Retinoic acid receptor and retinoid X receptor alterations in lung cancer precursor lesions

Smoking prevention will decrease lung cancer incidence in time. However, ea rly detection would improve lung cancer prognosis in subjects at risk provi ded that specific markers could be identified. We previously reported that retinoic acid receptor (RAR) and retinoid X receptor (RXR) expression was a ltered in lung tumors. RAR-beta gene status could be derived from correspon ding allelotyping and immunohistochemistry data. We now report the continue d study on lung cancer precursor lesions. Fluorescence PCR-based assays wer e used for allelotyping at the RAR/RXR loci of: (a) 66 lung precursor lesio ns found at the free resection margins of 41 patients undergoing surgery fo r lung cancer (+ 31 paired tumors); and (b) bronchial cells also found at t he free resection margins from 16 current and 8 never smokers operated on f or noncancerous diseases, Three microsatellites located at 3p14-21 and 9p21 were also used for interwork comparison. Immunohistochemistry was addition ally performed to evaluate P53 and RAR-beta expression in precursor lesions . chi(2) tests showed significant differences (P < 0.05) when comparing the results obtained from never smokers, smokers, squamous metaplasia, dysplas ia + in situ carcinoma, and tumors. Microsatellite changes occurred frequen tly in all samples, but without specificity for any group (P < 0.08-0.52). They were globally correlated with tobacco exposure (P < 0.04), for which t he RAR-gamma marker appeared as a preferential target (P < 0.004). Few repa ration error phenotypes were observed, mostly at the RXR-alpha and RXR-gamm a markers for which combined changes were also linearly increasing from nev er smokers to dysplasia + is situ carcinoma (P < 0.05 and P < 0.03). RAR-be ta marker losses also increased from the first to the last group studied (P < 0.01), with a concomitant decrease in RAR-beta protein expression and co rrelated p53 increased immunoreactivity (P < 0.02). Losses at 3p14, 3p21, a nd P16 were frequent, but no significant differences between groups could b e found, Unexpectedly, high constitutive homozygosity was observed near the RAR-alpha locus in squamous cell lung cancer cases. RARs/RXRs form homodim ers or heterodimers involved in ligand binding. Their added alterations cou ld result in a state of functional vitamin A deficiency in the affected bro nchial cells. Further deletion events drawn from a limited repertoire of sp ecific regions such as 3p14-21 and 9p21 could subsequently drive the defici ent cells to invasive carcinoma.