Multi-omics reveals heterogeneity in advanced small cell lung cancers

ABSTRACT: Small cell lung cancer (SCLC) is an aggressive disease, that is often diagnosed at advanced stage, when surgery is no longer feasible. The introduction of immunotherapy has provided benefit to a small proportion of patients; however overall survival has improved only marginally for most patients. Recent studies have started to unravel the molecular heterogeneity of SCLCs including tumour microenvironment. Here we demonstrated the suitability of EBUS-TBNA aspirates for multi-omics characterization of SCLCs, 82 samples underwent methylation profiling (EPIC arrays) with a subset of those also subjected whole genome sequencing (n=76), RNAseq (n=69) and cfDNA (n=67). Methylation profiling identified four sub-groups associated with distinct survival (p=0.075) and intrinsic and extrinsic features. Genomics did not identify molecular features associated with methylation-define sub-groups. Blood cfDNA sequencing detected 92.5% of TP53 and RB1 point mutations detected in tissue (n=67). Methylation and transcriptome further characterized distinct molecular features of the sub-groups. Tumours in Group 1 harbour expression of ASCL1 and high proportion of CD8 T cell (p<0.0001) and patients had better survival (p=0.0075). Group 2 was the largest, with tumours also expressing ASCL1, but CD8 T cells did not associate with the variable patient survival observed within this group. Tumours in group 3 had high expression of NEUROD1 (p=0.0004) and high proportion of fibroblasts (p<0.0001). Group 4 tumour harbour expression of POU2F3 and/or YAP1 and higher expression of non-neuroendocrine genes (p<0.0001). Groups 3 and 4 had patients with worse survival (p=0.0075). Methylation-define sub-groups presented differential expression of SLFN11(p=0.0014), TACSTD2 (p<0.0001), DLL3 (p<0.0001) and SEZ6 presented a higher expression in most SCLC (p<0.0001) when compared to other lung cancers. Supporting those as potential novel therapeutic vulnerabilities in SCLCs. Our results highlight the need for large multi-omic studies to better characterise less frequent SCLCs sub-groups that could be facilitated by EBUS-TBNA specimens and DNA methylation. Our study also supports biomarker-driven trials due SCLCs heterogeneity and distinct therapeutic vulnerabilities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307029 | GEO | 2026/05/15

REPOSITORIES: GEO