Genomic analyses identify molecular subtypes of pancreatic cancer

P. Bailey; D.K. Chang; K. Nones; A.L. Johns; A.M. Patch; M.C. Gingras; D.K. Miller; A.N. Christ; T.J.C. Bruxner; M.C. Quinn; C. Nourse; L.C. Murtaugh; I. Harliwong; S. Idrisoglu; S. Manning; E. Nourbakhsh; S. Wani; L. Fink; O. Holmes; V. Chin; M.J. Anderson; S. Kazakoff; C. Leonard; F. Newell; N. Waddell; S. Wood; Q. Xu; P.J. Wilson; N. Cloonan; K.S. Kassahn; D. Taylor; K. Quek; A. Robertson; L. Pantano; L. Mincarelli; L.N. Sanchez; L. Evers; J. Wu; M. Pinese; M.J. Cowley; M.D. Jones; E.K. Colvin; A.M. Nagrial; E.S. Humphrey; L.A. Chantrill; A. Mawson; J. Humphris; A. Chou; M. Pajic; C.J. Scarlett; A.V. Pinho; M. Giry-Laterriere; I. Rooman; J.S. Samra; Nikolajs Zeps

doi:10.1038/nature16965

Genomic analyses identify molecular subtypes of pancreatic cancer

P. Bailey, D.K. Chang, K. Nones, A.L. Johns, A.M. Patch, M.C. Gingras, D.K. Miller, A.N. Christ, T.J.C. Bruxner, M.C. Quinn, C. Nourse, L.C. Murtaugh, I. Harliwong, S. Idrisoglu, S. Manning, E. Nourbakhsh, S. Wani, L. Fink, O. Holmes, V. ChinM.J. Anderson, S. Kazakoff, C. Leonard, F. Newell, N. Waddell, S. Wood, Q. Xu, P.J. Wilson, N. Cloonan, K.S. Kassahn, D. Taylor, K. Quek, A. Robertson, L. Pantano, L. Mincarelli, L.N. Sanchez, L. Evers, J. Wu, M. Pinese, M.J. Cowley, M.D. Jones, E.K. Colvin, A.M. Nagrial, E.S. Humphrey, L.A. Chantrill, A. Mawson, J. Humphris, A. Chou, M. Pajic, C.J. Scarlett, A.V. Pinho, M. Giry-Laterriere, I. Rooman, J.S. Samra, Nikolajs Zeps

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Abstract

© 2016 Macmillan Publishers Limited. All rights reserved. Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

Original language	English
Pages (from-to)	47-52
Number of pages	6
Journal	Nature
Volume	531
Issue number	7592
Early online date	24 Feb 2016
DOIs	https://doi.org/10.1038/nature16965
Publication status	Published - 3 Mar 2016

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Bailey, P., Chang, D. K., Nones, K., Johns, A. L., Patch, A. M., Gingras, M. C., Miller, D. K., Christ, A. N., Bruxner, T. J. C., Quinn, M. C., Nourse, C., Murtaugh, L. C., Harliwong, I., Idrisoglu, S., Manning, S., Nourbakhsh, E., Wani, S., Fink, L., Holmes, O., ... Zeps, N. (2016). Genomic analyses identify molecular subtypes of pancreatic cancer. Nature, 531(7592), 47-52. https://doi.org/10.1038/nature16965

@article{bbdd0d5368ec48a6b8e706a48bfdb68f,

title = "Genomic analyses identify molecular subtypes of pancreatic cancer",

abstract = "{\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved. Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.",

author = "P. Bailey and D.K. Chang and K. Nones and A.L. Johns and A.M. Patch and M.C. Gingras and D.K. Miller and A.N. Christ and T.J.C. Bruxner and M.C. Quinn and C. Nourse and L.C. Murtaugh and I. Harliwong and S. Idrisoglu and S. Manning and E. Nourbakhsh and S. Wani and L. Fink and O. Holmes and V. Chin and M.J. Anderson and S. Kazakoff and C. Leonard and F. Newell and N. Waddell and S. Wood and Q. Xu and P.J. Wilson and N. Cloonan and K.S. Kassahn and D. Taylor and K. Quek and A. Robertson and L. Pantano and L. Mincarelli and L.N. Sanchez and L. Evers and J. Wu and M. Pinese and M.J. Cowley and M.D. Jones and E.K. Colvin and A.M. Nagrial and E.S. Humphrey and L.A. Chantrill and A. Mawson and J. Humphris and A. Chou and M. Pajic and C.J. Scarlett and A.V. Pinho and M. Giry-Laterriere and I. Rooman and J.S. Samra and Nikolajs Zeps",

