Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Andrew V. Biankin, Nicola Waddell, Karin S. Kassahn, Marie Claude Gingras, Lakshmi B. Muthuswamy, Amber L. Johns, David K. Miller, Peter J. Wilson, Ann Marie Patch, Jianmin Wu, David K. Chang, Mark J. Cowley, Brooke B. Gardiner, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi WaniMilena Gongora, Marina Pajic, Christopher J. Scarlett, Anthony J. Gill, Andreia V. Pinho, Ilse Rooman, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Qinying Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Gabriel Kolle, Felicity Newell, Mark Pinese, R. Scott Mead, Jeremy L. Humphris, Warren Kaplan, Marc D. Jones, Emily K. Colvin, Adnan M. Nagrial, Emily S. Humphrey, Angela Chou, Venessa T. Chin, Lorraine A. Chantrill, Amanda Mawson, Jaswinder S. Samra, James G. Kench, Jessica A. Lovell, Roger J. Daly, Neil D. Merrett, Christopher Toon, Krishna Epari, Nam Q. Nguyen, Andrew Barbour, Nikolajs Zeps, Nipun Kakkar, Fengmei Zhao, Yuan Qing Wu, Min Wang, Donna M. Muzny, William E. Fisher, F. Charles Brunicardi, Sally E. Hodges, Jeffrey G. Reid, Jennifer Drummond, Kyle Chang, Yi Han, Lora R. Lewis, Huyen Dinh, Christian J. Buhay, Timothy Beck, Lee Timms, Michelle Sam, Kimberly Begley, Andrew Brown, Deepa Pai, Ami Panchal, Nicholas Buchner, Richard De Borja, Robert E. Denroche, Christina K. Yung, Stefano Serra, Nicole Onetto, Debabrata Mukhopadhyay, Ming Sound Tsao, Patricia A. Shaw, Gloria M. Petersen, Steven Gallinger, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Rita T. Lawlor, Paola Capelli, Vincenzo Corbo, Maria Scardoni, Giampaolo Tortora, Margaret A. Tempero, Karen M. Mann, Nancy A. Jenkins, Pedro A. Perez-Mancera, David J. Adams, David A. Largaespada, Lodewyk F A Wessels, Alistair G. Rust, Lincoln D. Stein, David A. Tuveson, Neal G. Copeland, Elizabeth A. Musgrove, Aldo Scarpa, James R. Eshleman, Thomas J. Hudson, Robert L. Sutherland, David A. Wheeler, John V. Pearson, John Douglas Mcpherson, Richard A. Gibbs, Sean M. Grimmond

Research output: Contribution to journalArticle

1041 Citations (Scopus)

Abstract

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

Original languageEnglish (US)
Pages (from-to)399-405
Number of pages7
JournalNature
Volume491
Issue number7424
DOIs
StatePublished - Nov 15 2012
Externally publishedYes

Fingerprint

Pancreatic Neoplasms
Genome
Genes
Carcinogenesis
Adenocarcinoma
Exome
Beauty
Mutation
Axon Guidance
Mutagenesis
DNA Repair
DNA Damage
Chromatin
Cluster Analysis
Neoplasms
Animal Models

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Biankin, A. V., Waddell, N., Kassahn, K. S., Gingras, M. C., Muthuswamy, L. B., Johns, A. L., ... Grimmond, S. M. (2012). Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature, 491(7424), 399-405. https://doi.org/10.1038/nature11547

