Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4

Adam G. Sowalsky, Haydn T. Kissick, Sean J. Gerrin, Rachel J. Schaefer, Zheng Xia, Joshua W. Russo, M. Simo Arredouani, Glenn J. Bubley, Martin G. Sanda, Wei Li, Huihui Ye, Steven P. Balk

Research output: Research - peer-reviewArticle

  • 1 Citations

Abstract

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture–microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention.

LanguageEnglish (US)
Pages3823-3833
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number14
DOIs
StatePublished - Jul 15 2017
Externally publishedYes

Fingerprint

Clonal Evolution
Neoplasm Grading
Prostatic Neoplasms
Neoplasms
Gene Expression Profiling
Exome
Prostate
Histology
Lasers
Research Design
Biopsy
Mutation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sowalsky, A. G., Kissick, H. T., Gerrin, S. J., Schaefer, R. J., Xia, Z., Russo, J. W., ... Balk, S. P. (2017). Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4. Clinical Cancer Research, 23(14), 3823-3833. DOI: 10.1158/1078-0432.CCR-16-2414

Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4. / Sowalsky, Adam G.; Kissick, Haydn T.; Gerrin, Sean J.; Schaefer, Rachel J.; Xia, Zheng; Russo, Joshua W.; Arredouani, M. Simo; Bubley, Glenn J.; Sanda, Martin G.; Li, Wei; Ye, Huihui; Balk, Steven P.

In: Clinical Cancer Research, Vol. 23, No. 14, 15.07.2017, p. 3823-3833.

Research output: Research - peer-reviewArticle

Sowalsky, AG, Kissick, HT, Gerrin, SJ, Schaefer, RJ, Xia, Z, Russo, JW, Arredouani, MS, Bubley, GJ, Sanda, MG, Li, W, Ye, H & Balk, SP 2017, 'Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4' Clinical Cancer Research, vol 23, no. 14, pp. 3823-3833. DOI: 10.1158/1078-0432.CCR-16-2414
Sowalsky AG, Kissick HT, Gerrin SJ, Schaefer RJ, Xia Z, Russo JW et al. Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4. Clinical Cancer Research. 2017 Jul 15;23(14):3823-3833. Available from, DOI: 10.1158/1078-0432.CCR-16-2414
Sowalsky, Adam G. ; Kissick, Haydn T. ; Gerrin, Sean J. ; Schaefer, Rachel J. ; Xia, Zheng ; Russo, Joshua W. ; Arredouani, M. Simo ; Bubley, Glenn J. ; Sanda, Martin G. ; Li, Wei ; Ye, Huihui ; Balk, Steven P./ Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 14. pp. 3823-3833
@article{f8cb72bc594840928f4b818815afff8e,
title = "Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4",
abstract = "Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture–microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention.",
author = "Sowalsky, {Adam G.} and Kissick, {Haydn T.} and Gerrin, {Sean J.} and Schaefer, {Rachel J.} and Zheng Xia and Russo, {Joshua W.} and Arredouani, {M. Simo} and Bubley, {Glenn J.} and Sanda, {Martin G.} and Wei Li and Huihui Ye and Balk, {Steven P.}",
year = "2017",
month = "7",
doi = "10.1158/1078-0432.CCR-16-2414",
volume = "23",
pages = "3823--3833",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14",

}

TY - JOUR

T1 - Gleason score 7 prostate cancers emerge through branched evolution of clonal Gleason pattern 3 and 4

AU - Sowalsky,Adam G.

AU - Kissick,Haydn T.

AU - Gerrin,Sean J.

AU - Schaefer,Rachel J.

AU - Xia,Zheng

AU - Russo,Joshua W.

AU - Arredouani,M. Simo

AU - Bubley,Glenn J.

AU - Sanda,Martin G.

AU - Li,Wei

AU - Ye,Huihui

AU - Balk,Steven P.

PY - 2017/7/15

Y1 - 2017/7/15

N2 - Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture–microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention.

AB - Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established. Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture–microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities. Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci. Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention.

UR - http://www.scopus.com/inward/record.url?scp=85024123008&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85024123008&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-16-2414

DO - 10.1158/1078-0432.CCR-16-2414

M3 - Article

VL - 23

SP - 3823

EP - 3833

JO - Clinical Cancer Research

T2 - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 14

ER -