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Background <p>Small cell lung cancer (SCLC) is an aggressive disease that is often diagnosed at an advanced stage when surgery is no longer feasible. The lack of tumor tissue and rapid clinical decline of patients have hindered the feasibility of large omics studies. However, with advances in omics technologies recent studies have started to unravel the molecular heterogeneity of SCLCs.</p> Methods <p>Here, 82 fresh EBUS-TBNA aspirates underwent methylation profiling (EPIC arrays), with subsets of those subjected to whole-genome sequencing (<i>n</i> = 76), RNA-seq (<i>n</i> = 48) and blood cfDNA sequencing (<i>n</i> = 69) to characterize the molecular features of SCLCs.</p> Results <p>Methylation profiling revealed four sub-groups associated with distinct survival and extrinsic/intrinsic tumor features. Groups 1 and 2 presented increased expression of <i>ASCL1</i>. Group 1 tumors had a greater proportion of CD8 + T cells (immune enriched-NE) and patients with better survival. Group 2 (SCLC-A) harbored the largest number of cases, and high expression of <i>SLFN11</i> and <i>DLL3</i>, as potential therapeutic options. Group 3 tumors presented increased expression and hypomethylation of <i>NEUROD1</i> (SCLC-N), with a greater proportion of fibroblasts. Group 4 tumors expressed <i>POU2F3</i> and/or <i>YAP1,</i> had increased expression of non-neuroendocrine genes (non-NE) and had the worst survival. <i>TACSTD2</i> expression was higher in Group 4, suggesting a potential therapeutic option for this group. <i>SEZ6</i>, another potential therapeutic option, was highly expressed in most SCLCs. These results highlight that novel therapeutic options may need to be considered in the context of SCLC heterogeneity.</p> Conclusions <p>We showed that methylation of the most common source of tumor tissue in the clinical setting can stratify SCLCs with distinct clinical outcomes and potentially tailored therapeutic options. Methylation can characterize the intrinsic and extrinsic heterogeneity of SCLCs and fuel the discovery of novel therapeutic vulnerabilities to help bridge the gap between research and clinical application to improve care for SCLC patients.</p>

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Multi-omics reveals key molecular and cellular features of advanced small cell lung cancers associated with distinct therapeutic opportunities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年3月17日

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  • Katia Nones,
  • Vanessa Lakis,
  • Andrew J. Dalley,
  • Kimberley Ryan,
  • Haarika Chittoory,
  • Kaltin Ferguson,
  • Kate Fitzgerald,
  • Felicity Newell,
  • Lambros T. Koufariotis,
  • Farzad Bashirzadeh,
  • Jung Hwa Son,
  • Mahendra Singh,
  • Lakshmy Nandakumar,
  • David Fairbairn,
  • Margaret Cummings,
  • Daniel Steinfort,
  • Jemma J. Christie,
  • Matthew Gibney,
  • Jonathan P. Williamson,
  • Andrew Pattison,
  • Louise McIntosh,
  • Carl Pahoff,
  • Phan Tien Nguyen,
  • Jelena Solujic,
  • Michael Brown,
  • Scott Twaddell,
  • David Arnold,
  • Christopher Grainge,
  • Shailendra Gune,
  • Oliver Holmes,
  • Conrad Leonard,
  • Scott Wood,
  • John V. Pearson,
  • Sunil R. Lakhani,
  • Peter T. Simpson,
  • Nicola Waddell,
  • David Fielding

摘要

Background

Small cell lung cancer (SCLC) is an aggressive disease that is often diagnosed at an advanced stage when surgery is no longer feasible. The lack of tumor tissue and rapid clinical decline of patients have hindered the feasibility of large omics studies. However, with advances in omics technologies recent studies have started to unravel the molecular heterogeneity of SCLCs.

Methods

Here, 82 fresh EBUS-TBNA aspirates underwent methylation profiling (EPIC arrays), with subsets of those subjected to whole-genome sequencing (n = 76), RNA-seq (n = 48) and blood cfDNA sequencing (n = 69) to characterize the molecular features of SCLCs.

Results

Methylation profiling revealed four sub-groups associated with distinct survival and extrinsic/intrinsic tumor features. Groups 1 and 2 presented increased expression of ASCL1. Group 1 tumors had a greater proportion of CD8 + T cells (immune enriched-NE) and patients with better survival. Group 2 (SCLC-A) harbored the largest number of cases, and high expression of SLFN11 and DLL3, as potential therapeutic options. Group 3 tumors presented increased expression and hypomethylation of NEUROD1 (SCLC-N), with a greater proportion of fibroblasts. Group 4 tumors expressed POU2F3 and/or YAP1, had increased expression of non-neuroendocrine genes (non-NE) and had the worst survival. TACSTD2 expression was higher in Group 4, suggesting a potential therapeutic option for this group. SEZ6, another potential therapeutic option, was highly expressed in most SCLCs. These results highlight that novel therapeutic options may need to be considered in the context of SCLC heterogeneity.

Conclusions

We showed that methylation of the most common source of tumor tissue in the clinical setting can stratify SCLCs with distinct clinical outcomes and potentially tailored therapeutic options. Methylation can characterize the intrinsic and extrinsic heterogeneity of SCLCs and fuel the discovery of novel therapeutic vulnerabilities to help bridge the gap between research and clinical application to improve care for SCLC patients.