Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer

Clin Cancer Res. 2016 Jan 15;22(2):448-58. doi: 10.1158/1078-0432.CCR-15-0256. Epub 2015 Oct 7.

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-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.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Continental Population Groups / genetics*
  • Disease Progression
  • Extracellular Matrix Proteins / genetics*
  • Genetic Predisposition to Disease / genetics*
  • Germ Cells / metabolism
  • Humans
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Metastasis / genetics*
  • Polymorphism, Genetic / genetics*
  • Prostatectomy / methods
  • Prostatic Neoplasms / genetics*
  • Retrospective Studies
  • Risk
  • Tumor Microenvironment / genetics*

Substances

  • ASPN protein, human
  • Extracellular Matrix Proteins