PLoS ONE (Apr 2010)

Determination of angptl4 mRNA as a diagnostic marker of primary and metastatic clear cell renal-cell carcinoma.

  • Jérôme Verine,
  • Jacqueline Lehmann-Che,
  • Hany Soliman,
  • Jean-Paul Feugeas,
  • Jean-Sébastien Vidal,
  • Pierre Mongiat-Artus,
  • Stéphanie Belhadj,
  • Josette Philippe,
  • Matthieu Lesage,
  • Evelyne Wittmer,
  • Stéphane Chanel,
  • Anne Couvelard,
  • Sophie Ferlicot,
  • Nathalie Rioux-Leclercq,
  • Jean-Michel Vignaud,
  • Anne Janin,
  • Stéphane Germain

DOI
https://doi.org/10.1371/journal.pone.0010421
Journal volume & issue
Vol. 5, no. 4
p. e10421

Abstract

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BackgroundWe have previously shown that angiopoietin-like 4 (angptl4) mRNA, a hypoxia-inducible gene, is highly expressed in clear cell renal-cell carcinoma (ccRCC), the most common subtype of RCC for which no specific marker is available. We here investigated whether angptl4 mRNA 1) could be a useful diagnostic and/or prognostic marker of ccRCC in a large and comprehensive retrospective series, 2) induction is dependent on the VHL status of tumors.Methodology/principal findingsUsing in situ hybridization, we report that angptl4 mRNA is expressed in 100% of both sporadic (n = 102) and inherited (n = 6) primary ccRCCs, without any statistical association with nuclear grade (p = 0.39), tumor size (p = 0.09), stage grouping (p = 0.17), progression-free survival (p = 0.94), and overall survival (p = 0.80). Angptl4 mRNA was also expressed in 26 (87%) of 30 secondary ccRCCs but neither in any other secondary RCCs (n = 7). In contrast, angptl4 mRNA was neither expressed in 94% non-ccRCC renal tumors (papillary RCCs (n = 46), chromophobe RCCs (n = 28), and oncocytomas (n = 9)), nor in non-renal clear cell carcinomas (n = 39). Angptl4 expression was also examined in tumors associated (n = 23) or not associated (n = 66) with VHL disease. 40 (98%) hemangioblastomas expressed angptl4 whereas all pheochromocytomas (n = 23) and pancreatic tumors (n = 25) were angptl4-negative, whatever their VHL status.Conclusions/significanceAngptl4 mRNA expression was highly associated with ccRCC (p = 1.5 10(-49), Chi square test) allowing to define its expression as a diagnosis marker for primary ccRCC. Moreover, angptl4 mRNA allows to discriminate the renal origin of metastases of clear-cell carcinomas arising from various organs. Finally, inactivation of VHL gene is neither necessary nor sufficient for angptl4 mRNA induction.