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. / Biankin, Andrew V.; Waddell, Nicola; Kassahn, Karin S.; Gingras, Marie Claude; Muthuswamy, Lakshmi B.; Johns, Amber L.; Miller, David K.; Wilson, Peter J.; Patch, Ann Marie; Wu, Jianmin; Chang, David K.; Cowley, Mark J.; Gardiner, Brooke B.; Song, Sarah; Harliwong, Ivon; Idrisoglu, Senel; Nourse, Craig; Nourbakhsh, Ehsan; Manning, Suzanne; Wani, Shivangi; Gongora, Milena; Pajic, Marina; Scarlett, Christopher J.; Gill, Anthony J.; Pinho, Andreia V.; Rooman, Ilse; Anderson, Matthew; Holmes, Oliver; Leonard, Conrad; Taylor, Darrin; Wood, Scott; Xu, Qinying; Nones, Katia; Fink, J. Lynn; Christ, Angelika; Bruxner, Tim; Cloonan, Nicole; Kolle, Gabriel; Newell, Felicity; Pinese, Mark; Mead, R. Scott; Humphris, Jeremy L.; Kaplan, Warren; Jones, Marc D.; Colvin, Emily K.; Nagrial, Adnan M.; Humphrey, Emily S.; Chou, Angela; Chin, Venessa T.; Chantrill, Lorraine A.; Mawson, Amanda; Samra, Jaswinder S.; Kench, James G.; Lovell, Jessica A.; Daly, Roger J.; Merrett, Neil D.; Toon, Christopher; Epari, Krishna; Nguyen, Nam Q.; Barbour, Andrew; Zeps, Nikolajs; Kakkar, Nipun; Zhao, Fengmei; Wu, Yuan Qing; Wang, Min; Muzny, Donna M.; Fisher, William E.; Brunicardi, F. Charles; Hodges, Sally E.; Reid, Jeffrey G.; Drummond, Jennifer; Chang, Kyle; Han, Yi; Lewis, Lora R.; Dinh, Huyen; Buhay, Christian J.; Beck, Timothy; Timms, Lee; Sam, Michelle; Begley, Kimberly; Brown, Andrew; Pai, Deepa; Panchal, Ami; Buchner, Nicholas; De Borja, Richard; Denroche, Robert E.; Yung, Christina K.; Serra, Stefano; Onetto, Nicole; Mukhopadhyay, Debabrata; Tsao, Ming Sound; Shaw, Patricia A.; Petersen, Gloria M.; Gallinger, Steven; Hruban, Ralph H.; Maitra, Anirban; Iacobuzio-Donahue, Christine A.; Schulick, Richard D.; Wolfgang, Christopher L.; Morgan, Richard A.; Lawlor, Rita T.; Capelli, Paola; Corbo, Vincenzo; Scardoni, Maria; Tortora, Giampaolo; Tempero, Margaret A.; Mann, Karen M.; Jenkins, Nancy A.; Perez-Mancera, Pedro A.; Adams, David J.; Largaespada, David A.; Wessels, Lodewyk F A; Rust, Alistair G.; Stein, Lincoln D.; Tuveson, David A.; Copeland, Neal G.; Musgrove, Elizabeth A.; Scarpa, Aldo; Eshleman, James R.; Hudson, Thomas J.; Sutherland, Robert L.; Wheeler, David A.; Pearson, John V.; Mcpherson, John Douglas; Gibbs, Richard A.; Grimmond, Sean M.

In: Nature, Vol. 491, No. 7424, 15.11.2012, p. 399-405.

