Abstract 2966: The mutational landscape of localized gleason 6 and 7 prostate cancer

Prostate cancer (CaP) remains the most common male malignancy worldwide, leading to over 300,000 deaths per year. In Western countries, most prostate tumours are diagnosed while they are confined to the prostate and have relatively indolent histology, as assessed by the Gleason Score (GS). CaP is a...

Full description

Saved in:
Bibliographic Details
Published inCancer research (Chicago, Ill.) Vol. 75; no. 15_Supplement; p. 2966
Main Authors Fraser, Michael E., Sabelnykova, Veronica Y., Yamaguchi, Takafumi N., Meng, Alice, Heisler, Lawrence E., Zhang, Junyan, Livingstone, Julie, Huang, Vincent, Masella, Andre P., Yousif, Fouad, Xie, Michael, Harding, Nicholas J., Lin, Xihui, Kong, Haiying, Prokopec, Stephenie D., Berlin, Alejandro, Trudel, Dominique, Luo, Xuemei, Beck, Timothy E., de Borja, Richard, D'Costa, Alister, Denroche, Robert E., Fox, Natalie S., Lalonde, Emilie, Wong, Ada, Chong, Taryne, Sam, Michelle, Johns, Jeremy, Timms, Lee, Buchner, Nicholas, Orain, Michele, Picard, Valerie, Hovington, Helene, Chu, Kenneth C., P'ng, Christine, Lo, Bryan, Nguyen, Francis, Houlahan, Kathleen E., Cooper, Christopher, Govind, Shaylan K., Fung, Clement, Lacombe, Louis, Collins, Colin C., Fradet, Yves, Tetu, Bernard, van der Kwast, Theodorus, McPherson, John, Hudson, Thomas J., Bristow, Rob G., Boutros, Paul
Format Journal Article
LanguageEnglish
Published 01.08.2015
Online AccessGet full text

Cover

Loading…
Abstract Prostate cancer (CaP) remains the most common male malignancy worldwide, leading to over 300,000 deaths per year. In Western countries, most prostate tumours are diagnosed while they are confined to the prostate and have relatively indolent histology, as assessed by the Gleason Score (GS). CaP is a C-class tumour, characterized by large number of driver copy-number aberrations and genomic rearrangements. Therefore, while previous sequencing studies have focused largely on the coding regions of late-stage disease, herein we comprehensively characterized the copy-number profiles of 250 localized prostate cancers and analyzed the whole genomes of 124 matched tumour/normal pairs derived from patients with GS6 and GS7 prostate cancer. Using this – the largest whole-genome sequencing dataset of prostate cancer to date – we confirm the C-class character of the disease and identify strong genomic subtypes that stretch across multiple types of somatic alteration, including SNVs, CNAs and genomic rearrangements. We provide the first assessments of localized hyper-mutation phenomena (chromothripsis and kataegis) in prostate cancer, and identify specific genes driving higher levels of these hyper-mutations. We identify unexpected biases in the location and role of both non-coding SNVs and genomic rearrangements, including clear association with epigenetic processes, and with genome-wide profiling of methylation in 92 samples. Finally, we demonstrate a stark paucity of clinically-actionable mutations in localized GS6 and GS7 disease, even lacking those common in high-risk localized disease, indicating that novel therapeutic development against the recurrent targets identified here will be key to allowing less-aggressive, targeted treatment of early-stage disease. Citation Format: Michael E. Fraser, Veronica Y. Sabelnykova, Takafumi N. Yamaguchi, Alice Meng, Lawrence E. Heisler, Junyan Zhang, Julie Livingstone, Vincent Huang, Andre P. Masella, Fouad Yousif, Michael Xie, Nicholas J. Harding, Xihui Lin, Haiying Kong, Stephenie D. Prokopec, Alejandro Berlin, Dominique Trudel, Xuemei Luo, Timothy E. Beck, Richard de Borja, Alister D'Costa, Robert E. Denroche, Natalie S. Fox, Emilie