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Molecular phenotyping of small cell lung cancer using targeted cfDNA profiling of transcriptional regulatory regions

2024; American Association for the Advancement of Science; Volume: 10; Issue: 15 Linguagem: Inglês

10.1126/sciadv.adk2082

2375-2548

Joseph B. Hiatt, Anna-Lisa Doebley, Henry U. Arnold, Mohamed Adil, Holly Sandborg, Thomas Persse, Minjeong Ko, Feinan Wu, Álvaro Quintanal-Villalonga, Rafael Santana‐Davila, Keith D. Eaton, Caroline Dive, Charles M. Rudin, Anish Thomas, A. McGarry Houghton, Gavin Ha, David MacPherson,

RNA modifications and cancer

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.