Research output: Contribution to journalArticle

Biankin, AV, Waddell, N, Kassahn, KS, Gingras, MC, Muthuswamy, LB, Johns, AL, Miller, DK, Wilson, PJ, Patch, AM, Wu, J, Chang, DK, Cowley, MJ, Gardiner, BB, Song, S, Harliwong, I, Idrisoglu, S, Nourse, C, Nourbakhsh, E, Manning, S, Wani, S, Gongora, M, Pajic, M, Scarlett, CJ, Gill, AJ, Pinho, AV, Rooman, I, Anderson, M, Holmes, O, Leonard, C, Taylor, D, Wood, S, Xu, Q, Nones, K, Fink, JL, Christ, A, Bruxner, T, Cloonan, N, Kolle, G, Newell, F, Pinese, M, Mead, RS, Humphris, JL, Kaplan, W, Jones, MD, Colvin, EK, Nagrial, AM, Humphrey, ES, Chou, A, Chin, VT, Chantrill, LA, Mawson, A, Samra, JS, Kench, JG, Lovell, JA, Daly, RJ, Merrett, ND, Toon, C, Epari, K, Nguyen, NQ, Barbour, A, Zeps, N, Kakkar, N, Zhao, F, Wu, YQ, Wang, M, Muzny, DM, Fisher, WE, Brunicardi, FC, Hodges, SE, Reid, JG, Drummond, J, Chang, K, Han, Y, Lewis, LR, Dinh, H, Buhay, CJ, Beck, T, Timms, L, Sam, M, Begley, K, Brown, A, Pai, D, Panchal, A, Buchner, N, De Borja, R, Denroche, RE, Yung, CK, Serra, S, Onetto, N, Mukhopadhyay, D, Tsao, MS, Shaw, PA, Petersen, GM, Gallinger, S, Hruban, RH, Maitra, A, Iacobuzio-Donahue, CA, Schulick, RD, Wolfgang, CL, Morgan, RA, Lawlor, RT, Capelli, P, Corbo, V, Scardoni, M, Tortora, G, Tempero, MA, Mann, KM, Jenkins, NA, Perez-Mancera, PA, Adams, DJ, Largaespada, DA, Wessels, LFA, Rust, AG, Stein, LD, Tuveson, DA, Copeland, NG, Musgrove, EA, Scarpa, A, Eshleman, JR, Hudson, TJ, Sutherland, RL, Wheeler, DA, Pearson, JV, Mcpherson, JD, Gibbs, RA & Grimmond, SM 2012, 'Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes', Nature, vol. 491, no. 7424, pp. 399-405. https://doi.org/10.1038/nature11547
Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012 Nov 15;491(7424):399-405. https://doi.org/10.1038/nature11547
Biankin, Andrew V. ; Waddell, Nicola ; Kassahn, Karin S. ; Gingras, Marie Claude ; Muthuswamy, Lakshmi B. ; Johns, Amber L. ; Miller, David K. ; Wilson, Peter J. ; Patch, Ann Marie ; Wu, Jianmin ; Chang, David K. ; Cowley, Mark J. ; Gardiner, Brooke B. ; Song, Sarah ; Harliwong, Ivon ; Idrisoglu, Senel ; Nourse, Craig ; Nourbakhsh, Ehsan ; Manning, Suzanne ; Wani, Shivangi ; Gongora, Milena ; Pajic, Marina ; Scarlett, Christopher J. ; Gill, Anthony J. ; Pinho, Andreia V. ; Rooman, Ilse ; Anderson, Matthew ; Holmes, Oliver ; Leonard, Conrad ; Taylor, Darrin ; Wood, Scott ; Xu, Qinying ; Nones, Katia ; Fink, J. Lynn ; Christ, Angelika ; Bruxner, Tim ; Cloonan, Nicole ; Kolle, Gabriel ; Newell, Felicity ; Pinese, Mark ; Mead, R. Scott ; Humphris, Jeremy L. ; Kaplan, Warren ; Jones, Marc D. ; Colvin, Emily K. ; Nagrial, Adnan M. ; Humphrey, Emily S. ; Chou, Angela ; Chin, Venessa T. ; Chantrill, Lorraine A. ; Mawson, Amanda ; Samra, Jaswinder S. ; Kench, James G. ; Lovell, Jessica A. ; Daly, Roger J. ; Merrett, Neil D. ; Toon, Christopher ; Epari, Krishna ; Nguyen, Nam Q. ; Barbour, Andrew ; Zeps, Nikolajs ; Kakkar, Nipun ; Zhao, Fengmei ; Wu, Yuan Qing ; Wang, Min ; Muzny, Donna M. ; Fisher, William E. ; Brunicardi, F. Charles ; Hodges, Sally E. ; Reid, Jeffrey G. ; Drummond, Jennifer ; Chang, Kyle ; Han, Yi ; Lewis, Lora R. ; Dinh, Huyen ; Buhay, Christian J. ; Beck, Timothy ; Timms, Lee ; Sam, Michelle ; Begley, Kimberly ; Brown, Andrew ; Pai, Deepa ; Panchal, Ami ; Buchner, Nicholas ; De Borja, Richard ; Denroche, Robert E. ; Yung, Christina K. ; Serra, Stefano ; Onetto, Nicole ; Mukhopadhyay, Debabrata ; Tsao, Ming Sound ; Shaw, Patricia A. ; Petersen, Gloria M. ; Gallinger, Steven ; Hruban, Ralph H. ; Maitra, Anirban ; Iacobuzio-Donahue, Christine A. ; Schulick, Richard D. ; Wolfgang, Christopher