Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
EBioMedicine. 2024 Apr;102:105062. doi: 10.1016/j.ebiom.2024.105062. Epub 2024 Mar 15.
Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes.
IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype.
IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002).
This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response.
This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.
最近的研究报告了小细胞肺癌（SCLC）中新型转录因子为基础的分子亚型的预测和预后价值。我们进行了深入的分析，将多组学数据与免疫组织化学（IHC）配对，以阐明与亚型之间临床结果差异相关的潜在特征。
对来自 427 名 SCLC 患者（86.4%为男性，13.6%为女性）的 252 例 IHC、422 例靶向外显子测序和 189 例全转录组测序（WTS）数据进行了全面分析。根据 IHC 为基础的分子亚型分析了突变谱、基因表达谱和炎症特征的差异。
基于 IHC 的分子亚型，包括 90 例局限性疾病（35.7%）和 162 例广泛性疾病（64.3%），发现 ASCL1 亚型的发生率较高（IHC-A，56.3%），其次是 ASCL1/NEUROD1 共表达（IHC-AN，17.9%）、NEUROD1（IHC-N，12.3%）、POU2F3（IHC-P，9.1%）、三阴性（IHC-TN，4.4%）亚型。基于 IHC 的亚型与基于 WTS 的亚型和非负矩阵分解（NMF）聚类方法高度一致。IHC-AN 亚型在基因表达谱和临床结果方面与 IHC-A（而不是 IHC-N）相似。与 IHC-N（8.0 个月，调整后的 HR 2.3，95%CI 1.4-3.9，p=0.002）和 IHC-P（8.3 个月，调整后的 HR 1.7，95%CI 0.9-3.2，p=0.076）相比，IHC-A 患者的中位总生存期较长（15.2 个月）。炎性肿瘤占病例的 25%（包括 IHC-P 的 53%、IHC-A 的 26%、IHC-AN 的 17%、但 IHC-N 的仅 11%）。与最近的研究结果一致，炎性肿瘤比非炎性表型更有可能从一线免疫治疗中获益（p=0.002）。
本研究使用 IHC 和 WTS 从一个相当大的、真实世界的亚洲/非西方患者队列中提供了 SCLC 分子亚型的基本数据，包括发病率和基本人口统计学数据，与之前基于 NMF 的 SCLC 模型高度一致。此外，我们还根据分子亚型揭示了潜在的生物学途径活性、免疫原性和治疗结果，这些可能与临床结果的差异有关，包括免疫治疗反应。
这项工作得到了阿斯利康（AstraZeneca）、三星医疗中心未来医学 2030 项目（Samsung Medical Center [grant number SMX1240011]）、韩国国家研究基金会（NRF）资助的韩国政府（MSIT）[grant number 2020R1C1C1010626]和第 7 届阿斯利康-KHIDI（韩国健康产业发展研究所）肿瘤学研究计划的支持。
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