title: Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer.
abstract: OBJECTIVE
  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-repeat-length 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.
  
  
  METHODS
  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 stroma-specific 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.
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland. phurley2@jhmi.edu.
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Hurley
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Debasish
authors.initials: D
authors.lastname: Sundi
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Brian
authors.initials: B
authors.lastname: Shinder
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Simons
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hughes
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Miller
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Benzon
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Sheila F
authors.initials: SF
authors.lastname: Faraj
authors.affiliation: Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: George J
authors.initials: GJ
authors.lastname: Netto
authors.affiliation: Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: Ismael A
authors.initials: IA
authors.lastname: Vergara
authors.affiliation: Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Erho
authors.affiliation: Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
authors.forename: Elai
authors.initials: E
authors.lastname: Davicioni
authors.affiliation: Department of Urology, Mayo Clinic, Rochester, Minnesota.
authors.forename: R Jeffrey
authors.initials: RJ
authors.lastname: Karnes
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Guifang
authors.initials: G
authors.lastname: Yan
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Charles
authors.initials: C
authors.lastname: Ewing
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Sarah D
authors.initials: SD
authors.lastname: Isaacs
authors.affiliation: Department of Pathology and Molecular Medicine and Cancer Research Institute, Queens University, Kingston, Ontario, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Berman
authors.affiliation: Department of Epidemiology, Harvard University, T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Rider
authors.affiliation: Department of Epidemiology, Harvard University, T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Jordahl
authors.affiliation: Department of Epidemiology, Harvard University, T.H. Chan School of Public Health, Boston, Massachusetts.
authors.forename: Lorelei A
authors.initials: LA
authors.lastname: Mucci
authors.affiliation: The Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
authors.forename: Jessie
authors.initials: J
authors.lastname: Huang
authors.affiliation: The Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. The Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland. Physical Sciences-Oncology Center, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Steven S
authors.initials: SS
authors.lastname: An
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ben H
authors.initials: BH
authors.lastname: Park
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: William B
authors.initials: WB
authors.lastname: Isaacs
authors.affiliation: Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Marchionni
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland. Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ashley E
authors.initials: AE
authors.lastname: Ross
authors.affiliation: Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Edward M
authors.initials: EM
authors.lastname: Schaeffer
mesh_terms: D000483:Alleles; D000818:Animals; D018450:Disease Progression; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005854:Germ Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics*; D011468:Prostatectomy / Q000379:methods; D011471:Prostatic Neoplasms / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics*; D012189:Retrospective Studies; D012306:Risk; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C439889:ASPN protein, human; D016326:Extracellular Matrix Proteins