Lalonde, Ada Wong, Taryne Chong, Michelle Sam, Jeremy Johns, Lee Timms, Nicholas Buchner, Michele Orain, Valerie Picard, Helene Hovington, Kenneth C. Chu, Christine P'ng, Bryan Lo, Francis Nguyen, Kathleen E. Houlahan, Christopher Cooper, Shaylan K. Govind, Clement Fung, Louis Lacombe, Colin C. Collins, Yves Fradet, Bernard Tetu, Theodorus van der Kwast, John McPherson, Thomas J. Hudson, Rob G. Bristow, Paul Boutros. The mutational landscape of localized gleason 6 and 7 prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2966. doi:10.1158/1538-7445.AM2015-2966
AbstractList Prostate cancer (CaP) remains the most common male malignancy worldwide, leading to over 300,000 deaths per year. In Western countries, most prostate tumours are diagnosed while they are confined to the prostate and have relatively indolent histology, as assessed by the Gleason Score (GS). CaP is a C-class tumour, characterized by large number of driver copy-number aberrations and genomic rearrangements. Therefore, while previous sequencing studies have focused largely on the coding regions of late-stage disease, herein we comprehensively characterized the copy-number profiles of 250 localized prostate cancers and analyzed the whole genomes of 124 matched tumour/normal pairs derived from patients with GS6 and GS7 prostate cancer. Using this – the largest whole-genome sequencing dataset of prostate cancer to date – we confirm the C-class character of the disease and identify strong genomic subtypes that stretch across multiple types of somatic alteration, including SNVs, CNAs and genomic rearrangements. We provide the first assessments of localized hyper-mutation phenomena (chromothripsis and kataegis) in prostate cancer, and identify specific genes driving higher levels of these hyper-mutations. We identify unexpected biases in the location and role of both non-coding SNVs and genomic rearrangements, including clear association with epigenetic processes, and with genome-wide profiling of methylation in 92 samples. Finally, we demonstrate a stark paucity of clinically-actionable mutations in localized GS6 and GS7 disease, even lacking those common in high-risk localized disease, indicating that novel therapeutic development against the recurrent targets identified here will be key to allowing less-aggressive, targeted treatment of early-stage disease. Citation Format: Michael E. Fraser, Veronica Y. Sabelnykova, Takafumi N. Yamaguchi, Alice Meng, Lawrence E. Heisler, Junyan Zhang, Julie Livingstone, Vincent Huang, Andre P. Masella, Fouad Yousif, Michael Xie, Nicholas J. Harding, Xihui Lin, Haiying Kong, Stephenie D. Prokopec, Alejandro Berlin, Dominique Trudel, Xuemei Luo, Timothy E. Beck, Richard de Borja, Alister D'Costa, Robert E. Denroche, Natalie S. Fox, Emilie Lalonde, Ada Wong, Taryne Chong, Michelle Sam, Jeremy Johns, Lee Timms, Nicholas Buchner, Michele Orain, Valerie Picard, Helene Hovington, Kenneth C. Chu, Christine P'ng, Bryan Lo, Francis Nguyen, Kathleen E. Houlahan, Christopher Cooper, Shaylan K. Govind, Clement Fung, Louis Lacombe, Colin C. Collins, Yves Fradet, Bernard Tetu, Theodorus van der Kwast, John McPherson, Thomas J. Hudson, Rob G. Bristow, Paul Boutros. The mutational landscape of localized gleason 6 and 7 prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2966. doi:10.1158/1538-7445.AM2015-2966
Author Zhang, Junyan
Lo, Bryan
Sabelnykova, Veronica Y.
Trudel, Dominique
Lalonde, Emilie
Orain, Michele
McPherson, John
Lin, Xihui
Nguyen, Francis
D'Costa, Alister
Chong, Taryne
Heisler, Lawrence E.
Yamaguchi, Takafumi N.
P'ng, Christine
Luo, Xuemei
de Borja, Richard
Sam, Michelle
Beck, Timothy E.
van der Kwast, Theodorus
Johns, Jeremy
Livingstone, Julie
Prokopec, Stephenie D.
