In:
Cancer Science, Wiley, Vol. 108, No. 9 ( 2017-09), p. 1888-1896
Abstract:
The major driver mutations of lung cancer, EGFR mutations and EML 4‐ 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 carried out whole‐exome sequencing on 43 non‐ TRU ‐type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP 53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX 2‐1/ 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 NKX 2‐1/ TTF ‐1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX 2‐1/ TTF ‐1 mutations (one missense and one frameshift). Functional assays with the NK 2 homeobox 1 ( NKX 2‐1)/thyroid transcription factor 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 NKX 2‐1/ TTF ‐1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF ‐1‐postive/hepatocyte nuclear factor 4‐α ( HNF 4‐α)‐negative and TTF ‐1‐negative/ HNF 4‐α‐positive groups. NKX 2‐1/ TTF ‐1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5 AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX 2‐1/ TTF ‐1 gene body was highly methylated in NKX 2‐1/ TTF ‐1‐negative cases, including those without the NKX 2‐1/ TTF ‐1 mutations. The genetic or epigenetic inactivation of NKX 2‐1/ TTF ‐1 may play an essential role in the development and aberrant differentiation of non‐ TRU ‐type lung adenocarcinomas.
Type of Medium:
Online Resource
ISSN:
1347-9032
,
1349-7006
DOI:
10.1111/cas.2017.108.issue-9
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2115647-5
detail.hit.zdb_id:
2111204-6
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