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Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer.
Hurley, Paula J; Sundi, Debasish; Shinder, Brian; Simons, Brian W; Hughes, Robert M; Miller, Rebecca M; Benzon, Benjamin; Faraj, Sheila F; Netto, George J; Vergara, Ismael A; Erho, Nicholas; Davicioni, Elai; Karnes, R Jeffrey; Yan, Guifang; Ewing, Charles; Isaacs, Sarah D; Berman, David M; Rider, Jennifer R; Jordahl, Kristina M; Mucci, Lorelei A; Huang, Jessie; An, Steven S; Park, Ben H; Isaacs, William B; Marchionni, Luigi; Ross, Ashley E; Schaeffer, Edward M.
Afiliação
  • Hurley PJ; 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.
  • Sundi D; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Shinder B; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Simons BW; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. Department of Molecular and Comparative Pathobiology, Johns Hopkins University, Baltimore, Maryland.
  • Hughes RM; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Miller RM; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Benzon B; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Faraj SF; Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
  • Netto GJ; Department of Pathology, Johns Hopkins University, Baltimore, Maryland.
  • Vergara IA; Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
  • Erho N; Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
  • Davicioni E; Genome Dx Biosciences Inc., Vancouver, British Columbia, Canada.
  • Karnes RJ; Department of Urology, Mayo Clinic, Rochester, Minnesota.
  • Yan G; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Ewing C; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Isaacs SD; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Berman DM; Department of Pathology and Molecular Medicine and Cancer Research Institute, Queens University, Kingston, Ontario, Canada.
  • Rider JR; Department of Epidemiology, Harvard University, T.H. Chan School of Public Health, Boston, Massachusetts.
  • Jordahl KM; Department of Epidemiology, Harvard University, T.H. Chan School of Public Health, Boston, Massachusetts.
  • Mucci LA; Department of Epidemiology, Harvard University, T.H. Chan School of Public Health, Boston, Massachusetts.
  • Huang J; The Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
  • An SS; 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, M
  • Park BH; Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland.
  • Isaacs WB; Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland.
  • Marchionni L; Department of Oncology, Johns Hopkins University, Baltimore, Maryland.
  • Ross AE; 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
  • Schaeffer EM; 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.
Clin Cancer Res ; 22(2): 448-58, 2016 Jan 15.
Article em En | MEDLINE | ID: mdl-26446945
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Polimorfismo Genético / Neoplasias da Próstata / Proteínas da Matriz Extracelular / Predisposição Genética para Doença / Grupos Raciais / Microambiente Tumoral / Metástase Neoplásica Tipo de estudo: Etiology_studies / Observational_studies / Risk_factors_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Polimorfismo Genético / Neoplasias da Próstata / Proteínas da Matriz Extracelular / Predisposição Genética para Doença / Grupos Raciais / Microambiente Tumoral / Metástase Neoplásica Tipo de estudo: Etiology_studies / Observational_studies / Risk_factors_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2016 Tipo de documento: Article