2025 Hot Topic in Basic & Translational Science: Small Cell Lung Cancer - Posters-PP01.09: Non-Invasive Genomic and Transcriptomic Characterization of Small Cell Lung Cancer Using Circulating Tumor DNA

PP01.09: Non-Invasive Genomic and Transcriptomic Characterization of Small Cell Lung Cancer Using Circulating Tumor DNA

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This study explores non-invasive methods for genomic and transcriptomic characterization of Small Cell Lung Cancer (SCLC) using circulating tumor DNA (cfDNA). Conducted by a team from various institutions, the research focuses on alternatives to traditional tumor biopsies, which are challenging to obtain, especially during relapse. The observational study involved relapsed/refractory SCLC patients undergoing chemotherapy or immunotherapy in clinical trials.<br /><br />Three non-invasive techniques were employed: low-pass whole genome sequencing of cfDNA, chromatin immunoprecipitation of cell-free nucleosomes with active chromatin modifications (cfChIP-seq), and analysis of nucleosomal patterns in cfDNA fragmentation. These techniques were integrated with clinical data and matched tumor transcriptomes.<br /><br />The study found that cfDNA closely correlated with disease trajectory. Low tumor burden inferred from cfDNA and other techniques predicted longer overall survival. Frequent mutations in TP53 and RB1, as well as Myc, Notch, cell cycle regulators, and chromatin modifiers were identified, consistent with tumor samples.<br /><br />Phylogenetic analysis of cfDNA indicated a stable genetic landscape with dominant truncal clones. The cfChIP-seq technique, in particular, demonstrated a strong correlation with gene expression for a significant number of genes and transcription factors like ASCL1, NEUROD1, and POU2F3, highlighting its capability to accurately infer tumor gene expression patterns.<br /><br />The study concludes that cfDNA provides both genomic and epigenomic data, effectively classifying SCLC subtypes based on transcription factors. This non-invasive approach not only aligns with tumor transcriptomes but also serves as a predictive and prognostic tool for disease trajectory. Longitudinal tracking of cfDNA can offer critical insights into resistance mechanisms to SCLC treatments.

Asset Subtitle

Chirayu Mohindroo

Keywords

Small Cell Lung Cancer

circulating tumor DNA

non-invasive methods

cfDNA

genomic characterization

transcriptomic characterization

chemotherapy

immunotherapy

cfChIP-seq

tumor biopsies