We have reported that a mouse monoclonal antibody, 703D4, which recognizes heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP-A2/B1) can frequently detect lung cancer in exfoliated sputum epithelial cells 1-2 years earlier than routine chest X-ray or sputum cytomorphology. We along with others have shown that microsatellite alteration (MA) at selected loci can be recognized in sputum cells prior to clinical lung cancer. The present study was undertaken to determine how frequently the expression of hnRNP-A2/B1 message is associated with neoplastic clonal expansion as shown by MA in 41 cases of non-small cell lung cancer (NSCLC). We used Northern blotting to evaluate hnRNP-A2/B1 mRNA expression in lung tumor and remote noninvolved lung. We evaluated microsatellite instability (i.e. shifts; MI) or loss of heterozygosity (LOH) with a panel of 13 microsatellite markers at loci identified previously as susceptible in NSCLC. Of the 41 tumors, 25 (61%) over-expressed hnRNP-A2/B1 and 33 (80%) demonstrated MA in at least one of 13 loci (58% in at least two loci). The association between MA (one locus) and the overexpression of hnRNP-A2/B1 is statistically significant (P=0.0082), and those lung tumors with MA at two or more loci were significantly more likely to over-express hnRNP-A2/B1 mRNA (P=0.004). MA of loci on 3p were the only MA statistically associated with hnRNP-A2/B1 message overexpression (P=0.001). We conclude that lung tumor cells undergoing clonal expansion frequently upregulate hnRNP-A2/B1.