AUTHOR=Zhang Juxuan , Deng Jiaxing , Feng Xiao , Tan Yilong , Li Xin , Liu Yixin , Li Mengyue , Qi Haitao , Tang Lefan , Meng Qingwei , Yan Haidan , Qi Lishuang 

TITLE=Hierarchical identification of a transcriptional panel for the histological diagnosis of lung neuroendocrine tumors

JOURNAL=Frontiers in Genetics

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2022.944167

DOI=10.3389/fgene.2022.944167

ISSN=1664-8021

ABSTRACT=<p><bold>Background:</bold> Lung cancer is a complex disease composed of neuroendocrine (NE) and non-NE tumors. Accurate diagnosis of lung cancer is essential in guiding therapeutic management. Several transcriptional signatures have been reported to distinguish between adenocarcinoma (ADC) and squamous cell carcinoma (SCC) belonging to non-NE tumors. This study aims to identify a transcriptional panel that could distinguish the histological subtypes of NE tumors to complement the morphology-based classification of an individual.</p><p><bold>Methods:</bold> A public dataset with NE subtypes, including 21 small-cell lung cancer (SCLC), 56 large-cell NE carcinomas (LCNECs), and 24 carcinoids (CARCIs), and non-NE subtypes, including 85 ADC and 61 SCC, was used as a training set. In the training set, consensus clustering was first used to filter out the samples whose expression patterns disagreed with their histological subtypes. Then, a rank-based method was proposed to develop a panel of transcriptional signatures for determining the NE subtype for an individual, based on the within-sample relative gene expression orderings of gene pairs. Twenty-three public datasets with a total of 3,454 samples, which were derived from fresh-frozen, formalin-fixed paraffin-embedded, biopsies, and single cells, were used for validation. Clinical feasibility was tested in 10 SCLC biopsy specimens collected from cancer hospitals via bronchoscopy.</p><p><bold>Results:</bold> The NEsubtype-panel was composed of three signatures that could distinguish NE from non-NE, CARCI from non-CARCI, and SCLC from LCNEC step by step and ultimately determine the histological subtype for each NE sample. The three signatures achieved high average concordance rates with 97.31%, 98.11%, and 90.63%, respectively, in the 23 public validation datasets. It is worth noting that the 10 clinic-derived SCLC samples diagnosed via immunohistochemical staining were also accurately predicted by the NEsubtype-panel. Furthermore, the subtype-specific gene expression patterns and survival analyses provided evidence for the rationality of the reclassification by the NEsubtype-panel.</p><p><bold>Conclusion:</bold> The rank-based NEsubtype-panel could accurately distinguish lung NE from non-NE tumors and determine NE subtypes even in clinically challenging samples (such as biopsy). The panel together with our previously reported signature (<italic>KRT5</italic>-<italic>AGR2</italic>) for SCC and ADC would be an auxiliary test for the histological diagnosis of lung cancer.</p>