Fradet, Yves
Buchner, Nicholas
Hovington, Helene
Lacombe, Louis
Kong, Haiying
Bristow, Rob G.
Collins, Colin C.
Hudson, Thomas J.
Boutros, Paul
Masella, Andre P.
Huang, Vincent
Xie, Michael
Timms, Lee
Tetu, Bernard
Yousif, Fouad
Chu, Kenneth C.
Cooper, Christopher
Berlin, Alejandro
Fraser, Michael E.
Meng, Alice
Denroche, Robert E.
Houlahan, Kathleen E.
Wong, Ada
Harding, Nicholas J.
Fung, Clement
Picard, Valerie
Govind, Shaylan K.
Fox, Natalie S.
Author_xml – sequence: 1
  givenname: Michael E.
  surname: Fraser
  fullname: Fraser, Michael E.
– sequence: 2
  givenname: Veronica Y.
  surname: Sabelnykova
  fullname: Sabelnykova, Veronica Y.
– sequence: 3
  givenname: Takafumi N.
  surname: Yamaguchi
  fullname: Yamaguchi, Takafumi N.
– sequence: 4
  givenname: Alice
  surname: Meng
  fullname: Meng, Alice
– sequence: 5
  givenname: Lawrence E.
  surname: Heisler
  fullname: Heisler, Lawrence E.
– sequence: 6
  givenname: Junyan
  surname: Zhang
  fullname: Zhang, Junyan
– sequence: 7
  givenname: Julie
  surname: Livingstone
  fullname: Livingstone, Julie
– sequence: 8
  givenname: Vincent
  surname: Huang
  fullname: Huang, Vincent
– sequence: 9
  givenname: Andre P.
  surname: Masella
  fullname: Masella, Andre P.
– sequence: 10
  givenname: Fouad
  surname: Yousif
  fullname: Yousif, Fouad
– sequence: 11
  givenname: Michael
  surname: Xie
  fullname: Xie, Michael
– sequence: 12
  givenname: Nicholas J.
  surname: Harding
  fullname: Harding, Nicholas J.
– sequence: 13
  givenname: Xihui
  surname: Lin
  fullname: Lin, Xihui
– sequence: 14
  givenname: Haiying
  surname: Kong
  fullname: Kong, Haiying
– sequence: 15
  givenname: Stephenie D.
  surname: Prokopec
  fullname: Prokopec, Stephenie D.
– sequence: 16
  givenname: Alejandro
  surname: Berlin
  fullname: Berlin, Alejandro
– sequence: 17
  givenname: Dominique
  surname: Trudel
  fullname: Trudel, Dominique
– sequence: 18
  givenname: Xuemei
  surname: Luo
  fullname: Luo, Xuemei
– sequence: 19
  givenname: Timothy E.
  surname: Beck
  fullname: Beck, Timothy E.
– sequence: 20
  givenname: Richard
  surname: de Borja
  fullname: de Borja, Richard
– sequence: 21
  givenname: Alister
  surname: D'Costa
  fullname: D'Costa, Alister
– sequence: 22
  givenname: Robert E.
  surname: Denroche
  fullname: Denroche, Robert E.
– sequence: 23
  givenname: Natalie S.
  surname: Fox
  fullname: Fox, Natalie S.
– sequence: 24
  givenname: Emilie
  surname: Lalonde
  fullname: Lalonde, Emilie
– sequence: 25
  givenname: Ada
  surname: Wong
  fullname: Wong, Ada
– sequence: 26
  givenname: Taryne
  surname: Chong
  fullname: Chong, Taryne
– sequence: 27
  givenname: Michelle
  surname: Sam
  fullname: Sam, Michelle
– sequence: 28
  givenname: Jeremy
  surname: Johns
  fullname: Johns, Jeremy
– sequence: 29
  givenname: Lee
  surname: Timms
  fullname: Timms, Lee
– sequence: 30
  givenname: Nicholas
  surname: Buchner
  fullname: Buchner, Nicholas
– sequence: 31
  givenname: Michele
  surname: Orain
  fullname: Orain, Michele
– sequence: 32
  givenname: Valerie
  surname: Picard
  fullname: Picard, Valerie
– sequence: 33
  givenname: Helene
  surname: Hovington
  fullname: Hovington, Helene
– sequence: 34
  givenname: Kenneth C.
  surname: Chu
  fullname: Chu, Kenneth C.
