Whole genomes redefine the mutational landscape of pancreatic cancer

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...

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Main Authors:	Waddell, N., Pajic, M., Patch, A., Chang, D., Kassahn, K., Bailey, P., Johns, A., Miller, D., Nones, K., Quek, K., Quinn, M., Robertson, A., Fadlullah, M., Bruxner, T., Christ, A., Harliwong, I., Idrisoglu, S., Manning, S., Nourse, C., Nourbakhsh, E., Wani, S., Wilson, P., Markham, E., Cloonan, N., Anderson, M., Fink, J., Holmes, O., Kazakoff, S., Leonard, C., Newell, F., Poudel, B., Song, S., Taylor, D., Wood, S., Xu, Q., Wu, J., Pinese, M., Cowley, M., Lee, H., Jones, M., Nagrial, A., Humphris, J., Chantrill, L., Chin, V., Steinmann, A., Mawson, A., Humphrey, E., Colvin, E., Chou, A., Scarlett, C., Pinho, A., Giry-Laterriere, M., Rooman, I., Samra, J., Kench, J., Pettitt, J., Merrett, N., Toon, C., Epari, K., Nguyen, N., Barbour, A., Zeps, Nikolajs, Jamieson, N., Graham, J., Niclou, S., Bjerkvig, R., Grützmann, R., Aust, D., Hruban, R., Maitra, A., Iacobuzio-Donahue, C., Wolfgang, C., Morgan, R., Lawlor, R., Corbo, V., Bassi, C., Falconi, M., Zamboni, G., Tortora, G., Tempero, M., Gill, A., Eshleman, J., Pilarsky, C., Scarpa, A., Musgrove, E., Pearson, J., Biankin, A., Grimmond, S.
Format:	Journal Article
Published:	Nature Publishing Group 2015
Online Access:	http://hdl.handle.net/20.500.11937/47532

