Germline variants in asporin vary by race, modulate the tumor microenvironment, and are differentially associated with metastatic prostate cancer

Paula Hurley, Debasish Sundi, Brian Shinder, Brian W. Simons, Robert M. Hughes, Rebecca M. Miller, Benjamin Benzon, Sheila F. Faraj, George J. Netto, Ismael A. Vergara, Nicholas Erho, Elai Davicioni, R. Jeffrey Karnes, Guifang Yan, Charles Ewing, Sarah D. Isaacs, David M. Berman, Jennifer R. Rider, Kristina M. Jordahl, Lorelei A. MucciJessie Huang, Steven An, Ben H. Park, William B Isaacs, Luigi Marchionni, Ashley E. Ross, Edward M. Schaeffer

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)448-458
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number2
DOIs
StatePublished - Jan 15 2016

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Tumor Microenvironment
Prostatic Neoplasms
Confidence Intervals
Heterografts
Neoplasm Metastasis
D-Aspartic Acid
Recurrence
Prostatectomy
Proportional Hazards Models
Research Design
Alleles
Morbidity
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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; 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; Park, Ben H.; Isaacs, William B; Marchionni, Luigi; Ross, Ashley E.; Schaeffer, Edward M.

In: Clinical Cancer Research, Vol. 22, No. 2, 15.01.2016, p. 448-458.

Research output: Contribution to journalArticle

Hurley, P, Sundi, D, Shinder, B, Simons, BW, Hughes, RM, Miller, RM, Benzon, B, Faraj, SF, Netto, GJ, Vergara, IA, Erho, N, Davicioni, E, Karnes, RJ, Yan, G, Ewing, C, Isaacs, SD, Berman, DM, Rider, JR, Jordahl, KM, Mucci, LA, Huang, J, An, S, Park, BH, Isaacs, WB, Marchionni, L, Ross, AE & Schaeffer, EM 2016, 'Germline variants in asporin vary by race, modulate the tumor microenvironment, and are differentially associated with metastatic prostate cancer', Clinical Cancer Research, vol. 22, no. 2, pp. 448-458. https://doi.org/10.1158/1078-0432.CCR-15-0256
Hurley, Paula ; 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 ; Park, Ben H. ; Isaacs, William B ; Marchionni, Luigi ; Ross, Ashley E. ; Schaeffer, Edward M. / Germline variants in asporin vary by race, modulate the tumor microenvironment, and are differentially associated with metastatic prostate cancer. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 2. pp. 448-458.
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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.",
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T1 - Germline variants in asporin vary by race, modulate the tumor microenvironment, and are differentially associated with metastatic prostate cancer

AU - Hurley, Paula

AU - Sundi, Debasish

AU - Shinder, Brian

AU - Simons, Brian W.

AU - Hughes, Robert M.

AU - Miller, Rebecca M.

AU - Benzon, Benjamin

AU - Faraj, Sheila F.

AU - Netto, George J.

AU - Vergara, Ismael A.

AU - Erho, Nicholas

AU - Davicioni, Elai

AU - Karnes, R. Jeffrey

AU - Yan, Guifang

AU - Ewing, Charles

AU - Isaacs, Sarah D.

AU - Berman, David M.

AU - Rider, Jennifer R.

AU - Jordahl, Kristina M.

AU - Mucci, Lorelei A.

AU - Huang, Jessie

AU - An, Steven

AU - Park, Ben H.

AU - Isaacs, William B

AU - Marchionni, Luigi

AU - Ross, Ashley E.

AU - Schaeffer, Edward M.

PY - 2016/1/15

Y1 - 2016/1/15

N2 - 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.

AB - 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.

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