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Retinoic Acid Receptor and Retinoid X Receptor Alterations in Lung Cancer Precursor Lesions¹

Centre Lorrain d’Etudes et de Recherches sur les Cancers Pulmonaires, Faculté de Médecine, 54505 Vandoeuvre-Lès-Nancy, France [N. M., G. F., T. L., H. F., R. V., E. P., D. L. F., J. S., J. B., T. B., J-M. V., Y. M.]; Hopital Universitaire, Service d’Epidémiologie, 54000 Nancy, France [F. A.]; Hopital Universitaire, Service de Biologie Moléculaire, 67098 Strasbourg, France [M-P. G.]; and Centre Jules Bordet, 1000 Bruxelles, Belgium [P. V.]

Smoking prevention will decrease lung cancer incidence in time. However, early detection would improve lung cancer prognosis in subjects at risk provided that specific markers could be identified. We previously reported that retinoic acid receptor (RAR) and retinoid X receptor (RXR) expression was altered in lung tumors. RAR-ß gene status could be derived from corresponding allelotyping and immunohistochemistry data. We now report the continued study on lung cancer precursor lesions. Fluorescence PCR-based assays were used for allelotyping at the RAR/RXR loci of: (a) 66 lung precursor lesions found at the free resection margins of 41 patients undergoing surgery for lung cancer (+ 31 paired tumors); and (b) bronchial cells also found at the free resection margins from 16 current and 8 never smokers operated on for noncancerous diseases. Three microsatellites located at 3p14–21 and 9p21 were also used for interwork comparison. Immunohistochemistry was additionally performed to evaluate P53 and RAR-ß expression in precursor lesions. ² tests showed significant differences (P < 0.05) when comparing the results obtained from never smokers, smokers, squamous metaplasia, dysplasia + in situ carcinoma, and tumors. Microsatellite changes occurred frequently 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 the RAR- marker appeared as a preferential target (P < 0.004). Few reparation error phenotypes were observed, mostly at the RXR- and RXR- markers for which combined changes were also linearly increasing from never smokers to dysplasia + in situ carcinoma (P < 0.05 and P < 0.03). RAR-ß marker losses also increased from the first to the last group studied (P < 0.01), with a concomitant decrease in RAR-ß protein expression and correlated p53 increased immunoreactivity (P < 0.02). Losses at 3p14, 3p21, and P16 were frequent, but no significant differences between groups could be found. Unexpectedly, high constitutive homozygosity was observed near the RAR- locus in squamous cell lung cancer cases. RARs/RXRs form homodimers or heterodimers involved in ligand binding. Their added alterations could result in a state of functional vitamin A deficiency in the affected bronchial cells. Further deletion events drawn from a limited repertoire of specific regions such as 3p14–21 and 9p21 could subsequently drive the deficient cells to invasive carcinoma.

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