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Genetics and Genomics

Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway



Large cell lung carcinoma (LCLC) is an exceptionally aggressive disease with a poor prognosis. At present, little is known about the molecular pathology of LCLC.


Ultra-deep sequencing of cancer-related genes and exome sequencing were used to detect the LCLC mutational in 118 tumor-normal pairs. The cell function test was employed to confirm the potential carcinogenic mutation of PI3K pathway.


The mutation pattern is determined by the predominance of A > C mutations. Genes with a significant non-silent mutation frequency (FDR) < 0.05) include TP53 (47.5%), EGFR (13.6%) and PTEN (12.1%). Moreover, PI3K signaling (including EGFR, FGRG4, ITGA1, ITGA5, and ITGA2B) is the most mutated pathway, influencing 61.9% (73/118) of the LCLC samples. The cell function test confirmed that the potential carcinogenic mutation of PI3K pathway had a more malignant cell function phenotype. Multivariate analysis further revealed that patients with the PI3K signaling pathway mutations have a poor prognosis (P = 0.007).


These results initially identified frequent mutation of PI3K signaling pathways in LCLC and indicate potential targets for the treatment of this fatal type of LCLC.

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Fig. 1: Somatic SNV signature in LCLC.
Fig. 2: Significantly mutated genes in LCLC.
Fig. 3: Somatic mutations of the PI3K signaling pathway in LCLC.
Fig. 4: Somatic alterations of four genes and their oncogenic effects on normal and LCLC cells.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request. Whole-exome sequencing data and target sequencing data from this study are available for download through the NCBI Sequence Read Archive under accession number PRJNA639383, PRJNA639657, and PRJNA643364. These submission will be released upon publication. Release of BioProject or BioSamples is also triggered by the release of submitted data.


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We would like to thank Prof. Wen Li for data analysis and critical discussion of the manuscript.


his study was supported partly by the National Natural Science Foundation of China (82272766, 81702243 and 81472202), Construction of Clinical Medical Center for Tumor Biological Samples in Nantong (HS2016004), Natural Science Foundation of Shanghai (21140903500), Basic Medical Research Program of Navy Military Medical University Affiliated Changhai Hospital (2021JCMS11), Program of Navy Military Medical University (2022MS019), Program of Key Research and Development Program of Hunan Province (2021NK2026), and Key Program of Hunan Provincial Department of Science and Technology (2021JJ30060 and 2020WK2020).

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Authors and Affiliations



LKH, JBL, CYW and DF conceived and directed the study. JHG, YSM, JWL, JH, GXJ, LKH, HML, CYW and DF contributed to the project design. JHG, YSM, LKH, JH, GXJ, HML, WW, XD, QYF, LKH and DF performed experiments. YSM, JWL, JH, HML, JBL, CYW and DF performed bioinformatics data analysis. LKH, YSM, GXJ, JBL, CYW, and DF contributed samples, data and comments on the manuscript. JHG, YSM, JWL, LKH, JH, HML, CYW, and DF analyzed and interpreted data. YSM, LKH, JH, JWL, GXJ, JBL, CYW, and DF contributed reagents, materials and/or analysis tools. LKH, YSM, and DF wrote the manuscript. JHG, YSM, JWL, GXJ, JH and HML contributed equally to this work. All authors contributed to the final version of the manuscript and approved the final manuscript.

Corresponding authors

Correspondence to Chun-Yan Wu, Ji-Bin Liu, Da Fu or Li-Kun Hou.

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The authors declare no competing interests.

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The study was approved by the Ethics Committee of Tongji University School of Medicine and Shanghai Pulmonary Hospital (K15-199). Each participant provided their written informed consent to participate in this study.

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Guo, JH., Ma, YS., Lin, JW. et al. Whole-exome and targeted gene sequencing of large-cell lung carcinoma reveals recurrent mutations in the PI3K pathway. Br J Cancer (2023).

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