-501
Numero di pagine	7
Rivista	Nature
Volume	518
DOI	https://doi.org/10.1038/nature14169
Stato di pubblicazione	Pubblicato - 2015

Keywords

Adenocarcinoma
Animals
Carcinoma, Pancreatic Ductal
DNA Mutational Analysis
DNA Repair
Female
Genes, BRCA1
Genes, BRCA2
Genetic Markers
Genome, Human
Genomic Instability
Genomics
Genotype
Humans
Mice
Mutation
Pancreatic Neoplasms
Platinum
Point Mutation
Poly(ADP-ribose) Polymerase Inhibitors
Xenograft Model Antitumor Assays

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10.1038/nature14169

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Waddell, N., Pajic, M., Patch, A-M., Chang, D. K., Kassahn, K. S., Bailey, P., Johns, A. L., Miller, D., Nones, K., Quek, K., Quinn, M. C. J., Robertson, A. J., Fadlullah, M. Z. H., Bruxner, T. J. C., Christ, A. N., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., ... Grimmond, S. M. (2015). Whole genomes redefine the mutational landscape of pancreatic cancer. Nature, 518, 495-501. https://doi.org/10.1038/nature14169

@article{8ee4beeb624140a68a8038afe8357861,

title = "Whole genomes redefine the mutational landscape of pancreatic cancer",

abstract = "Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.",

keywords = "Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, DNA Mutational Analysis, DNA Repair, Female, Genes, BRCA1, Genes, BRCA2, Genetic Markers, Genome, Human, Genomic Instability, Genomics, Genotype, Humans, Mice, Mutation, Pancreatic Neoplasms, Platinum, Point Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Xenograft Model Antitumor Assays, Adenocarcinoma, Animals, Carcinoma, Pancreatic Ductal, DNA Mutational Analysis, DNA Repair, Female, Genes, BRCA1, Genes, BRCA2, Genetic Markers, Genome, Human, Genomic Instability, Genomics, Genotype, Humans, Mice, Mutation, Pancreatic Neoplasms, Platinum, Point Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Xenograft Model Antitumor Assays",

author = "Nicola Waddell and Marina Pajic and Ann-Marie Patch and Chang, {David K.} and Kassahn, {Karin S.} and Peter Bailey and Johns, {Amber L.} and David Miller and Katia Nones and Kelly Quek and Quinn, {Michael C. J.} and Robertson, {Alan J.} and Fadlullah, {Muhammad Z. H.} and Bruxner, {Tim J. C.} and Christ, {Angelika N.} and Ivon Harliwong and Senel Idrisoglu and Suzanne Manning and Craig Nourse and Ehsan Nourbakhsh and Shivangi Wani and Wilson, {Peter J.} and Emma Markham and Nicole Cloonan and Anderson, {Matthew J.} and Fink, {J. Lynn} and Oliver Holmes and Kazakoff, {Stephen H.} and Conrad Leonard and Felicity Newell and Barsha Poudel and Sarah Song and Darrin Taylor and Nick Waddell and Scott Wood and Qinying Xu and Jianmin Wu and Mark Pinese and Cowley, {Mark J.} and Lee, {Hong C.} and Jones, {Marc D.} and Nagrial, {Adnan M.} and Jeremy Humphris and Chantrill, {Lorraine A.} and Venessa Chin and Steinmann, {Angela M.} and Amanda Mawson and Humphrey, {Emily S.} and Colvin, {Emily K.} and Angela Chou and Scarlett, {Christopher J.} and Pinho, {Andreia V.} and Marc Giry-Laterriere and Ilse Rooman and Samra, {Jaswinder S.} and Kench, {James G.} and Pettitt, {Jessica A.} and Merrett, {Neil D.} and Christopher Toon and Krishna Epari and Nguyen, {Nam Q.} and Andrew Barbour and Nikolajs Zeps and Jamieson, {Nigel B.} and Graham, {Janet S.} and Niclou, {Simone P.} and Rolf Bjerkvig and Robert Gr{\"u}tzmann and Daniela Aust and Hruban, {Ralph H.} and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Lawlor, {Rita T.} and Vincenzo Corbo and Claudio Bassi and Massimo Falconi and Giuseppe Zamboni and Giampaolo Tortora and Tempero, {Margaret A.} and Gill, {Anthony J.} and Eshleman, {James R.} and Christian Pilarsky and Aldo Scarpa and Musgrove, {Elizabeth A.} and Pearson, {John V.} and Biankin, {Andrew V.} and Grimmond, {Sean M.}",

