Prognostic Value of Plasma and Urine Glycosaminoglycan Scores in Clear Cell Renal Cell Carcinoma

Francesco Gatto, Marco Maruzzo, Cristina Magro, Umberto Basso, Jens Nielsen, Francesco Gatto, Marco Maruzzo, Cristina Magro, Umberto Basso, Jens Nielsen

Abstract

Background: The prognosis of metastatic clear cell renal cell carcinoma (ccRCC) vastly improved since the introduction of antiangiogenic-targeted therapy. However, it is still unclear which biological processes underlie ccRCC aggressiveness and affect prognosis. Here, we checked whether a recently discovered systems biomarker based on plasmatic or urinary measurements of glycosaminoglycans (GAGs) aggregated into diagnostic scores correlated with ccRCC prognosis.

Methods: Thirty-one patients with a diagnosis of ccRCC (23 metastatic) were prospectively enrolled, and their urine and plasma biomarker scores were correlated to progression-free survival (PFS) and overall survival (OS) as either a dichotomous ("Low" vs. "High") or a continuous variable in a multivariate survival analysis.

Results: The survival difference between "High"- vs. "Low"-scored patients was significant in the case of urine scores (2-year PFS rate = 53.3 vs. 100%, p = 3 × 10-4 and 2-year OS rate = 73.3 vs. 100%, p = 0.0078) and in the case of OS for plasma scores (2-year PFS rate = 60 vs. 84%, p = 0.0591 and 2-year OS rate = 66.7 vs. 90%, p = 0.0206). In multivariate analysis, the urine biomarker score as a continuous variable was an independent predictor of PFS [hazard ratio (HR): 4.62, 95% CI: 1.66-12.83, p = 0.003] and OS (HR: 10.13, 95% CI: 1.80-57.04, p = 0.009).

Conclusion: This is the first report on an association between plasma or urine GAG scores and the prognosis of ccRCC patients. Prospective trials validating the prognostic and predictive role of this novel systems biomarker are warranted.

Keywords: kidney cancer; molecular biomarkers; prognostic biomarkers; systems medicine.

Figures

Figure 1
Figure 1
Kaplan–Meier curves for PFS (left) or OS (right) in ccRCC patients according to urine biomarker score level. The prospective cohort of patients (N = 29) was classified as 14 “Low” (solid) vs. 15 “High” (dashed) biomarker score at the time of sampling.
Figure 2
Figure 2
Kaplan–Meier curves for PFS (left) or OS (right) in ccRCC patients according to plasma biomarker score level. The prospective cohort of patients (N = 30) was classified as 15 “Low” (solid) vs. 15 “High” (dashed) biomarker score at the time of sampling.
Figure 3
Figure 3
Kaplan–Meier curves for PFS (left) or OS (right) limited to patients with metastatic ccRCC according to the urine (A) or plasma (B) biomarker score level. The prospective cohort of patients (N = 23) was classified as “Low” (solid) vs. “High” (dashed) biomarker score at the time of sampling.
Figure 4
Figure 4
Kaplan–Meier curves for PFS (left) or OS (right) calculated from date of first treatment start for metastatic disease according to the urine (A) or plasma (B) biomarker score level. The prospective cohort of patients (N = 23) was classified as “Low” (solid) vs. “High” (dashed) biomarker score at the time of sampling.

