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The NKX2-1 gene, located on chromosome 14, encodes thyroid transcription factor 1 (TTF1), essential for lung development and expressed in peripheral lung cells.1 TTF1 is found in approximately 75% of adenocarcinomas of pulmonary origin. TTF1 immunohistochemistry (IHC) staining is a key marker to determine tumour origin, especially in lung lesions.2 Typically, positive TTF1 IHC suggests a pulmonary origin, while negative results suggest an extrapulmonary origin. However, this diagnostic approach may be confounded by genetic alterations, such as NKX2-1 mutations, which can reduce or eliminate TTF1 expression even in pulmonary tumours. This study examines the frequency of NKX2-1 mutations in solid tumours and discusses the implications for interpreting negative TTF1 IHC results, particularly in non-mucinous pulmonary carcinomas. Despite their rarity, NKX2-1 mutations can significantly impact the accuracy of TTF1-based diagnostic algorithms, underscoring the need for careful interpretation in surgical pathology.
This study was performed under the approval of research ethics board of University of Pennsylvania. Our study retrospectively analysed massively parallel sequencing data from 4413 solid tumour specimens sequenced at the Center for Personalized Diagnostics, University of Pennsylvania, between September 2016 and May 2020. The primary objective was to identify NKX2-1 gene variants and assess their potential impact on TTF1 IHC results.
In this cohort, we identified 63 NKX2-1 variants across 56 cases, representing approximately 1.3% of all sequenced solid tumours (online supplemental figure 1). These variants comprised 14 frameshift mutations, 5 in-frame indels, 35 missense …
Footnotes
Handling editor Runjan Chetty.
X @MoPathGuy
Contributors All authors contributed to manuscript writing. J-YY, JR and SP designed the study. J-YY, and FE-SN performed the data analysis. J-YY is the guarantor.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; internally peer reviewed.
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