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Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies

Small‐cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non‐small‐cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the real...

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Autores principales: Wang, Haiyong, Wu, Shuangxiu, Li, Zhenzhen, Zhang, Chenyue, Shang, Xiaoling, Zhao, Chenglong, Li, Zhenxiang, Lin, Jiamao, Guo, Jun, Wang, Zhehai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899606/
https://www.ncbi.nlm.nih.gov/pubmed/36178064
http://dx.doi.org/10.1111/cas.15606
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author Wang, Haiyong
Wu, Shuangxiu
Li, Zhenzhen
Zhang, Chenyue
Shang, Xiaoling
Zhao, Chenglong
Li, Zhenxiang
Lin, Jiamao
Guo, Jun
Wang, Zhehai
author_facet Wang, Haiyong
Wu, Shuangxiu
Li, Zhenzhen
Zhang, Chenyue
Shang, Xiaoling
Zhao, Chenglong
Li, Zhenxiang
Lin, Jiamao
Guo, Jun
Wang, Zhehai
author_sort Wang, Haiyong
collection PubMed
description Small‐cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non‐small‐cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole‐exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker‐directed drug development and targeted therapies in clinical trials. Our study would provide an in‐depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype‐specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.
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spelling pubmed-98996062023-02-09 Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies Wang, Haiyong Wu, Shuangxiu Li, Zhenzhen Zhang, Chenyue Shang, Xiaoling Zhao, Chenglong Li, Zhenxiang Lin, Jiamao Guo, Jun Wang, Zhehai Cancer Sci ORIGINAL ARTICLES Small‐cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non‐small‐cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole‐exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker‐directed drug development and targeted therapies in clinical trials. Our study would provide an in‐depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype‐specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC. John Wiley and Sons Inc. 2022-10-28 /pmc/articles/PMC9899606/ /pubmed/36178064 http://dx.doi.org/10.1111/cas.15606 Text en © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle ORIGINAL ARTICLES
Wang, Haiyong
Wu, Shuangxiu
Li, Zhenzhen
Zhang, Chenyue
Shang, Xiaoling
Zhao, Chenglong
Li, Zhenxiang
Lin, Jiamao
Guo, Jun
Wang, Zhehai
Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
title Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
title_full Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
title_fullStr Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
title_full_unstemmed Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
title_short Molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
title_sort molecular subtyping of small‐cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies
topic ORIGINAL ARTICLES
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9899606/
https://www.ncbi.nlm.nih.gov/pubmed/36178064
http://dx.doi.org/10.1111/cas.15606
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