Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity
IntroductionSmall cell lung cancer (SCLC) has recently been characterized as heterogeneous tumors due to consensus nomenclature for distinct molecular subtypes on the basis of differential expression of four transcription markers (ASCL1, NEUROD1, POU2F3, and YAP1). It is necessary to validate molecu...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-03-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2022.779276/full |
| _version_ | 1819349515717574656 |
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| author | Jing Qi Jiaqi Zhang Ningbo Liu Lujun Zhao Bo Xu |
| author_facet | Jing Qi Jiaqi Zhang Ningbo Liu Lujun Zhao Bo Xu |
| author_sort | Jing Qi |
| collection | DOAJ |
| description | IntroductionSmall cell lung cancer (SCLC) has recently been characterized as heterogeneous tumors due to consensus nomenclature for distinct molecular subtypes on the basis of differential expression of four transcription markers (ASCL1, NEUROD1, POU2F3, and YAP1). It is necessary to validate molecular subtype classification in primary SCLC tumors by immunohistochemical (IHC) staining and investigate its relevance to survival outcomes.MethodsUsing a large number of surgically resected primary SCLC tumors, we assessed the mRNA and protein levels of the four subtype markers (ASCL1, NEUROD1, POU2F3 and YAP1) in two independent cohorts, respectively. Next, molecular subtypes defined by the four subtype markers was conducted to identify the association with clinicopathologic characteristics, survival outcomes, the expression of classic neuroendocrine markers, and molecules related to tumor immune microenvironment.ResultsSamples were categorized into four subtypes based on the relative expression levels of the four subtype markers, yielding to ASCL1, NEUROD1, POU2F3 and YAP1 subtypes, respectively. The combined neuroendocrine differentiation features were more prevalent in either ASCL1 or NEUROD1 subtypes. Kaplan-Meier analyses found that patients with tumors of the YAP1 subtype and ASCL1 subtype obtained the best and worst prognosis on both mRNA and IHC levels, respectively. Based on multivariate Cox proportional-hazards regression model, molecular subtype classification determined by IHC was identified as an independent indicator for survival outcomes in primary SCLC tumors. Correlation analyses indicated that the four subtype markers in SCLC cancer cells were interacted with its tumor immune microenvironment. Specifically, tumors positive for YAP1 was associated with fewer CTLA4+ T cell infiltration, while more immune-inhibitory receptors (FoxP3,PD1, and CTLA4) and fewer immune-promoting receptor (CD8) were found in tumors positive for ASCL1.ConclusionsWe validated the new molecular subtype classification and clinical relevance on both mRNA and protein levels from primary SCLC tumors. The molecular subtypes determined by IHC could be a pre-selected effective biomarker significantly influenced on prognosis in patients with SCLC, which warrants further studies to provide better preventative and therapeutic options for distinct molecular subtypes. |
| first_indexed | 2024-12-24T19:01:45Z |
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| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-24T19:01:45Z |
| publishDate | 2022-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-4a05f1f02cbc4ad2b05bc8122363fd5a2022-12-21T16:43:11ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2022-03-011210.3389/fonc.2022.779276779276Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer ImmunityJing Qi0Jiaqi Zhang1Ningbo Liu2Lujun Zhao3Bo Xu4Department of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaDepartment of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaDepartment of Biochemistry and Molecular Biology, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin, ChinaIntroductionSmall cell lung cancer (SCLC) has recently been characterized as heterogeneous tumors due to consensus nomenclature for distinct molecular subtypes on the basis of differential expression of four transcription markers (ASCL1, NEUROD1, POU2F3, and YAP1). It is necessary to validate molecular subtype classification in primary SCLC tumors by immunohistochemical (IHC) staining and investigate its relevance to survival outcomes.MethodsUsing a large number of surgically resected primary SCLC tumors, we assessed the mRNA and protein levels of the four subtype markers (ASCL1, NEUROD1, POU2F3 and YAP1) in two independent cohorts, respectively. Next, molecular subtypes defined by the four subtype markers was conducted to identify the association with clinicopathologic characteristics, survival outcomes, the expression of classic neuroendocrine markers, and molecules related to tumor immune microenvironment.ResultsSamples were categorized into four subtypes based on the relative expression levels of the four subtype markers, yielding to ASCL1, NEUROD1, POU2F3 and YAP1 subtypes, respectively. The combined neuroendocrine differentiation features were more prevalent in either ASCL1 or NEUROD1 subtypes. Kaplan-Meier analyses found that patients with tumors of the YAP1 subtype and ASCL1 subtype obtained the best and worst prognosis on both mRNA and IHC levels, respectively. Based on multivariate Cox proportional-hazards regression model, molecular subtype classification determined by IHC was identified as an independent indicator for survival outcomes in primary SCLC tumors. Correlation analyses indicated that the four subtype markers in SCLC cancer cells were interacted with its tumor immune microenvironment. Specifically, tumors positive for YAP1 was associated with fewer CTLA4+ T cell infiltration, while more immune-inhibitory receptors (FoxP3,PD1, and CTLA4) and fewer immune-promoting receptor (CD8) were found in tumors positive for ASCL1.ConclusionsWe validated the new molecular subtype classification and clinical relevance on both mRNA and protein levels from primary SCLC tumors. The molecular subtypes determined by IHC could be a pre-selected effective biomarker significantly influenced on prognosis in patients with SCLC, which warrants further studies to provide better preventative and therapeutic options for distinct molecular subtypes.https://www.frontiersin.org/articles/10.3389/fonc.2022.779276/fullmolecular subtypeprognosisimmune microenvironmentimmunohistochemistrysmall cell lung cancer |
| spellingShingle | Jing Qi Jiaqi Zhang Ningbo Liu Lujun Zhao Bo Xu Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity Frontiers in Oncology molecular subtype prognosis immune microenvironment immunohistochemistry small cell lung cancer |
| title | Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity |
| title_full | Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity |
| title_fullStr | Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity |
| title_full_unstemmed | Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity |
| title_short | Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity |
| title_sort | prognostic implications of molecular subtypes in primary small cell lung cancer and their correlation with cancer immunity |
| topic | molecular subtype prognosis immune microenvironment immunohistochemistry small cell lung cancer |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2022.779276/full |
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