4 research outputs found
Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.
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.
Themethylation status of FHIT promoterwas assessed by nested
methylation-specific polymerase chain reaction (MSP-PCR) in 232
tumor and 225 normal lung samples ofwhich a subset of 187 patients
had available normal/tumorDNA 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 presentwhenmethylation and LOHwere analyzed together (P5
0.0064). Loss of FHIT protein expression was significantly more
frequent in squamous cell carcinoma histotype (P , 0.0001) and in
smokers (P5 0.008). FHIT methylation in normal lung was associated
with an increased risk of progressive disease (OR, 2.27; P 5 0.0415).
Conclusions:Our results indicate thatdifferentmolecularmechanisms
interplay to inactivate FHIT expression and support the proposition
that FHIT methylation in normal lung tissue could represent a prognostic
marker for progressive disease
EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration. European Respiratory
The European Early Lung Cancer (EUELC) project aims to determine if specific
genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium.
In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk
of developing progressive lung cancer were recruited from 12 centres in eight European
countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In
addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial
Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of
biological specimens.
The molecular–pathological investigations were subdivided into specific work packages that
were delivered by EUELC Partners. The work packages encompassed mutational analysis,
genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and
chip-based technologies, as well as in-depth analysis of FHIT and RARb genes, the telomerase
catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways.
The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC
Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the
view to using such biomarkers for early diagnosis and as intermediate end-points in future
chemopreventive programmes