Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-TRU-type lung adenocarcinomas

Abstract

The major driver mutations of lung cancer, the EGFR mutations and EML4-ALK fusion, are mainly detected in terminal respiratory unit (TRU)-type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non-TRU-type lung cancer, we conducted whole-exome sequencing on 43 non-TRU-type lung adenocarcinomas based on morphology (17 acinar, 9 solid, 2 enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2-1/TTF-1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2-1/TTF-1 mutations (5 frameshift, 2 nonsense, and one missense) were identified, with one case harboring two distinct NKX2-1/TTF-1 mutations (one missense and one frameshift). Functional assays with the NKX2-1/TTF-1 mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2-1/TTF-1 mutations (5cases), while 1 enteric and 1 acinar adenocarcinoma harbored the NKX2-1/TTF-1 mutation. Immunohistochemistry showed that the cohort was largely divided into TTF-1-postive/HNF4-alpha-negative and TTF-1-negative/HNF4-alpha-positive groups. NKX2-1/TTF-1 mutations were exclusively found in the latter, in which the gastrointestinal markers, MUC5AC and CK20, were frequently expressed. Bisulfate-sequencing revealed that the NKX2-1/TTF-1 gene body was highly methylated in NKX2-1/TTF-1-negative cases, including those without the NKX2-1/TTF-1 mutations. The genetic or epigenetic inactivation of NKX2-1/TTF-1 may play an essential role in the development and aberrant differentiation of non-TRU-type lung adenocarcinomas.

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