L. ; Morgan, Richard A. ; Lawlor, Rita T. ; Capelli, Paola ; Corbo, Vincenzo ; Scardoni, Maria ; Tortora, Giampaolo ; Tempero, Margaret A. ; Mann, Karen M. ; Jenkins, Nancy A. ; Perez-Mancera, Pedro A. ; Adams, David J. ; Largaespada, David A. ; Wessels, Lodewyk F A ; Rust, Alistair G. ; Stein, Lincoln D. ; Tuveson, David A. ; Copeland, Neal G. ; Musgrove, Elizabeth A. ; Scarpa, Aldo ; Eshleman, James R. ; Hudson, Thomas J. ; Sutherland, Robert L. ; Wheeler, David A. ; Pearson, John V. ; Mcpherson, John Douglas ; Gibbs, Richard A. ; Grimmond, Sean M. / Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. In: Nature. 2012 ; Vol. 491, No. 7424. pp. 399-405.
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abstract = "Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.",
author = "Biankin, {Andrew V.} and Nicola Waddell and Kassahn, {Karin S.} and Gingras, {Marie Claude} and Muthuswamy, {Lakshmi B.} and Johns, {Amber L.} and Miller, {David K.} and Wilson, {Peter J.} and Patch, {Ann Marie} and Jianmin Wu and Chang, {David K.} and Cowley, {Mark J.} and Gardiner, {Brooke B.} and Sarah Song and Ivon Harliwong and Senel Idrisoglu and Craig Nourse and Ehsan Nourbakhsh and Suzanne Manning and Shivangi Wani and Milena Gongora and Marina Pajic and Scarlett, {Christopher J.} and Gill, {Anthony J.} and Pinho, {Andreia V.} and Ilse Rooman and Matthew Anderson and Oliver Holmes and Conrad Leonard and Darrin Taylor and Scott Wood and Qinying Xu and Katia Nones and Fink, {J. Lynn} and Angelika Christ and Tim Bruxner and Nicole Cloonan and Gabriel Kolle and Felicity Newell and Mark Pinese and Mead, {R. Scott} and Humphris, {Jeremy L.} and Warren Kaplan and Jones, {Marc D.} and Colvin, {Emily K.} and Nagrial, {Adnan M.} and Humphrey, {Emily S.} and Angela Chou and Chin, {Venessa T.} and Chantrill, {Lorraine A.} and Amanda Mawson and Samra, {Jaswinder S.} and Kench, {James G.} and Lovell, {Jessica A.} and Daly, {Roger J.} and Merrett, {Neil D.} and Christopher Toon and Krishna Epari and Nguyen, {Nam Q.} and Andrew Barbour and Nikolajs Zeps and Nipun Kakkar and Fengmei Zhao and Wu, {Yuan Qing} and Min Wang and Muzny, {Donna M.} and Fisher, {William E.} and Brunicardi, {F. Charles} and Hodges, {Sally E.} and Reid, {Jeffrey G.} and Jennifer Drummond and Kyle Chang and Yi Han and Lewis, {Lora R.} and Huyen Dinh and Buhay, {Christian J.} and Timothy Beck and Lee Timms and Michelle Sam and Kimberly Begley and Andrew Brown and Deepa Pai and Ami Panchal and Nicholas Buchner and {De Borja}, Richard and Denroche, {Robert E.} and Yung, {Christina K.} and Stefano Serra and Nicole Onetto and Debabrata Mukhopadhyay and Tsao, {Ming Sound} and Shaw, {Patricia A.} and Petersen, {Gloria M.} and Steven Gallinger and Hruban, {Ralph H.} and Anirban Maitra and Iacobuzio-Donahue, {Christine A.} and Schulick, {Richard D.} and Wolfgang, {Christopher L.} and Morgan, {Richard A.} and Lawlor, {Rita T.} and Paola Capelli and Vincenzo Corbo and Maria Scardoni and Giampaolo Tortora and Tempero, {Margaret A.} and Mann, {Karen M.} and Jenkins, {Nancy A.} and Perez-Mancera, {Pedro A.} and Adams, {David J.} and Largaespada, {David A.} and Wessels, {Lodewyk F A} and Rust, {Alistair G.} and Stein, {Lincoln D.} and Tuveson, {David A.} and Copeland, {Neal G.} and Musgrove, {Elizabeth A.} and Aldo Scarpa and Eshleman, {James R.} and Hudson, {Thomas J.} and Sutherland, {Robert L.} and Wheeler, {David A.} and Pearson, {John V.} and Mcpherson, {John Douglas} and Gibbs, {Richard A.} and Grimmond, {Sean M.}",
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T1 - Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

