title: Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.
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.
authors.affiliation: The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.forename: Karin S
authors.initials: KS
authors.lastname: Kassahn
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gingras
authors.forename: Lakshmi B
authors.initials: LB
authors.lastname: Muthuswamy
authors.forename: Amber L
authors.initials: AL
authors.lastname: Johns
authors.forename: David K
authors.initials: DK
authors.lastname: Miller
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wilson
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.forename: Jianmin
authors.initials: J
authors.lastname: Wu
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.forename: Brooke B
authors.initials: BB
authors.lastname: Gardiner
authors.forename: Sarah
authors.initials: S
authors.lastname: Song
authors.forename: Ivon
authors.initials: I
authors.lastname: Harliwong
authors.forename: Senel
authors.initials: S
authors.lastname: Idrisoglu
authors.forename: Craig
authors.initials: C
authors.lastname: Nourse
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nourbakhsh
authors.forename: Suzanne
authors.initials: S
authors.lastname: Manning
authors.forename: Shivangi
authors.initials: S
authors.lastname: Wani
authors.forename: Milena
authors.initials: M
authors.lastname: Gongora
authors.forename: Marina
authors.initials: M
authors.lastname: Pajic
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Scarlett
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.forename: Andreia V
authors.initials: AV
authors.lastname: Pinho
authors.forename: Ilse
authors.initials: I
authors.lastname: Rooman
authors.forename: Matthew
authors.initials: M
authors.lastname: Anderson
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.forename: Conrad
authors.initials: C
authors.lastname: Leonard
authors.forename: Darrin
authors.initials: D
authors.lastname: Taylor
authors.forename: Scott
authors.initials: S
authors.lastname: Wood
authors.forename: Qinying
authors.initials: Q
authors.lastname: Xu
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.forename: J Lynn
authors.initials: JL
authors.lastname: Fink
authors.forename: Angelika
authors.initials: A
authors.lastname: Christ
authors.forename: Tim
authors.initials: T
authors.lastname: Bruxner
authors.forename: Nicole
authors.initials: N
authors.lastname: Cloonan
authors.forename: Gabriel
authors.initials: G
authors.lastname: Kolle
authors.forename: Felicity
authors.initials: F
authors.lastname: Newell
authors.forename: Mark
authors.initials: M
authors.lastname: Pinese
authors.forename: R Scott
authors.initials: RS
authors.lastname: Mead
authors.forename: Jeremy L
authors.initials: JL
authors.lastname: Humphris
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.forename: Marc D
authors.initials: MD
authors.lastname: Jones
authors.forename: Emily K
authors.initials: EK
authors.lastname: Colvin
authors.forename: Adnan M
authors.initials: AM
authors.lastname: Nagrial
authors.forename: Emily S
authors.initials: ES
authors.lastname: Humphrey
authors.forename: Angela
authors.initials: A
authors.lastname: Chou
authors.forename: Venessa T
authors.initials: VT
authors.lastname: Chin
authors.forename: Lorraine A
authors.initials: LA
authors.lastname: Chantrill
authors.forename: Amanda
authors.initials: A
authors.lastname: Mawson
authors.forename: Jaswinder S
authors.initials: JS
authors.lastname: Samra
authors.forename: James G
authors.initials: JG
authors.lastname: Kench
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Lovell
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.forename: Neil D
authors.initials: ND
authors.lastname: Merrett
authors.forename: Christopher
authors.initials: C
authors.lastname: Toon
authors.forename: Krishna
authors.initials: K
authors.lastname: Epari
authors.forename: Nam Q
authors.initials: NQ
authors.lastname: Nguyen
authors.forename: Andrew
authors.initials: A
authors.lastname: Barbour
authors.forename: Nikolajs
authors.initials: N
authors.lastname: Zeps
authors.forename: Nipun
authors.initials: N
authors.lastname: Kakkar
authors.forename: Fengmei
authors.initials: F
authors.lastname: Zhao
authors.forename: Yuan Qing
authors.initials: YQ
authors.lastname: Wu
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.forename: F Charles
authors.initials: FC
authors.lastname: Brunicardi
authors.forename: Sally E
authors.initials: SE
authors.lastname: Hodges
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.forename: Jennifer
authors.initials: J
authors.lastname: Drummond
authors.forename: Kyle
authors.initials: K
authors.lastname: Chang
authors.forename: Yi
authors.initials: Y
authors.lastname: Han
authors.forename: Lora R
authors.initials: LR
authors.lastname: Lewis
authors.forename: Huyen
authors.initials: H
authors.lastname: Dinh
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Buhay
authors.forename: Timothy
authors.initials: T
authors.lastname: Beck
authors.forename: Lee
authors.initials: L
authors.lastname: Timms
authors.forename: Michelle
authors.initials: M
authors.lastname: Sam
authors.forename: Kimberly
authors.initials: K
authors.lastname: Begley
authors.forename: Andrew
authors.initials: A
authors.lastname: Brown
authors.forename: Deepa
authors.initials: D
authors.lastname: Pai
authors.forename: Ami
authors.initials: A
authors.lastname: Panchal
authors.forename: Nicholas
authors.initials: N
authors.lastname: Buchner
authors.forename: Richard
authors.initials: R
authors.lastname: De Borja
authors.forename: Robert E
authors.initials: RE
authors.lastname: Denroche
authors.forename: Christina K
authors.initials: CK
authors.lastname: Yung
authors.forename: Stefano
authors.initials: S
authors.lastname: Serra
authors.forename: Nicole
authors.initials: N
authors.lastname: Onetto
authors.forename: Debabrata
authors.initials: D
authors.lastname: Mukhopadhyay
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Shaw
authors.forename: Gloria M
authors.initials: GM
authors.lastname: Petersen
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.forename: Richard D
authors.initials: RD
authors.lastname: Schulick
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Morgan
authors.forename: Rita T
authors.initials: RT
authors.lastname: Lawlor
authors.forename: Paola
authors.initials: P
authors.lastname: Capelli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Corbo
authors.forename: Maria
authors.initials: M
authors.lastname: Scardoni
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Tortora
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Tempero
authors.forename: Karen M
authors.initials: KM
authors.lastname: Mann
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Perez-Mancera
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Stein
authors.forename: David A
authors.initials: DA
authors.lastname: Tuveson
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
authors.forename: Aldo
authors.initials: A
authors.lastname: Scarpa
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.forename: John D
authors.initials: JD
authors.lastname: McPherson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology*; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome / Q000235:genetics*; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011506:Proteins / Q000235:genetics; D015398:Signal Transduction
chemical_list: D011506:Proteins