Implications of thyroid transcription factor-1 gene methylation in carcinogenesis of interstitial pneumonia-related non-terminal respiratory unit lung adenocarcinoma

The present study aimed to elucidate the mechanisms underlying the histogenesis of interstitial pneumonia (IP)-related lung adenocarcinoma (LADC). We focused on the methylation of thyroid transcription factor 1 (TTF-1). The TTF-1 locus was highly methylated in IP-LADCs compared to non-IP-LADCs. Among the IP-LADCs, the non-terminal respiratory unit (TRU) LADCs showed marked hypermethylation in CpG sites in a particular intragenic region. This region was also found to be highly methylated in the IP lungs. The hierarchical dendrogram based on methylation levels divided the IP lungs into three different clusters. One of them showed a methylation profile similar to that of non-TRU LADCs. The non-TRU LADCs developed from this cluster with a significantly higher frequency. Moreover, bronchiolar metaplasia lining honeycomb/cystic lesions in IP lungs, IP-related non-TRU LADCs, and bronchiolar epithelia in healthy lungs were separately collected by microdissection and examined for methylation. Bronchiolar metaplasia showed hypermethylation, but bronchiolar epithelia did not. The methylation patterns in bronchiolar metaplasia were similar to those in non-TRU LADCs. In summary, a particular region of TTF-1 was highly methylated in IP-related non-TRU LADCs and bronchiolar metaplasia, supporting the theory that IP-related non-TRU LADCs may develop from bronchiolar metaplasia lining honeycomb/cystic lesions.