year = "2015",

doi = "10.1038/nature14169",

language = "English",

volume = "518",

pages = "495--501",

journal = "Nature",

issn = "0028-0836",

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

}

Waddell, N, Pajic, M, Patch, A-M, Chang, DK, Kassahn, KS, Bailey, P, Johns, AL, Miller, D, Nones, K, Quek, K, Quinn, MCJ, Robertson, AJ, Fadlullah, MZH, Bruxner, TJC, Christ, AN, Harliwong, I, Idrisoglu, S, Manning, S, Nourse, C, Nourbakhsh, E, Wani, S, Wilson, PJ, Markham, E, Cloonan, N, Anderson, MJ, Fink, JL, Holmes, O, Kazakoff, SH, Leonard, C, Newell, F, Poudel, B, Song, S, Taylor, D, Waddell, N, Wood, S, Xu, Q, Wu, J, Pinese, M, Cowley, MJ, Lee, HC, Jones, MD, Nagrial, AM, Humphris, J, Chantrill, LA, Chin, V, Steinmann, AM, Mawson, A, Humphrey, ES, Colvin, EK, Chou, A, Scarlett, CJ, Pinho, AV, Giry-Laterriere, M, Rooman, I, Samra, JS, Kench, JG, Pettitt, JA, Merrett, ND, Toon, C, Epari, K, Nguyen, NQ, Barbour, A, Zeps, N, Jamieson, NB, Graham, JS, Niclou, SP, Bjerkvig, R, Grützmann, R, Aust, D, Hruban, RH, Maitra, A, Iacobuzio-Donahue, CA, Wolfgang, CL, Morgan, RA, Lawlor, RT, Corbo, V, Bassi, C, Falconi, M, Zamboni, G, Tortora, G, Tempero, MA, Gill, AJ, Eshleman, JR, Pilarsky, C, Scarpa, A, Musgrove, EA, Pearson, JV, Biankin, AV & Grimmond, SM 2015, 'Whole genomes redefine the mutational landscape of pancreatic cancer', Nature, vol. 518, pagg. 495-501. https://doi.org/10.1038/nature14169

TY - JOUR

T1 - Whole genomes redefine the mutational landscape of pancreatic cancer

AU - Waddell, Nicola

AU - Pajic, Marina

AU - Patch, Ann-Marie

AU - Chang, David K.

AU - Kassahn, Karin S.

AU - Bailey, Peter

AU - Johns, Amber L.

AU - Miller, David

AU - Nones, Katia

AU - Quek, Kelly

AU - Quinn, Michael C. J.

AU - Robertson, Alan J.

AU - Fadlullah, Muhammad Z. H.

AU - Bruxner, Tim J. C.

AU - Christ, Angelika N.

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Manning, Suzanne

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Wani, Shivangi

AU - Wilson, Peter J.

AU - Markham, Emma

AU - Cloonan, Nicole

AU - Anderson, Matthew J.

AU - Fink, J. Lynn

AU - Holmes, Oliver

AU - Kazakoff, Stephen H.

AU - Leonard, Conrad

AU - Newell, Felicity

AU - Poudel, Barsha

AU - Song, Sarah

AU - Taylor, Darrin

AU - Waddell, Nick

AU - Wood, Scott

AU - Xu, Qinying

AU - Wu, Jianmin

AU - Pinese, Mark

AU - Cowley, Mark J.

AU - Lee, Hong C.

AU - Jones, Marc D.

AU - Nagrial, Adnan M.

AU - Humphris, Jeremy

AU - Chantrill, Lorraine A.

AU - Chin, Venessa

AU - Steinmann, Angela M.

AU - Mawson, Amanda

AU - Humphrey, Emily S.

AU - Colvin, Emily K.

AU - Chou, Angela

AU - Scarlett, Christopher J.

AU - Pinho, Andreia V.

AU - Giry-Laterriere, Marc

AU - Rooman, Ilse

AU - Samra, Jaswinder S.

AU - Kench, James G.

AU - Pettitt, Jessica A.

AU - Merrett, Neil D.

AU - Toon, Christopher

AU - Epari, Krishna

AU - Nguyen, Nam Q.

AU - Barbour, Andrew

AU - Zeps, Nikolajs

AU - Jamieson, Nigel B.

AU - Graham, Janet S.

AU - Niclou, Simone P.

AU - Bjerkvig, Rolf

AU - Grützmann, Robert

AU - Aust, Daniela

AU - Hruban, Ralph H.

AU - Maitra, Anirban

AU - Iacobuzio-Donahue, Christine A.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Lawlor, Rita T.

AU - Corbo, Vincenzo

AU - Bassi, Claudio

AU - Falconi, Massimo

AU - Zamboni, Giuseppe

AU - Tortora, Giampaolo

AU - Tempero, Margaret A.

AU - Gill, Anthony J.

AU - Eshleman, James R.

AU - Pilarsky, Christian

AU - Scarpa, Aldo

AU - Musgrove, Elizabeth A.

AU - Pearson, John V.

AU - Biankin, Andrew V.

AU - Grimmond, Sean M.

PY - 2015

Y1 - 2015

N2 - Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

AB - Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

KW - Adenocarcinoma

KW - Animals

KW - Carcinoma, Pancreatic Ductal

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Markers

KW - Genome, Human

KW - Genomic Instability

KW - Genomics

KW - Genotype

KW - Humans

KW - Mice

KW - Mutation

KW - Pancreatic Neoplasms

KW - Platinum

KW - Point Mutation

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Xenograft Model Antitumor Assays

KW - Adenocarcinoma

KW - Animals

KW - Carcinoma, Pancreatic Ductal

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Female

KW - Genes, BRCA1

KW - Genes, BRCA2

KW - Genetic Markers

KW - Genome, Human

KW - Genomic Instability

KW - Genomics

KW - Genotype

KW - Humans

KW - Mice

KW - Mutation

KW - Pancreatic Neoplasms

KW - Platinum

KW - Point Mutation

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Xenograft Model Antitumor Assays

UR - http://hdl.handle.net/10807/172577

U2 - 10.1038/nature14169

DO - 10.1038/nature14169

M3 - Article

SN - 0028-0836

VL - 518

SP - 495

EP - 501

JO - Nature

JF - Nature

ER -

Whole genomes redefine the mutational landscape of pancreatic cancer

Abstract

Keywords

OSS delle Nazioni Unite

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