@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.}",
note = "Funding Information: The authors wish to express their gratitude to the patients and the families of patients who contributed to this study. The authors acknowledge excellent technical assistance from Cesar Vazquez, Bonnie Wong, Dr. Victoria Petkova, and Olga Voznesensky. This work was supported by the NIH (T32 CA081156 to A.G. Sowalsky; P01 CA163227 to S.P. Balk; DF/HCC-Prostate Cancer SPORE P50 CA090381 to S.P. Balk and A.G. Sowalsky; and R01 HG007538 to W. Li), the Department of Defense Prostate Cancer Research Program (Postdoctoral Training Award W81XWH-13-1-0267, Idea Development Award W81XWH-15-1-0710, and Exploration-Hypothesis Development Award W81XWH-15-1-0136; to A.G. Sowalsky, Idea Development Awards W81XWH-11-1-0295, W81XWH-08-1-0414, and W81XWH-07-1-0443; to S.P. Balk), CPRIT (RP110471 and RP150292; to W. Li), the Prostate Cancer Foundation (Young Investigator Awards; to A.G. Sowalsky, H.T. Kissick, and H. Ye, and a Challenge Award; to S.P. Balk), a High Impact Mazzone Award from the Dana-Farber/Harvard Cancer Center (to S.P. Balk), a Translational Grant from the V Foundation for Cancer Research (to S.P. Balk), and the Intramural Research Program of the NIH, National Cancer Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.",
year = "2017",
month = jul,
day = "15",
doi = "10.1158/1078-0432.CCR-16-2414",
language = "English (US)",
volume = "23",
pages = "3823--3833",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "14",
}