Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions Journal Article
| Authors: | Hiatt, J. B.; Doebley, A. L.; Arnold, H. U.; Adil, M.; Sandborg, H.; Persse, T. W.; Ko, M.; Wu, F.; Villalonga, A. Q.; Santana-Davila, R.; Eaton, K.; Dive, C.; Rudin, C. M.; Thomas, A.; Houghton, A. M.; Ha, G.; MacPherson, D. |
| Article Title: | Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions |
| Abstract: | We report an approach for cancer phenotyping based on targeted sequencing of cell-free DNA (cfDNA) for small cell lung cancer (SCLC). In SCLC, differential activation of transcription factors (TFs), such as ASCL1, NEUROD1, POU2F3, and REST defines molecular subtypes. We designed a targeted capture panel that identifies chromatin organization signatures at 1535 TF binding sites and 13,240 gene transcription start sites and detects exonic mutations in 842 genes. Sequencing of cfDNA from SCLC patient-derived xenograft models captured TF activity and gene expression and revealed individual highly informative loci. Prediction models of ASCL1 and NEUROD1 activity using informative loci achieved areas under the receiver operating characteristic curve (AUCs) from 0.84 to 0.88 in patients with SCLC. As non-SCLC (NSCLC) often transforms to SCLC following targeted therapy, we applied our framework to distinguish NSCLC from SCLC and achieved an AUC of 0.99. Our approach shows promising utility for SCLC subtyping and transformation monitoring, with potential applicability to diverse tumor types. © 2024 American Association for the Advancement of Science. All rights reserved. |
| Keywords: | metabolism; carcinoma, non-small-cell lung; lung neoplasms; pathology; lung tumor; gene expression regulation; gene expression regulation, neoplastic; transcription; binding sites; biological organs; diseases; gene encoding; small-cell lung cancer; small cell lung cancer; small cell lung carcinoma; regulatory sequences, nucleic acid; non small cell lung cancer; regulatory sequence; cancer patients; humans; human; transcription start site; regulatory regions; cell-free nucleic acids; cell-free; cell free nucleic acid; chromatin organization; phenotyping; dna profiling; gene transcriptions; transcription factor binding sites |
| Journal Title: | Science Advances |
| Volume: | 10 |
| Issue: | 15 |
| ISSN: | 2375-2548 |
| Publisher: | Amer Assoc Advancement Science |
| Date Published: | 2024-04-12 |
| Start Page: | eadk2082 |
| Language: | English |
| DOI: | 10.1126/sciadv.adk2082 |
| PUBMED: | 38598634 |
| PROVIDER: | scopus |
| PMCID: | PMC11006233 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
