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


RESULTS
Using 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
Angptl4 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.
Verine
Jérôme
J
INSERM, U833, Paris, France.
Lehmann-Che
Jacqueline
J
Soliman
Hany
H
Feugeas
Jean-Paul
JP
Vidal
Jean-Sébastien
JS
Mongiat-Artus
Pierre
P
Belhadj
Stéphanie
S
Philippe
Josette
J
Lesage
Matthieu
M
Wittmer
Evelyne
E
Chanel
Stéphane
S
Couvelard
Anne
A
Ferlicot
Sophie
S
Rioux-Leclercq
Nathalie
N
Vignaud
Jean-Michel
JM
Janin
Anne
A
Germain
Stéphane
S
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics*; D015415:Biomarkers; D002292:Carcinoma, Renal Cell / Q000175:diagnosis* / Q000473:pathology / Q000556:secondary; D003937:Diagnosis, Differential; D006801:Humans; D017403:In Situ Hybridization; D025202:Molecular Diagnostic Techniques; D009362:Neoplasm Metastasis; D012333:RNA, Messenger / Q000032:analysis*; D012334:RNA, Neoplasm / Q000032:analysis; D012189:Retrospective Studies
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015415:Biomarkers; D012333:RNA, Messenger; D012334:RNA, Neoplasm
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