year = "2016",

month = mar,

day = "3",

doi = "10.1038/nature16965",

language = "English",

volume = "531",

pages = "47--52",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "7592",

}

Bailey, P, Chang, DK, Nones, K, Johns, AL, Patch, AM, Gingras, MC, Miller, DK, Christ, AN, Bruxner, TJC, Quinn, MC, Nourse, C, Murtaugh, LC, Harliwong, I, Idrisoglu, S, Manning, S, Nourbakhsh, E, Wani, S, Fink, L, Holmes, O, Chin, V, Anderson, MJ, Kazakoff, S, Leonard, C, Newell, F, Waddell, N, Wood, S, Xu, Q, Wilson, PJ, Cloonan, N, Kassahn, KS, Taylor, D, Quek, K, Robertson, A, Pantano, L, Mincarelli, L, Sanchez, LN, Evers, L, Wu, J, Pinese, M, Cowley, MJ, Jones, MD, Colvin, EK, Nagrial, AM, Humphrey, ES, Chantrill, LA, Mawson, A, Humphris, J, Chou, A, Pajic, M, Scarlett, CJ, Pinho, AV, Giry-Laterriere, M, Rooman, I, Samra, JS & Zeps, N 2016, 'Genomic analyses identify molecular subtypes of pancreatic cancer', Nature, vol. 531, no. 7592, pp. 47-52. https://doi.org/10.1038/nature16965

TY - JOUR

T1 - Genomic analyses identify molecular subtypes of pancreatic cancer

AU - Bailey, P.

AU - Chang, D.K.

AU - Nones, K.

AU - Johns, A.L.

AU - Patch, A.M.

AU - Gingras, M.C.

AU - Miller, D.K.

AU - Christ, A.N.

AU - Bruxner, T.J.C.

AU - Quinn, M.C.

AU - Nourse, C.

AU - Murtaugh, L.C.

AU - Harliwong, I.

AU - Idrisoglu, S.

AU - Manning, S.

AU - Nourbakhsh, E.

AU - Wani, S.

AU - Fink, L.

AU - Holmes, O.

AU - Chin, V.

AU - Anderson, M.J.

AU - Kazakoff, S.

AU - Leonard, C.

AU - Newell, F.

AU - Waddell, N.

AU - Wood, S.

AU - Xu, Q.

AU - Wilson, P.J.

AU - Cloonan, N.

AU - Kassahn, K.S.

AU - Taylor, D.

AU - Quek, K.

AU - Robertson, A.

AU - Pantano, L.

AU - Mincarelli, L.

AU - Sanchez, L.N.

AU - Evers, L.

AU - Wu, J.

AU - Pinese, M.

AU - Cowley, M.J.

AU - Jones, M.D.

AU - Colvin, E.K.

AU - Nagrial, A.M.

AU - Humphrey, E.S.

AU - Chantrill, L.A.

AU - Mawson, A.

AU - Humphris, J.

AU - Chou, A.

AU - Pajic, M.

AU - Scarlett, C.J.

AU - Pinho, A.V.

AU - Giry-Laterriere, M.

AU - Rooman, I.

AU - Samra, J.S.

AU - Zeps, Nikolajs

PY - 2016/3/3

Y1 - 2016/3/3

N2 - © 2016 Macmillan Publishers Limited. All rights reserved. Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

AB - © 2016 Macmillan Publishers Limited. All rights reserved. Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63ΔN transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.

U2 - 10.1038/nature16965

DO - 10.1038/nature16965

M3 - Article

C2 - 26909576

VL - 531

SP - 47

EP - 52

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7592

ER -

Genomic analyses identify molecular subtypes of pancreatic cancer

Abstract

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