– sequence: 35
  givenname: Christine
  surname: P'ng
  fullname: P'ng, Christine
– sequence: 36
  givenname: Bryan
  surname: Lo
  fullname: Lo, Bryan
– sequence: 37
  givenname: Francis
  surname: Nguyen
  fullname: Nguyen, Francis
– sequence: 38
  givenname: Kathleen E.
  surname: Houlahan
  fullname: Houlahan, Kathleen E.
– sequence: 39
  givenname: Christopher
  surname: Cooper
  fullname: Cooper, Christopher
– sequence: 40
  givenname: Shaylan K.
  surname: Govind
  fullname: Govind, Shaylan K.
– sequence: 41
  givenname: Clement
  surname: Fung
  fullname: Fung, Clement
– sequence: 42
  givenname: Louis
  surname: Lacombe
  fullname: Lacombe, Louis
– sequence: 43
  givenname: Colin C.
  surname: Collins
  fullname: Collins, Colin C.
– sequence: 44
  givenname: Yves
  surname: Fradet
  fullname: Fradet, Yves
– sequence: 45
  givenname: Bernard
  surname: Tetu
  fullname: Tetu, Bernard
– sequence: 46
  givenname: Theodorus
  surname: van der Kwast
  fullname: van der Kwast, Theodorus
– sequence: 47
  givenname: John
  surname: McPherson
  fullname: McPherson, John
– sequence: 48
  givenname: Thomas J.
  surname: Hudson
  fullname: Hudson, Thomas J.
– sequence: 49
  givenname: Rob G.
  surname: Bristow
  fullname: Bristow, Rob G.
– sequence: 50
  givenname: Paul
  surname: Boutros
  fullname: Boutros, Paul
BookMark eNqdj01qwzAQRoeQQJ2fIxTmAk4lx7Kd7kJp6SY778VEGbcOimQkd5GcvhYtPUBXw8w3D963hLnzjgEepdhKqZonqXZNXpel2h6OhZAqL_ZVNYPs7z6HTAjR5KqsiwdYxniZViWFyqA9nOIYyIyYoGdsPxmvXyONvXdk0ZI7R0MDo-_QekO2v_MZPyxT9A4rnHKscQg-TgyjIWc4rGHRkY28-Z0rUG-v7ct7bqa_GLjTQ-ivFG5aCp0q6KSqk6r-qaCTze6_3DdeSFCp
ContentType Journal Article
DBID AAYXX
CITATION
DOI 10.1158/1538-7445.AM2015-2966
DatabaseName CrossRef
DatabaseTitle CrossRef
DatabaseTitleList CrossRef
DeliveryMethod fulltext_linktorsrc
Discipline Medicine
EISSN 1538-7445
EndPage 2966
ExternalDocumentID 10_1158_1538_7445_AM2015_2966
GroupedDBID ---
-ET
18M
29B
2WC
34G
39C
476
53G
5GY
5RE
5VS
6J9
AAYXX
ABOCM
ACGFO
ACIWK
ACPRK
ACSVP
ADBBV
ADCOW
ADNWM
AENEX
AFHIN
AFOSN
AFRAH
ALMA_UNASSIGNED_HOLDINGS
BAWUL
BTFSW
CITATION
CS3
DIK
DU5
EBS
EJD
F5P
FRP
GX1
H13
IH2
KQ8
L7B
LSO
OK1
P0W
P2P
PQQKQ
RCR
RHF
RHI
RNS
SJN
TR2
W2D
W8F
WH7
WOQ
YKV
YZZ
ID FETCH-crossref_primary_10_1158_1538_7445_AM2015_29663
ISSN 0008-5472
IngestDate Thu Nov 21 23:17:05 EST 2024
IsPeerReviewed true
IsScholarly true
Issue 15_Supplement
Language English
LinkModel OpenURL
MergedId FETCHMERGED-crossref_primary_10_1158_1538_7445_AM2015_29663
ParticipantIDs crossref_primary_10_1158_1538_7445_AM2015_2966
PublicationCentury 2000
PublicationDate 2015-08-01
PublicationDateYYYYMMDD 2015-08-01
PublicationDate_xml – month: 08
  year: 2015
  text: 2015-08-01
  day: 01
PublicationDecade 2010
PublicationTitle Cancer research (Chicago, Ill.)
