背景:最近的研究报道了基于转录因子的新型分子亚型在小细胞肺癌(SCLC)中的预测和预后价值。我们对多组学数据与免疫组织化学(IHC)进行了深入分析,以阐明与亚型之间临床结果差异相关的基本特征。
方法:IHC(n=252),靶外显子组测序(n=422),和全转录组测序(WTS,n=189)数据来自427名患者(86.4%为男性,对13.6%女性)的SCLC进行了全面分析。突变谱的差异,基因表达谱,根据基于IHC的分子亚型分析炎症特征。
结果:基于IHC的分子亚型,包括90种局限性疾病(35.7%)和162种广泛疾病(64.3%),显示ASCL1亚型的高发病率(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类似于IHC-A(而不是IHC-N)。与IHC-N(8.0个月,调整后的HR2.3,95%CI1.4-3.9,p=0.002)和IHC-P(8.3个月,调整后的HR1.7,95%CI0.9-3.2,p=0.076)。炎症肿瘤占病例的25%(包括IHC-P的53%,26%的IHC-A,IHC-AN的17%,但只有11%的IHC-N)。与最近的发现一致,与未发炎的表型相比,发炎的肿瘤更有可能从一线免疫治疗中获益(p=0.002).
结论:这项研究提供了基本数据,包括使用IHC和WTS的SCLC分子亚型的发病率和基本人口统计学,真实世界的亚洲/非西方患者队列,与以前的基于NMF的SCLC模型高度一致。此外,我们揭示了潜在的生物途径活性,免疫原性,和基于分子亚型的治疗结果,可能与临床结果的差异有关,包括免疫疗法反应。
背景:这项工作得到了阿斯利康的支持,三星医疗中心的未来医学2030项目[授权号SMX1240011],韩国国家研究基金会(NRF)赠款由韩国政府(MSIT)[赠款编号2020R1C1C1010626]和第七届阿斯利康-KHIDI(韩国健康产业发展研究所)肿瘤学研究计划资助。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
BACKGROUND: 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.