Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma

Sixty-six replacing growth-type early lung adenocarcinomas, measuring 2 cin or less across their greatest dimension, were used to investigate allelic losses at eight loci on the eight chromosomes carrying the principal cancer -associated genes. In total, 2 (16.7%) of 12 type A tumors (localized bronc hioloalveolar carcinoma, LBAC) and 11 (39.3%) of 28 type B tumors (LBAC wit h alveolar collapse), which correspond to early lung adenocarcinomas includ ing cancers in situ, showed allelic losses in one or more of the regions ex amined. In contrast, 25 (96.2%) of 26 type C tumors (LBAC with active fibro blastic proliferation), which correspond to small but advanced tumors, show ed allelic losses in one or more regions. The change in histology from type A to type C was characterized by a significant rise in the incidence of al lelic losses (P < 0.01). Deletions of 3p, 17p, 18q, and 22q increased signi ficantly during malignant progression. In type C tumors that showed heterog eneous histological features, the tumor cells in the central fibrotic areas exhibited more allelic losses than those in the peripheral bronchioloalveo lar growths and were, therefore, considered to have progressed to a more ad vanced stage than the tumor cells in the peripheral regions.