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author	Waddell, N. Pajic, M. Patch, A. Chang, D. Kassahn, K. Bailey, P. Johns, A. Miller, D. Nones, K. Quek, K. Quinn, M. Robertson, A. Fadlullah, M. Bruxner, T. Christ, A. Harliwong, I. Idrisoglu, S. Manning, S. Nourse, C. Nourbakhsh, E. Wani, S. Wilson, P. Markham, E. Cloonan, N. Anderson, M. Fink, J. Holmes, O. Kazakoff, S. Leonard, C. Newell, F. Poudel, B. Song, S. Taylor, D. Waddell, N. Wood, S. Xu, Q. Wu, J. Pinese, M. Cowley, M. Lee, H. Jones, M. Nagrial, A. Humphris, J. Chantrill, L. Chin, V. Steinmann, A. Mawson, A. Humphrey, E. Colvin, E. Chou, A. Scarlett, C. Pinho, A. Giry-Laterriere, M. Rooman, I. Samra, J. Kench, J. Pettitt, J. Merrett, N. Toon, C. Epari, K. Nguyen, N. Barbour, A. Zeps, Nikolajs Jamieson, N. Graham, J. Niclou, S. Bjerkvig, R. Grützmann, R. Aust, D. Hruban, R. Maitra, A. Iacobuzio-Donahue, C. Wolfgang, C. Morgan, R. Lawlor, R. Corbo, V. Bassi, C. Falconi, M. Zamboni, G. Tortora, G. Tempero, M. Gill, A. Eshleman, J. Pilarsky, C. Scarpa, A. Musgrove, E. Pearson, J. Biankin, A. Grimmond, S.
author_facet	Waddell, N. Pajic, M. Patch, A. Chang, D. Kassahn, K. Bailey, P. Johns, A. Miller, D. Nones, K. Quek, K. Quinn, M. Robertson, A. Fadlullah, M. Bruxner, T. Christ, A. Harliwong, I. Idrisoglu, S. Manning, S. Nourse, C. Nourbakhsh, E. Wani, S. Wilson, P. Markham, E. Cloonan, N. Anderson, M. Fink, J. Holmes, O. Kazakoff, S. Leonard, C. Newell, F. Poudel, B. Song, S. Taylor, D. Waddell, N. Wood, S. Xu, Q. Wu, J. Pinese, M. Cowley, M. Lee, H. Jones, M. Nagrial, A. Humphris, J. Chantrill, L. Chin, V. Steinmann, A. Mawson, A. Humphrey, E. Colvin, E. Chou, A. Scarlett, C. Pinho, A. Giry-Laterriere, M. Rooman, I. Samra, J. Kench, J. Pettitt, J. Merrett, N. Toon, C. Epari, K. Nguyen, N. Barbour, A. Zeps, Nikolajs Jamieson, N. Graham, J. Niclou, S. Bjerkvig, R. Grützmann, R. Aust, D. Hruban, R. Maitra, A. Iacobuzio-Donahue, C. Wolfgang, C. Morgan, R. Lawlor, R. Corbo, V. Bassi, C. Falconi, M. Zamboni, G. Tortora, G. Tempero, M. Gill, A. Eshleman, J. Pilarsky, C. Scarpa, A. Musgrove, E. Pearson, J. Biankin, A. Grimmond, S.
author_sort	Waddell, N.
building	Curtin Institutional Repository
collection	Online Access
description	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.
first_indexed	2025-11-14T09:34:46Z
format	Journal Article
id	curtin-20.500.11937-47532
institution	Curtin University Malaysia
institution_category	Local University
last_indexed	2025-11-14T09:34:46Z
publishDate	2015
publisher	Nature Publishing Group
recordtype	eprints
repository_type	Digital Repository
spelling	curtin-20.500.11937-475322018-03-29T09:07:10Z Whole genomes redefine the mutational landscape of pancreatic cancer Waddell, N. Pajic, M. Patch, A. Chang, D. Kassahn, K. Bailey, P. Johns, A. Miller, D. Nones, K. Quek, K. Quinn, M. Robertson, A. Fadlullah, M. Bruxner, T. Christ, A. Harliwong, I. Idrisoglu, S. Manning, S. Nourse, C. Nourbakhsh, E. Wani, S. Wilson, P. Markham, E. Cloonan, N. Anderson, M. Fink, J. Holmes, O. Kazakoff, S. Leonard, C. Newell, F. Poudel, B. Song, S. Taylor, D. Waddell, N. Wood, S. Xu, Q. Wu, J. Pinese, M. Cowley, M. Lee, H. Jones, M. Nagrial, A. Humphris, J. Chantrill, L. Chin, V. Steinmann, A. Mawson, A. Humphrey, E. Colvin, E. Chou, A. Scarlett, C. Pinho, A. Giry-Laterriere, M. Rooman, I. Samra, J. Kench, J. Pettitt, J. Merrett, N. Toon, C. Epari, K. Nguyen, N. Barbour, A. Zeps, Nikolajs Jamieson, N. Graham, J. Niclou, S. Bjerkvig, R. Grützmann, R. Aust, D. Hruban, R. Maitra, A. Iacobuzio-Donahue, C. Wolfgang, C. Morgan, R. Lawlor, R. Corbo, V. Bassi, C. Falconi, M. Zamboni, G. Tortora, G. Tempero, M. Gill, A. Eshleman, J. Pilarsky, C. Scarpa, A. Musgrove, E. Pearson, J. Biankin, A. Grimmond, S. 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. 2015 Journal Article http://hdl.handle.net/20.500.11937/47532 10.1038/nature14169 Nature Publishing Group restricted
spellingShingle	Waddell, N. Pajic, M. Patch, A. Chang, D. Kassahn, K. Bailey, P. Johns, A. Miller, D. Nones, K. Quek, K. Quinn, M. Robertson, A. Fadlullah, M. Bruxner, T. Christ, A. Harliwong, I. Idrisoglu, S. Manning, S. Nourse, C. Nourbakhsh, E. Wani, S. Wilson, P. Markham, E. Cloonan, N. Anderson, M. Fink, J. Holmes, O. Kazakoff, S. Leonard, C. Newell, F. Poudel, B. Song, S. Taylor, D. Waddell, N. Wood, S. Xu, Q. Wu, J. Pinese, M. Cowley, M. Lee, H. Jones, M. Nagrial, A. Humphris, J. Chantrill, L. Chin, V. Steinmann, A. Mawson, A. Humphrey, E. Colvin, E. Chou, A. Scarlett, C. Pinho, A. Giry-Laterriere, M. Rooman, I. Samra, J. Kench, J. Pettitt, J. Merrett, N. Toon, C. Epari, K. Nguyen, N. Barbour, A. Zeps, Nikolajs Jamieson, N. Graham, J. Niclou, S. Bjerkvig, R. Grützmann, R. Aust, D. Hruban, R. Maitra, A. Iacobuzio-Donahue, C. Wolfgang, C. Morgan, R. Lawlor, R. Corbo, V. Bassi, C. Falconi, M. Zamboni, G. Tortora, G. Tempero, M. Gill, A. Eshleman, J. Pilarsky, C. Scarpa, A. Musgrove, E. Pearson, J. Biankin, A. Grimmond, S. Whole genomes redefine the mutational landscape of pancreatic cancer
title	Whole genomes redefine the mutational landscape of pancreatic cancer
title_full	Whole genomes redefine the mutational landscape of pancreatic cancer
title_fullStr	Whole genomes redefine the mutational landscape of pancreatic cancer
title_full_unstemmed	Whole genomes redefine the mutational landscape of pancreatic cancer
title_short	Whole genomes redefine the mutational landscape of pancreatic cancer
title_sort	whole genomes redefine the mutational landscape of pancreatic cancer
url	http://hdl.handle.net/20.500.11937/47532

Whole genomes redefine the mutational landscape of pancreatic cancer

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