PublicationYear 2015
SSID ssj0005105
Score 4.411171
Snippet Prostate cancer (CaP) remains the most common male malignancy worldwide, leading to over 300,000 deaths per year. In Western countries, most prostate tumours...
SourceID crossref
SourceType Aggregation Database
StartPage 2966
Title Abstract 2966: The mutational landscape of localized gleason 6 and 7 prostate cancer
Volume 75
hasFullText 1
inHoldings 1
isFullTextHit
isPrint
link http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3dSwJBEF_MIHqJPumbfejtuAv19tTeJAwpDAILfTr2ztVEPaPOIP-5_rVm9uuOkshADm_Pm9tzfszO7v5mhpALv8JZWcQlN4pxmxEmPm4dhkm3z4MafPrCjyXb4j5oPfq3XdYtFD5zrKV5GnnxYmlcyX-0Cm2gV4ySXUGzVig0wHfQLxxBw3D8k44bES5UxKlThumE4U9M56lZ4JNxvMhwQpdQjlqjBTiYw4ngWHgwkDsHVeRoybgiZIDFmq2bJS-AFkenBHqWe76KvCGNy2Ti5ZYSwAl-UwjQZHyn6dkVHB6JSfIxnr1Lb_VJyJy83OnZX_T4lA-xNIuEEB_zwXw6cu7tdeTfqpAcTdczixUlZqlymQGuucxX1Xo8kdncqq-yShqjrMqpGPCxUNY4zchA2trWgyA3cpvTn6MCw0gH-xyv0ZZ9y27PZ-H-NjpazqKcLbFaiGJCFBMqMSGKWSPrmIkRizfcPWTp6pnm0Jq31iFkIOZyaW9yzlHOy-lsky09PaENhbUdUhDJLtloawLGHukYyFEUdEUBcDQDHLWAo7MBtYCjGnA0oHCdVqkBHFWA2yfsptm5brmmV-GLyoES_vpvVA5IMZkl4pDQoMKrjPfLFfC0_ZjFdZghlAc1cDSDKBL1_hHxVpN9vOoNJ2QzQ-IpKaavc3EGjmQanUtlfQGCRmuk
link.rule.ids 314,780,784,27924,27925
linkProvider Colorado Alliance of Research Libraries
openUrl ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Abstract+2966%3A+The+mutational+landscape+of+localized+gleason+6+and+7+prostate+cancer&rft.jtitle=Cancer+research+%28Chicago%2C+Ill.%29&rft.au=Fraser%2C+Michael+E.&rft.au=Sabelnykova%2C+Veronica+Y.&rft.au=Yamaguchi%2C+Takafumi+N.&rft.au=Meng%2C+Alice&rft.date=2015-08-01&rft.issn=0008-5472&rft.eissn=1538-7445&rft.volume=75&rft.issue=15_Supplement&rft.spage=2966&rft.epage=2966&rft_id=info:doi/10.1158%2F1538-7445.AM2015-2966&rft.externalDBID=n%2Fa&rft.externalDocID=10_1158_1538_7445_AM2015_2966
thumbnail_l http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0008-5472&client=summon
thumbnail_m http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0008-5472&client=summon
thumbnail_s http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0008-5472&client=summon