References

    1. Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet (2009) 373:1119–32.10.1016/S0140-6736(09)60229-4
    1. Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev (2008) 34:193–205.10.1016/j.ctrv.2007.12.001
    1. Wahlgren T, Harmenberg U, Sandström P, Lundstam S, Kowalski J, Jakobsson M, et al. Treatment and overall survival in renal cell carcinoma: a Swedish population-based study (2000-2008). Br J Cancer (2013) 108:1541–9.10.1038/bjc.2013.119
    1. Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol (2014) 32:2765–72.10.1200/JCO.2013.54.6911
    1. Larkin J, Paine A, Foley G, Mitchell S, Chen C. First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis. Expert Opin Pharmacother (2015) 16:1915–27.10.1517/14656566.2015.1058359
    1. Heng DY, Signorovitch J, Swallow E, Li N, Zhong Y, Qin P, et al. Comparative effectiveness of second-line targeted therapies for metastatic renal cell carcinoma: a systematic review and meta-analysis of real-world observational studies. PLoS One (2014) 9:e114264.10.1371/journal.pone.0114264
    1. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol (2016) 17:917–27.10.1016/S1470-2045(16)30107-3
    1. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med (2015) 373:1803–13.10.1056/NEJMoa1510665
    1. Modi PK, Farber NJ, Singer EA. Precision oncology: identifying predictive biomarkers for the treatment of metastatic renal cell carcinoma. Transl Cancer Res (2016) 5:S76–80.10.21037/tcr.2016.06.05
    1. Gatto F, Nookaew I, Nielsen J. Chromosome 3p loss of heterozygosity is associated with a unique metabolic network in clear cell renal carcinoma. Proc Natl Acad Sci U S A (2014) 111:E866–75.10.1073/pnas.1319196111
    1. Creighton CJ, Morgan M, Gunaratne PH, Wheeler DA, Gibbs RA, Robertson A, et al. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature (2013) 499(7456):43–9.10.1038/nature12222
    1. Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, et al. An integrated metabolic Atlas of clear cell renal cell carcinoma. Cancer Cell (2016) 29:104–16.10.1016/j.ccell.2015.12.004
    1. Frew IJ, Moch H. A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annu Rev Pathol (2015) 10:263–89.10.1146/annurev-pathol-012414-040306
    1. Gatto F, Volpi N, Nilsson H, Nookaew I, Maruzzo M, Roma A, et al. Glycosaminoglycan profiling in patients’ plasma and urine predicts the occurrence of metastatic clear cell renal cell carcinoma. Cell Rep (2016) 15:1822–36.10.1016/j.celrep.2016.04.056
    1. Altman DG, McShane LM, Sauerbrei W, Taube SE. Reporting recommendations for tumor marker prognostic studies (REMARK): explanation and elaboration. PLoS Med (2012) 9:e1001216.10.1371/journal.pmed.1001216
    1. Galeotti F, Coppa GV, Zampini L, Maccari F, Galeazzi T, Padella L, et al. Capillary electrophoresis separation of human milk neutral and acidic oligosaccharides derivatized with 2-aminoacridone. Electrophoresis (2014) 35:811–8.10.1002/elps.201300490
    1. Kottler R, Mank M, Hennig R, Müller-Werner B, Stahl B, Reichl U, et al. Development of a high-throughput glycoanalysis method for the characterization of oligosaccharides in human milk utilizing multiplexed capillary gel electrophoresis with laser-induced fluorescence detection. Electrophoresis (2013) 34:2323–36.10.1002/elps.201300016
    1. Albiges L, Oudard S, Negrier S, Caty A, Gravis G, Joly F, et al. Complete remission with tyrosine kinase inhibitors in renal cell carcinoma. J Clin Oncol (2012) 30:482–7.10.1200/JCO.2011.37.2516
    1. Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J, et al. State of the science: an update on renal cell carcinoma. Mol Cancer Res (2012) 10:859–80.10.1158/1541-7786.MCR-12-0117
    1. Moch H, Srigley J, Delahunt B, Montironi R, Egevad L, Tan PH. Biomarkers in renal cancer. Virchows Arch (2014) 464:359–65.10.1007/s00428-014-1546-1
    1. Parker AS, Eckel-Passow JE, Serie D, Hilton T, Parasramka M, Joseph RW, et al. Higher expression of topoisomerase II alpha is an independent marker of increased risk of cancer-specific death in patients with clear cell renal cell carcinoma. Eur Urol (2014) 66:929–35.10.1016/j.eururo.2013.12.017
    1. Barabasi AL, Oltvai ZN. Network biology: understanding the cell’s functional organization. Nat Rev Genet (2004) 5:101–13.10.1038/nrg1272
    1. Rossi E, Fassan M, Aieta M, Zilio F, Celadin R, Borin M, et al. Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to sunitinib in metastatic renal cancer. Br J Cancer (2012) 107:1286–94.10.1038/bjc.2012.388
    1. Maroto P, Rini B. Molecular biomarkers in advanced renal cell carcinoma. Clin Cancer Res (2014) 20:2060–71.10.1158/1078-0432.CCR-13-1351
    1. Maruzzo M, Basso U, Diminutto A, Roma A, Zustovich F, Brunello A, et al. Role of dose exposure and inflammatory status in a single center, real-world analysis of sunitinib in patients with metastatic renal cell carcinoma. Future Oncol (2016) 12:909–19.10.2217/fon.16.14
    1. Sun M, Shariat SF, Cheng C, Ficarra V, Murai M, Oudard S, et al. Prognostic factors and predictive models in renal cell carcinoma: a contemporary review. Eur Urol (2011) 60:644–61.10.1016/j.eururo.2011.06.041
    1. Negrier S, Perol D, Menetrier-Caux C, Escudier B, Pallardy M, Ravaud A, et al. Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6 – from the Groupe Francais d’Immunotherapie. J Clin Oncol (2004) 22:2371–8.10.1200/JCO.2004.06.121
    1. Ramankulov A, Lein M, Johannsen M, Schrader M, Miller K, Loening SA, et al. Serum amyloid A as indicator of distant metastases but not as early tumor marker in patients with renal cell carcinoma. Cancer Lett (2008) 269:85–92.10.1016/j.canlet.2008.04.022
    1. Rasmuson T, Grankvist K, Jacobsen J, Olsson T, Ljungberg B. Serum insulin-like growth factor-1 is an independent predictor of prognosis in patients with renal cell carcinoma. Acta Oncol (2004) 43:744–8.10.1080/02841860410017260
    1. Ucakturk E, Akman O, Sun X, Baydar DE, Dolgun A, Zhang F, et al. Changes in composition and sulfation patterns of glycoaminoglycans in renal cell carcinoma. Glycoconj J (2016) 33:103–12.10.1007/s10719-015-9643-1
    1. Afratis N, Gialeli C, Nikitovic D, Tsegenidis T, Karousou E, Theocharis AD, et al. Glycosaminoglycans: key players in cancer cell biology and treatment. FEBS J (2012) 279:1177–97.10.1111/j.1742-4658.2012.08529.x
    1. Taylor KR, Gallo RL. Glycosaminoglycans and their proteoglycans: host-associated molecular patterns for initiation and modulation of inflammation. FASEB J (2006) 20:9–22.10.1096/fj.05-4682rev
    1. Silver DJ, Siebzehnrubl FA, Schildts MJ, Yachnis AT, Smith GM, Smith AA, et al. Chondroitin sulfate proteoglycans potently inhibit invasion and serve as a central organizer of the brain tumor microenvironment. J Neurosci (2013) 33:15603–17.10.1523/JNEUROSCI.3004-12.2013

Source: PubMed

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