Clinical Chemistry
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Clinical Chemistry 55: 1834-1842, 2009. First published August 6, 2009; 10.1373/clinchem.2009.123695
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(Clinical Chemistry. 2009;55:1834-1842.)
© 2009 American Association for Clinical Chemistry, Inc.

Cancer Diagnostics

Increased Tissue Factor Expression Is Associated with Reduced Survival in Non–Small Cell Lung Cancer and with Mutations of TP53 and PTEN

Sandra Regina1,2, Jean-Baptiste Valentin1, Sébastien Lachot1, Etienne Lemarié2,3, Jérôme Rollin1,2 and Yves Gruel1,2,a

1 Department of Hematology-Hemostasis, Trousseau Hospital and François Rabelais University, Tours, France;2 INSERM, Tours;3 Department of Pneumology, Bretonneau Hospital and François Rabelais University, Tours, France.

aAddress correspondence to this author at: Professor Yves Gruel, INSERM U 618, "Protéases et Vectorisation Pulmonaires," Faculté de Médecine, 10 bis Bd Tonnellé, 37032 Tours Cedex, France. Fax +33-2-47-36-60-46; e-mail gruel{at}med.univ-tours.fr.

Background: Tissue factor (TF), the main initiator of blood coagulation, is also a signaling protein that regulates cancer progression. TF synthesis was recently shown to be affected by tumor suppressor genes (TSGs) in tumor cell lines. We therefore studied TF gene (F3) expression and the status of genes coding for tumor protein p53 (TP53), phosphatase and tensin homolog (PTEN), and serine/threonine kinase 11 (STK11) in non–small cell lung cancer (NSCLC). Heparanase (HPSE) gene expression was also measured because this endo-β-D-glucuronidase was recently shown to enhance TF gene expression.

Methods: TF and heparanase mRNA expression was measured by real-time PCR in 53 NSCLC tumors. Exons 5–8 of TP53 were sequenced from genomic DNA. Mutations of PTEN and STK11 were screened by multiplex ligation-dependent probe amplification.

Results: TF mRNA levels were significantly higher in T3–T4 tumors (P = 0.04) and in stages III–IV of NSCLC (P = 0.03). Mutations of TP53, STK11, and PTEN were identified in 20 (37.7%), 21 (39%), and 20 (37.7%) of tumors, respectively. TF expression was higher in mutated TP53 (TP53Mut) (P = 0.02) and PTENMut (P = 0.03) samples. Moreover, TF mRNA increased from 2700 copies (no mutation) to 11 6415 when 3 TSG were mutated. Heparanase gene expression did not differ according to TF gene (F3) expression or TSG mutation. The median survival time was shorter in patients with tumor TF mRNA levels above median values (relative risk 2.2; P = 0.03, multivariate analysis) and when TP53 was mutated (relative risk 1.8; P = 0.02).

Conclusions: These results provide clear evidence that combined oncogene events affecting TSG dramatically increase TF gene expression in lung tumors. Moreover, this study suggests that TF gene expression could be used as a prognostic marker in NSCLC. .






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Copyright © 2009 by the American Association for Clinical Chemistry.