Molecular subtypes based on ferroptosis-related genes and tumor microenvironment infiltration characterization in small cell lung cancer

Xin Wang^1,2Zhenyi Xu³Zhen Lin⁴Dawei Wu⁵Yu Tang⁵Zhihua Pei⁶Yibo Gao^7*Jie He^7*

• ¹Chinese Academy of Medical Sciences and Peking Union Medical College, Dongcheng, China
• ²Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, China
• ³Huadong Hospital Affiliated to Fudan University, Shanghai, China
• ⁴Department of Oncology, Zhejiang Provincial People's Hospital, Hangzhou, Jiangsu Province, China
• ⁵Department of Clinical Trials Center, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
• ⁶Hubei Key Laboratory of Agricultural Bioinformatics, College of Informatics, Huazhong Agricultural University, Wuhan, China
• ⁷Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

Background: Ferroptosis is an iron-dependent form of regulated cell death associated with cancer. However, the characteristics of ferroptosis in small cell lung cancer (SCLC) are still uncertain. This study aimed to explore the application value of ferroptosis-related genes (FRGs) classification in prognosis and characteristics prediction to provide clues for targeted SCLC therapy.Method: We systematically characterized mRNA expression and genetic alterations of FRGs in SCLC, evaluating their expression pattern in 181 samples from 3 datasets. Unsupervised clustering analysis was performed to identify the molecular subtypes based on FRGs. We then conducted association analyses between FRG subtypes and various tumor microenvironment (TME) characteristics, traditional key transcript factor subtypes, clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. Furthermore, the novel classification was validated in an independent cohort of 34 samples from Beijing.Result: In this study, we identified three distinct ferroptosis subtypes in SCLC: S1, S2, and S3. We found that patients in S2 had the poorest prognosis. The FRG classification was correlated with the NOTCH pathway, MYC pathway, Neuroendocrine (NE), and epithelial-to-mesenchymal transition (EMT) process. Additionally, the FRG classification was strongly associated with TME 4 subtypes. To validate the classification, we employed an independent cohort. The FRG classification could also help to guide the prediction of chemical drugs. Finally, the heatmap showed the landscape of FRG subtypes, TME subtypes, NE subtypes, key transcription subtypes, age, gender, and stage.Conclusion: Our identification of new SCLC subtypes provides novel insights into tumor biology and has potential clinical implications for the management of SCLC.