Whole genomes redefine the mutational landscape of pancreatic cancer

N. Waddell; M. Pajic; Patch A. -M.; D. K. Chang; K. S. Kassahn; P. Bailey; A. L. Johns; D. Miller; K. Nones; K. Quek; M. C. J. Quinn; A. J. Robertson; M. Z. H. Fadlullah; T. J. C. Bruxner; A. N. Christ; I. Harliwong; S. Idrisoglu; S. Manning; C. Nourse; E. Nourbakhsh; S. Wani; P. J. Wilson; E. Markham; N. Cloonan; M. J. Anderson; J. L. Fink; O. Holmes; S. H. Kazakoff; C. Leonard; F. Newell; B. Poudel; S. Song; D. Taylor; N. Waddell; S. Wood; Q. Xu; J. Wu; M. Pinese; M. J. Cowley; H. C. Lee; M. D. Jones; A. M. Nagrial; J. Humphris; L. A. Chantrill; V. Chin; A. M. Steinmann; A. Mawson; E. S. Humphrey; E. K. Colvin; A. Chou; C. J. Scarlett; A. V. Pinho; M. Giry-Laterriere; I. Rooman; J. S. Samra; J. G. Kench; J. A. Pettitt; N. D. Merrett; C. Toon; K. Epari; N. Q. Nguyen; A. Barbour; N. Zeps; N. B. Jamieson; J. S. Graham; S. P. Niclou; R. Bjerkvig; R. Grutzmann; D. Aust; R. H. Hruban; A. Maitra; C. A. Iacobuzio-Donahue; C. L. Wolfgang; R. A. Morgan; R. T. Lawlor; V. Corbo; C. Bassi; M. Falconi; G. Zamboni; Giampaolo Tortora; M. A. Tempero; A. J. Gill; J. R. Eshleman; C. Pilarsky; A. Scarpa; E. A. Musgrove; J. V. Pearson; A. V. Biankin; S. M. Grimmond

doi:10.1038/nature14169

Whole genomes redefine the mutational landscape of pancreatic cancer

N. Waddell, M. Pajic, Patch A. -M., D. K. Chang, K. S. Kassahn, P. Bailey, A. L. Johns, D. Miller, K. Nones, K. Quek, M. C. J. Quinn, A. J. Robertson, M. Z. H. Fadlullah, T. J. C. Bruxner, A. N. Christ, I. Harliwong, S. Idrisoglu, S. Manning, C. Nourse, E. NourbakhshS. Wani, P. J. Wilson, E. Markham, N. Cloonan, M. J. Anderson, J. L. Fink, O. Holmes, S. H. Kazakoff, C. Leonard, F. Newell, B. Poudel, S. Song, D. Taylor, N. Waddell, S. Wood, Q. Xu, J. Wu, M. Pinese, M. J. Cowley, H. C. Lee, M. D. Jones, A. M. Nagrial, J. Humphris, L. A. Chantrill, V. Chin, A. M. Steinmann, A. Mawson, E. S. Humphrey, E. K. Colvin, A. Chou, C. J. Scarlett, A. V. Pinho, M. Giry-Laterriere, I. Rooman, J. S. Samra, J. G. Kench, J. A. Pettitt, N. D. Merrett, C. Toon, K. Epari, N. Q. Nguyen, A. Barbour, N. Zeps, N. B. Jamieson, J. S. Graham, S. P. Niclou, R. Bjerkvig, R. Grutzmann, D. Aust, R. H. Hruban, A. Maitra, C. A. Iacobuzio-Donahue, C. L. Wolfgang, R. A. Morgan, R. T. Lawlor, V. Corbo, C. Bassi, M. Falconi, G. Zamboni, Giampaolo Tortora, M. A. Tempero, A. J. Gill, J. R. Eshleman, C. Pilarsky, A. Scarpa, E. A. Musgrove, J. V. Pearson, A. V. Biankin^*, S. M. Grimmond

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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	Inglese
pagine (da-a)	495-501
Numero di pagine	7
Rivista	Nature
Volume	518
Numero di pubblicazione	7540
DOI	https://doi.org/10.1038/nature14169
Stato di pubblicazione	Pubblicato - 2015

