Clinicopathological features and prognostic implications of <scp>ASCL1</scp> expression in surgically resected small cell lung cancer

Wei, Jiacong; Liu, Li; Guo, Yongli; Zhang, Jinyao; Wang, Xin; Dong, Jiyan; Xing, Puyuan; Jin, Ying; Yang, Lin; Li, Junling

doi:10.1111/1759-7714.13705

Cited by 7 publications

(8 citation statements)

References 22 publications

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“…Since RB1 status was not detected in our study, we were curious to scrutiny this apparently discrepancy of their study and found that nearly half of RB1 expression did not co-express YAP1 both in cell lines and tumors, which may explain the reverse trend towards survival of YAP1 expression. Recently, a few studies has been investigated the distribution pattern and prognostic value of ASCL1 expression in SCLC tumors at the protein level by IHC, yielding to a broader range of 42.5-80% for ASCL1 expression and a significant tendency of prolonged OS for ASCL1 negative group (22)(23)(24). Herein, the destructive effect of ASCL1 subtype on OS and DFS were also obtained both in mRNA and protein levels.…”

Section: Discussionmentioning

confidence: 95%

“…Recently, a few studies has been investigated the distribution pattern and prognostic value of ASCL1 expression in SCLC tumors at the protein level by IHC, yielding to a broader range of 42.5-80% for ASCL1 expression and a significant tendency of prolonged OS for ASCL1 negative group ( 22 – 24 ). Herein, the destructive effect of ASCL1 subtype on OS and DFS were also obtained both in mRNA and protein levels.…”

Section: Discussionmentioning

confidence: 99%

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Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity

Zhang

Liu

et al. 2022

Front. Oncol.

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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.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity

Zhang

Liu

et al. 2022

Front. Oncol.

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“…Our previous work already showed ASCL1 was a NE related marker. 15 As an inhibitory ligand of Notching pathway, DLL3 also plays an essential role in NE transformation and maintenance. We analyzed the relationship between DLL3 expression and several conventional NE markers, such as SYN, CgA, CD56, and TTF1 in this study.…”

Section: Discussionmentioning

confidence: 99%

“…ASCL1 (ab74065, Abcam) and DLL3 (E3J5R, Cell Signal Technology) staining was examined on SCLC tissue microarrays. The SCLC tissue microarrays of the 247 cases were constructed as described previously 15 . All the staining was carried out on the fully automatic Roche IHC instruments (Roche Diagnosis) according to the manufacturer's protocols.…”

Section: Methodsmentioning

confidence: 99%

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ASCL1 and DLL3 expressions and their clinicopathological implications in surgically resected pure small cell lung cancer: A study of 247 cases from the National Cancer Center of China

Dong

Liu

et al. 2021

Thoracic Cancer

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Objective Small cell lung cancer (SCLC) is one of the most aggressive malignancies characterized by neuroendocrine (NE) differentiation. The Delta‐like protein 3 (DLL3), as a direct downstream target of ASCL1, is involved in NE differentiation and carcinogenesis of SCLC. This study aims to investigate the relationship between ASCL1 and DLL3 expressions and their clinicopathological implications in SCLC. Methods A total of 247 surgically resected pure SCLC samples with limited clinical stage and follow‐up data were retrieved in this retrospective study. ASCL1 and DLL3 protein expression was detected by immunohistochemistry staining. The correlations between ASCL1 and DLL3 expressions, as well as their clinicopathological features, were analyzed by χ2 tests. Disease‐free survival (DFS) and overall survival (OS) in SCLC patients with ASCL1/DLL3 low and high expressions were compared by the Kaplan‐Meier method and log‐rank tests. Results ASCL1 high expression was detected in 105 (42.5%) patients. Its expression was positively correlated with the clinical stage (p = 0.02) and nerve invasion (p = 0.03). DLL3 high expression was observed in 188 (72.8%) patients and was correlated with vascular invasion (p = 0.04). ASCL1 expression was positively associated with DLL3 expression (p = 0.03). In addition, DLL3 expression has a strong correlation with the expression of thyroid transcription factor‐1 (TTF1) and conventional NE markers. Conclusion ASCL1 and DLL3 were highly expressed in SCLC tumor samples, and a positive correlation between these two markers was observed. Co‐analysis of ASCL1 and DLL3 may identify a distinct SCLC subgroup benefit from targeted therapy. Therefore, ASCL1 and DLL3 could be potential biomarkers served for the selection of related patients.

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Immunotherapy for small cell lung cancer: the current state and future trajectories

Qiang,

Liu,

Yang

et al. 2024

Discov Onc

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Small cell lung cancer (SCLC) constitutes approximately 10% to 15% of all lung cancer diagnoses and represents a pressing global public health challenge due to its high mortality rates. The efficacy of conventional treatments for SCLC is suboptimal, characterized by limited anti-tumoral effects and frequent relapses. In this context, emerging research has pivoted towards immunotherapy combined with chemotherapy, a rapidly advancing field that has shown promise in ameliorating the clinical outcomes of SCLC patients. Through originally developed for non-small cell lung cancer (NSCLC), these therapies have extended new treatment avenues for SCLC. Currently, a nexus of emerging hot-spot treatments has demonstrated significant therapeutic efficacy. Based on the amalgamation of chemotherapy and immunotherapy, and the development of new immunotherapy agents, the treatment of SCLC has seen the hoping future. Progress has been achieved in enhancing the tumor immune microenvironment through the concomitant use of chemotherapy, immunotherapy, and tyrosine kinase inhibitors (TKI), as evinced by emerging clinical trial data. Moreover, a tripartite approach involving immunotherapy, targeted therapy, and chemotherapy appears auspicious for future clinical applications. Overcoming resistance to post-immunotherapy regimens remains an urgent area of exploration. Finally, bispecific antibodies, adoptive cell transfer (ACT), oncolytic virus, monotherapy, including Delta-like ligand 3 (DLL3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), as well as precision medicine, may present a prospective route towards achieving curative outcomes in SCLC. This review aims to synthesize extant literature and highlight future directions in SCLC treatment, acknowledging the persistent challenges in the field. Furthermore, the continual development of novel therapeutic agents and technologies renders the future of SCLC treatment increasingly optimistic.

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Clinicopathological features and prognostic implications of ASCL1 expression in surgically resected small cell lung cancer

Cited by 7 publications

References 22 publications

Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity

Prognostic Implications of Molecular Subtypes in Primary Small Cell Lung Cancer and Their Correlation With Cancer Immunity

ASCL1 and DLL3 expressions and their clinicopathological implications in surgically resected pure small cell lung cancer: A study of 247 cases from the National Cancer Center of China

Immunotherapy for small cell lung cancer: the current state and future trajectories

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