We surveyed the occurrence of novel alleles at microsatellite sequences in non‐small cell lung cancers (NSCLC) using 61 tetranucleotide repeat markers. The presence of at least one new allele, consistent with microsatellite instability (MSI), was observed in 26 of 61 (43%) markers involving 30 of 47 (64%) NSCLC. Twelve of the 26 markers detected new alleles in 2 or more tumors and 11 of these 12 markers contained an AAAG repeat sequence. Using this panel of 12 markers, MSI was detected in 24 of 47 (51%) NSCLC and 10 of 18 (56%) head and neck cancers but was only observed in 8 of 38 (21%) bladder cancers and 3 of 25 (12%) kidney cancers. Our results suggested that about 50% of respiratory tract cancers exhibited microsatellite instability predominantly at AAAG sequences. This distinct type of instability was termed EMAST for elevated microsatellite alterations at selected tetranucleotide repeats. The identification of markers with EMAST should have potential application for the molecular detection of respiratory tract cancers. © 2001 Wiley‐Liss, Inc.

The accumulation of genetic alterations in the respiratory epithelium may give rise to cancer and often is accompanied by a series of histologic alterations over a period of several years. Recent studies have identified some molecular alterations in histologically normal-appearing epithelium among patients with lung cancer. To extend these observations, we investigated clonal genetic alterations by using fluorescence in situ hybridization (FISH) analysis and immunohistochemistry in 69 biopsy samples of histologically normal-appearing bronchial epithelium from 22 patients with or without lung cancer. Thirty-seven biopsy specimens from 13 patients were examined for loss of 3p14, and 48 biopsy specimens from 18 patients were examined for loss at 9p21 by FISH. P16(INK4a) expression was analyzed in 54 biopsy samples from 19 patients. In at least one biopsy specimen from five of the 13 patients with primary lung cancer, FISH or immunohistochemistry detected loss of the 3p14 or 9p21 region. In contrast, no alterations were detected for the same regions in the nine patients without primary lung cancer. Our results support the concept that the normal epithelial surface of large bronchi of patients with lung cancer has molecular changes suggestive of the outgrowth of numerous clonal foci.