All Science Journal Classification (ASJC) codes

Multidisciplinare

Keywords

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

OSS delle Nazioni Unite

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10.1038/nature14169

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Waddell, N., Pajic, M., -M., P. A., 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(7540), 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, BRCA1, BRCA2, Carcinoma, DNA Mutational Analysis, DNA Repair, Female, Genes, Genetic Markers, Genome, Genomic Instability, Genomics, Genotype, Human, Humans, Mice, Mutation, Pancreatic Ductal, Pancreatic Neoplasms, Platinum, Point Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Xenograft Model Antitumor Assays, Adenocarcinoma, Animals, BRCA1, BRCA2, Carcinoma, DNA Mutational Analysis, DNA Repair, Female, Genes, Genetic Markers, Genome, Genomic Instability, Genomics, Genotype, Human, Humans, Mice, Mutation, Pancreatic Ductal, Pancreatic Neoplasms, Platinum, Point Mutation, Poly(ADP-ribose) Polymerase Inhibitors, Xenograft Model Antitumor Assays",

author = "N. Waddell and M. Pajic and -M., {Patch A.} and Chang, {D. K.} and Kassahn, {K. S.} and P. Bailey and Johns, {A. L.} and D. Miller and K. Nones and K. Quek and Quinn, {M. C. J.} and Robertson, {A. J.} and Fadlullah, {M. Z. H.} and Bruxner, {T. J. C.} and Christ, {A. N.} and I. Harliwong and S. Idrisoglu and S. Manning and C. Nourse and E. Nourbakhsh and S. Wani and Wilson, {P. J.} and E. Markham and N. Cloonan and Anderson, {M. J.} and Fink, {J. L.} and O. Holmes and Kazakoff, {S. H.} and C. Leonard and F. Newell and B. Poudel and S. Song and D. Taylor and N. Waddell and S. Wood and Q. Xu and J. Wu and M. Pinese and Cowley, {M. J.} and Lee, {H. C.} and Jones, {M. D.} and Nagrial, {A. M.} and J. Humphris and Chantrill, {L. A.} and V. Chin and Steinmann, {A. M.} and A. Mawson and Humphrey, {E. S.} and Colvin, {E. K.} and A. Chou and Scarlett, {C. J.} and Pinho, {A. V.} and M. Giry-Laterriere and I. Rooman and Samra, {J. S.} and Kench, {J. G.} and Pettitt, {J. A.} and Merrett, {N. D.} and C. Toon and K. Epari and Nguyen, {N. Q.} and A. Barbour and N. Zeps and Jamieson, {N. B.} and Graham, {J. S.} and Niclou, {S. P.} and R. Bjerkvig and R. Grutzmann and D. Aust and Hruban, {R. H.} and A. Maitra and Iacobuzio-Donahue, {C. A.} and Wolfgang, {C. L.} and Morgan, {R. A.} and Lawlor, {R. T.} and V. Corbo and C. Bassi and M. Falconi and G. Zamboni and Giampaolo Tortora and Tempero, {M. A.} and Gill, {A. J.} and Eshleman, {J. R.} and C. Pilarsky and A. Scarpa and Musgrove, {E. A.} and Pearson, {J. V.} and Biankin, {A. V.} and Grimmond, {S. M.}",

year = "2015",

doi = "10.1038/nature14169",

language = "English",

volume = "518",

pages = "495--501",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Research",

number = "7540",

}

Waddell, N, Pajic, M, -M., PA, 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, Grutzmann, 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, n. 7540, pagg. 495-501. https://doi.org/10.1038/nature14169

TY - JOUR

T1 - Whole genomes redefine the mutational landscape of pancreatic cancer

AU - Waddell, N.

AU - Pajic, M.

AU - -M., Patch A.

AU - Chang, D. K.

AU - Kassahn, K. S.

AU - Bailey, P.

AU - Johns, A. L.

AU - Miller, D.

AU - Nones, K.

AU - Quek, K.

AU - Quinn, M. C. J.

