Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer

Shanna A Arnold Egloff, Liping Du, Holli A. Loomans, Alina Starchenko, Pei Fang Su, Tatiana Ketova, Paul B. Knoll, Jifeng Wang, Ahmed Q. Haddad, Oluwole Fadare, Justin M. Cates, Yair Lotan, Yu Shyr, Peter E. Clark, Andries Zijlstra

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95% CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3% (concordanceindex, 78.5% vs. 75.2%). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95% CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.

Original languageEnglish (US)
Pages (from-to)722-741
Number of pages20
JournalOncotarget
Volume8
Issue number1
DOIs
StatePublished - 2017

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Activated-Leukocyte Cell Adhesion Molecule
Cystectomy
Urinary Bladder Neoplasms
Biomarkers
Survival
Urine
Cell Movement
Neoplasms
Validation Studies
Carcinoma in Situ
Hematuria
Adjuvant Chemotherapy
Mycobacterium bovis
Lymph Node Excision
Fluorescent Antibody Technique
Creatinine
Lymph Nodes
Enzyme-Linked Immunosorbent Assay

Keywords

  • ALCAM
  • Bladder cancer
  • Metastasis
  • Transitional cell carcinoma
  • Urothelial cell carcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer. / Egloff, Shanna A Arnold; Du, Liping; Loomans, Holli A.; Starchenko, Alina; Su, Pei Fang; Ketova, Tatiana; Knoll, Paul B.; Wang, Jifeng; Haddad, Ahmed Q.; Fadare, Oluwole; Cates, Justin M.; Lotan, Yair; Shyr, Yu; Clark, Peter E.; Zijlstra, Andries.

In: Oncotarget, Vol. 8, No. 1, 2017, p. 722-741.

Research output: Contribution to journalArticle

Egloff, SAA, Du, L, Loomans, HA, Starchenko, A, Su, PF, Ketova, T, Knoll, PB, Wang, J, Haddad, AQ, Fadare, O, Cates, JM, Lotan, Y, Shyr, Y, Clark, PE & Zijlstra, A 2017, 'Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer', Oncotarget, vol. 8, no. 1, pp. 722-741. https://doi.org/10.18632/oncotarget.13546
Egloff, Shanna A Arnold ; Du, Liping ; Loomans, Holli A. ; Starchenko, Alina ; Su, Pei Fang ; Ketova, Tatiana ; Knoll, Paul B. ; Wang, Jifeng ; Haddad, Ahmed Q. ; Fadare, Oluwole ; Cates, Justin M. ; Lotan, Yair ; Shyr, Yu ; Clark, Peter E. ; Zijlstra, Andries. / Shed urinary ALCAM is an independent prognostic biomarker of three-year overall survival after cystectomy in patients with bladder cancer. In: Oncotarget. 2017 ; Vol. 8, No. 1. pp. 722-741.
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abstract = "Proteins involved in tumor cell migration can potentially serve as markers of invasive disease. Activated Leukocyte Cell Adhesion Molecule (ALCAM) promotes adhesion, while shedding of its extracellular domain is associated with migration. We hypothesized that shed ALCAM in biofluids could be predictive of progressive disease. ALCAM expression in tumor (n = 198) and shedding in biofluids (n = 120) were measured in two separate VUMC bladder cancer cystectomy cohorts by immunofluorescence and enzyme-linked immunosorbent assay, respectively. The primary outcome measure was accuracy of predicting 3-year overall survival (OS) with shed ALCAM compared to standard clinical indicators alone, assessed by multivariable Cox regression and concordance-indices. Validation was performed by internal bootstrap, a cohort from a second institution (n = 64), and treatment of missing data with multiple-imputation. While ALCAM mRNA expression was unchanged, histological detection of ALCAM decreased with increasing stage (P = 0.004). Importantly, urine ALCAM was elevated 17.0-fold (P < 0.0001) above non-cancer controls, correlated positively with tumor stage (P = 0.018), was an independent predictor of OS after adjusting for age, tumor stage, lymph-node status, and hematuria (HR, 1.46; 95{\%} CI, 1.03-2.06; P = 0.002), and improved prediction of OS by 3.3{\%} (concordanceindex, 78.5{\%} vs. 75.2{\%}). Urine ALCAM remained an independent predictor of OS after accounting for treatment with Bacillus Calmette-Guerin, carcinoma in situ, lymph-node dissection, lymphovascular invasion, urine creatinine, and adjuvant chemotherapy (HR, 1.10; 95{\%} CI, 1.02-1.19; P = 0.011). In conclusion, shed ALCAM may be a novel prognostic biomarker in bladder cancer, although prospective validation studies are warranted. These findings demonstrate that markers reporting on cell motility can act as prognostic indicators.",
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AU - Egloff, Shanna A Arnold

AU - Du, Liping

AU - Loomans, Holli A.

AU - Starchenko, Alina

AU - Su, Pei Fang

AU - Ketova, Tatiana

AU - Knoll, Paul B.

AU - Wang, Jifeng

AU - Haddad, Ahmed Q.

AU - Fadare, Oluwole

AU - Cates, Justin M.

AU - Lotan, Yair

AU - Shyr, Yu

AU - Clark, Peter E.

AU - Zijlstra, Andries

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