Accumulation of losses of heterozygosity and multistep carcinogenesis in pulmonary adenocarcinoma.

Sixty-six replacing growth-type early lung adenocarcinomas, measuring 2 cm 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 bronchioloalveolar carcinoma, LBAC) and 11 (39.3%) of 28 type B tumors (LBAC with alveolar collapse), which correspond to early lung adenocarcinomas including cancers in situ, showed allelic losses in one or more of the regions examined. In contrast, 25 (96.2%) of 26 type C tumors (LBAC with active fibroblastic proliferation), which correspond to small but advanced tumors, showed 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 allelic losses (P < 0.01). Deletions of 3p, 17p, 18q, and 22q increased significantly during malignant progression. In type C tumors that showed heterogeneous histological features, the tumor cells in the central fibrotic areas exhibited more allelic losses than those in the peripheral bronchioloalveolar growths and were, therefore, considered to have progressed to a more advanced stage than the tumor cells in the peripheral regions.