@article{081520132df84bffa88d74099a412263,
title = "Germline variants in asporin vary by race, modulate the tumor microenvironment, and are differentially associated with metastatic prostate cancer",
abstract = "Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeatlength have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental Design: Germline ASPN D-repeat-length was retrospectively analyzed in 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes, including metastasis. Orthotopic xenografts were used to establish allele- and stromaspecific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 [HR, 1.72; 95% confidence interval (CI), 1.05-2.81, P = 0.032] and heterozygosity for ASPN D13/14 (HR, 1.86; 95% CI, 1.03-3.35, P = 0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR, 0.44; 95% CI, 0.21-0.94, P = 0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient-based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes, including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression.",
author = "Hurley, {Paula J.} and Debasish Sundi and Brian Shinder and Simons, {Brian W.} and Hughes, {Robert M.} and Miller, {Rebecca M.} and Benjamin Benzon and Faraj, {Sheila F.} and Netto, {George J.} and Vergara, {Ismael A.} and Nicholas Erho and Elai Davicioni and Karnes, {R. Jeffrey} and Guifang Yan and Charles Ewing and Isaacs, {Sarah D.} and Berman, {David M.} and Rider, {Jennifer R.} and Jordahl, {Kristina M.} and Mucci, {Lorelei A.} and Jessie Huang and An, {Steven S.} and Park, {Ben H.} and Isaacs, {William B.} and Luigi Marchionni and Ross, {Ashley E.} and Schaeffer, {Edward M.}",
note = "Funding Information: The authors thank Phuoc Tran, Ballentine Carter, Ken Pienta, Patrick Walsh, John Isaacs, and Mike Brown for helpful discussions and/or critical reading of this article. They also thank John Isaacs for reagents and Laura Kasch-Semenza at the Johns Hopkins GRCF Fragment Analysis Facility and the Prostate Cancer Biorepository Network (PCBN), supported by the Department of Defense Prostate Cancer Research Program, DOD Award No W81XWH-10-2-0056 and W81XWH-10-2-0046. This work was supported by The Department of Defense Prostate Cancer Research Program Idea Award, DOD Award No PC110902 (to P.J. Hurley, L. Marchionni, E.M. Schaeffer); Flight Attendant Medical Research Institute Young Clinical Scientist Award (to P.J. Hurley); The Patrick C. Walsh Prostate Cancer Fund Beth W. and A. Ross Myer Scholar (to P.J. Hurley); The Prostate Cancer Foundation Hagen Challenge Award (to E.M. Schaeffer, P.J. Hurley); NIH grant T32DK007552 (to D. Sundi); NIH grant P30CA006973 (to L. Marchionni); and The Johns Hopkins Clinician Scientist Award (to A.E. Ross). 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. Publisher Copyright: {\textcopyright} 2015 American Association for Cancer Research.",
year = "2016",
month = jan,
day = "15",
doi = "10.1158/1078-0432.CCR-15-0256",
language = "English (US)",
volume = "22",
pages = "448--458",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "2",
}