AU - Biankin, Andrew V.

AU - Waddell, Nicola

AU - Kassahn, Karin S.

AU - Gingras, Marie Claude

AU - Muthuswamy, Lakshmi B.

AU - Johns, Amber L.

AU - Miller, David K.

AU - Wilson, Peter J.

AU - Patch, Ann Marie

AU - Wu, Jianmin

AU - Chang, David K.

AU - Cowley, Mark J.

AU - Gardiner, Brooke B.

AU - Song, Sarah

AU - Harliwong, Ivon

AU - Idrisoglu, Senel

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Manning, Suzanne

AU - Wani, Shivangi

AU - Gongora, Milena

AU - Pajic, Marina

AU - Scarlett, Christopher J.

AU - Gill, Anthony J.

AU - Pinho, Andreia V.

AU - Rooman, Ilse

AU - Anderson, Matthew

AU - Holmes, Oliver

AU - Leonard, Conrad

AU - Taylor, Darrin

AU - Wood, Scott

AU - Xu, Qinying

AU - Nones, Katia

AU - Fink, J. Lynn

AU - Christ, Angelika

AU - Bruxner, Tim

AU - Cloonan, Nicole

AU - Kolle, Gabriel

AU - Newell, Felicity

AU - Pinese, Mark

AU - Mead, R. Scott

AU - Humphris, Jeremy L.

AU - Kaplan, Warren

AU - Jones, Marc D.

AU - Colvin, Emily K.

AU - Nagrial, Adnan M.

AU - Humphrey, Emily S.

AU - Chou, Angela

AU - Chin, Venessa T.

AU - Chantrill, Lorraine A.

AU - Mawson, Amanda

AU - Samra, Jaswinder S.

AU - Kench, James G.

AU - Lovell, Jessica A.

AU - Daly, Roger J.

AU - Merrett, Neil D.

AU - Toon, Christopher

AU - Epari, Krishna

AU - Nguyen, Nam Q.

AU - Barbour, Andrew

AU - Zeps, Nikolajs

AU - Kakkar, Nipun

AU - Zhao, Fengmei

AU - Wu, Yuan Qing

AU - Wang, Min

AU - Muzny, Donna M.

AU - Fisher, William E.

AU - Brunicardi, F. Charles

AU - Hodges, Sally E.

AU - Reid, Jeffrey G.

AU - Drummond, Jennifer

AU - Chang, Kyle

AU - Han, Yi

AU - Lewis, Lora R.

AU - Dinh, Huyen

AU - Buhay, Christian J.

AU - Beck, Timothy

AU - Timms, Lee

AU - Sam, Michelle

AU - Begley, Kimberly

AU - Brown, Andrew

AU - Pai, Deepa

AU - Panchal, Ami

AU - Buchner, Nicholas

AU - De Borja, Richard

AU - Denroche, Robert E.

AU - Yung, Christina K.

AU - Serra, Stefano

AU - Onetto, Nicole

AU - Mukhopadhyay, Debabrata

AU - Tsao, Ming Sound

AU - Shaw, Patricia A.

AU - Petersen, Gloria M.

AU - Gallinger, Steven

AU - Hruban, Ralph H.

AU - Maitra, Anirban

AU - Iacobuzio-Donahue, Christine A.

AU - Schulick, Richard D.

AU - Wolfgang, Christopher L.

AU - Morgan, Richard A.

AU - Lawlor, Rita T.

AU - Capelli, Paola

AU - Corbo, Vincenzo

AU - Scardoni, Maria

AU - Tortora, Giampaolo

AU - Tempero, Margaret A.

AU - Mann, Karen M.

AU - Jenkins, Nancy A.

AU - Perez-Mancera, Pedro A.

AU - Adams, David J.

AU - Largaespada, David A.

AU - Wessels, Lodewyk F A

AU - Rust, Alistair G.

AU - Stein, Lincoln D.

AU - Tuveson, David A.

AU - Copeland, Neal G.

AU - Musgrove, Elizabeth A.

AU - Scarpa, Aldo

AU - Eshleman, James R.

AU - Hudson, Thomas J.

AU - Sutherland, Robert L.

AU - Wheeler, David A.

AU - Pearson, John V.

AU - Mcpherson, John Douglas

AU - Gibbs, Richard A.

AU - Grimmond, Sean M.

PY - 2012/11/15

Y1 - 2012/11/15

N2 - Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

AB - Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

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