AU - Robertson, A. J.

AU - Fadlullah, M. Z. H.

AU - Bruxner, T. J. C.

AU - Christ, A. N.

AU - Harliwong, I.

AU - Idrisoglu, S.

AU - Manning, S.

AU - Nourse, C.

AU - Nourbakhsh, E.

AU - Wani, S.

AU - Wilson, P. J.

AU - Markham, E.

AU - Cloonan, N.

AU - Anderson, M. J.

AU - Fink, J. L.

AU - Holmes, O.

AU - Kazakoff, S. H.

AU - Leonard, C.

AU - Newell, F.

AU - Poudel, B.

AU - Song, S.

AU - Taylor, D.

AU - Waddell, N.

AU - Wood, S.

AU - Xu, Q.

AU - Wu, J.

AU - Pinese, M.

AU - Cowley, M. J.

AU - Lee, H. C.

AU - Jones, M. D.

AU - Nagrial, A. M.

AU - Humphris, J.

AU - Chantrill, L. A.

AU - Chin, V.

AU - Steinmann, A. M.

AU - Mawson, A.

AU - Humphrey, E. S.

AU - Colvin, E. K.

AU - Chou, A.

AU - Scarlett, C. J.

AU - Pinho, A. V.

AU - Giry-Laterriere, M.

AU - Rooman, I.

AU - Samra, J. S.

AU - Kench, J. G.

AU - Pettitt, J. A.

AU - Merrett, N. D.

AU - Toon, C.

AU - Epari, K.

AU - Nguyen, N. Q.

AU - Barbour, A.

AU - Zeps, N.

AU - Jamieson, N. B.

AU - Graham, J. S.

AU - Niclou, S. P.

AU - Bjerkvig, R.

AU - Grutzmann, R.

AU - Aust, D.

AU - Hruban, R. H.

AU - Maitra, A.

AU - Iacobuzio-Donahue, C. A.

AU - Wolfgang, C. L.

AU - Morgan, R. A.

AU - Lawlor, R. T.

AU - Corbo, V.

AU - Bassi, C.

AU - Falconi, M.

AU - Zamboni, G.

AU - Tortora, Giampaolo

AU - Tempero, M. A.

AU - Gill, A. J.

AU - Eshleman, J. R.

AU - Pilarsky, C.

AU - Scarpa, A.

AU - Musgrove, E. A.

AU - Pearson, J. V.

AU - Biankin, A. V.

AU - Grimmond, S. 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 - BRCA1

KW - BRCA2

KW - Carcinoma

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Female

KW - Genes

KW - Genetic Markers

KW - Genome

KW - Genomic Instability

KW - Genomics

KW - Genotype

KW - Human

KW - Humans

KW - Mice

KW - Mutation

KW - Pancreatic Ductal

KW - Pancreatic Neoplasms

KW - Platinum

KW - Point Mutation

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Xenograft Model Antitumor Assays

KW - Adenocarcinoma

KW - Animals

KW - BRCA1

KW - BRCA2

KW - Carcinoma

KW - DNA Mutational Analysis

KW - DNA Repair

KW - Female

KW - Genes

KW - Genetic Markers

KW - Genome

KW - Genomic Instability

KW - Genomics

KW - Genotype

KW - Human

KW - Humans

KW - Mice

KW - Mutation

KW - Pancreatic Ductal

KW - Pancreatic Neoplasms

KW - Platinum

KW - Point Mutation

KW - Poly(ADP-ribose) Polymerase Inhibitors

KW - Xenograft Model Antitumor Assays

UR - https://publicatt.unicatt.it/handle/10807/172577

UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=84924056345&origin=inward

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84924056345&origin=inward

U2 - 10.1038/nature14169

DO - 10.1038/nature14169

M3 - Article

SN - 0028-0836

VL - 518

SP - 495

EP - 501

JO - Nature

JF - Nature

IS - 7540

ER -

Whole genomes redefine the mutational landscape of pancreatic cancer

Abstract

All Science Journal Classification (ASJC) codes

Keywords

OSS delle Nazioni Unite

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