Opposite roles of FOXA1 and NKX2-1 in lung cancer progression

Gene copy number profiles of primary lung tumors were screened for high-level amplifications. We detected 22 high-level amplifications in various loci, including 14q13. This locus is known to harbor the adenocarcinoma (AC) lineage-specific target gene NKX2-1, which is not expressed in squamous cell carcinoma (SCC). As the 14q amplification was also found in SCC, we investigated whether or not FOXA1 might be the corresponding target gene for SCC. Focusing on these two target genes, we assessed gene amplifications and protein expression of NKX2-1 and FOXA1 in primary lung tumors (n = 554) and brain metastases (n = 68). Primary AC (n = 194) showed positive protein expression of NKX2-1 in 58.2% of the samples compared with 4.2% of primary SCC samples (n = 212). Positive staining for FOXA1 was seen in 34.7% of the SCC samples, which was comparable with 39.6% in the AC samples. For brain metastases, FOXA1 expression was slightly higher in the SCC samples (55.6%) compared with the non-matched primary SCC tumor samples (43.4%), whereas NKX2-1 expression was comparable in both primary tumors and brain metastases. Positive FOXA1 and NKX2-1 expression was associated with a gain or amplification in 34.6% and 28.6% of cases, respectively. The expression of NKX2-1 was associated with early stage and grade among the AC cases. In contrast, FOXA1 expression in SCC was associated with distant metastases as well as an unfavorable survival rate (P = 0.039). These results suggest that both FOXA1 and NKX2-1 may act as lineage-specific target genes within the 14q amplicon with opposite functions in lung cancer.