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Fragile Histidine Triad Gene Inactivation in Lung Cancer

The European Early Lung Cancer Project

Carla Verri^1,*, Luca Roz^1,*, Davide Conte¹, Triantafillos Liloglou², Anna Livio¹, Aurelien Vesin³, Alessandra Fabbri⁴, Francesca Andriani¹, Christian Brambilla³, Luca Tavecchio⁵, Giuseppe Calarco⁶, Elisa Calabrò⁵, Andrea Mancini⁶, Diego Tosi⁷, Paolo Bossi⁷, John K. Field², Elisabeth Brambilla^3,, Gabriella Sozzi^1, and the EUELC Consortium

¹ Department of Experimental Oncology; ⁴ Department of Pathology; ⁵ Department of Thoracic Surgery; ⁶ Department of Endoscopy; ⁷ Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; ² University of Liverpool, Division of Surgery & Oncology, Liverpool, United Kingdom; and ³ Department of Pathology, INSERM U823, Albert Bonniot Institute, Grenoble, France

Correspondence and requests for reprints should be addressed to Gabriella Sozzi, Ph.D., Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. E-mail: gabriella.sozzi{at}istitutotumori.mi.it

Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer.

Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors.

Methods: FHIT immunostaining was performed on 305 tumor samples. The methylation status of FHIT promoter was assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples of which a subset of 187 patients had available normal/tumor DNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers.

Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7% of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was present when methylation and LOH were analyzed together (P = 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P < 0.0001) and in smokers (P = 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P = 0.0415).

Conclusions: Our results indicate that different molecular mechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.

Key Words: lung cancer • FHIT gene • methylation • prognostic biomarker

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The loss of fragile histidine triad (FHIT) protein expression was frequently observed in primary non–small cell lung cancer. The FHIT gene function is inactivated by different biological mechanisms as promoter methylation and loss of heterozygosity at the FHIT locus. What This Study Adds to the Field The association between FHIT methylation in normal tissue and prognosis suggest that FHIT methylation in normal lung could represent a prognostic marker for early recurrence.

 

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