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.
| Language | English (US) |
|---|---|
| Pages | 3823-3833 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 14 |
| DOIs | |
| State | Published - Jul 15 2017 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Oncology
- Cancer Research
Cite this
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: Contribution to journal › Article
}
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 -