Abstract 327P
Background
Further investigation of genetic alterations in SCLC, a rare and aggressive form of lung cancer, is crucial to identify novel therapeutic targets.We are focusing on CTCs due to their high metastatic potential, and their representativeness for disease progression at diagnosis.
Methods
Our group has developed a unique method to isolate live CTCs from blood samples collected from SCLC patients (Ricordel et al. Sci Rep 2023). We built a Snakemake bioinformatics pipeline to perform alignment, variant calling and copy number alterations (CNAs) calling of CTCs WES samples. To compare genetic alterations of CTCs versus primary tumor, we used WES data from SCLC primary tumors of an external cohort (Liu et al. Cell 2024).
Results
We have successfully characterized genetic alterations of 22 CTCs from SCLC patients, validating their oncological potential. Our analysis revealed a significantly higher mutational load in CTCs compared to primary tumor, with many mutations occurring in genes known from the literature to be recurrently mutated in SCLC. Specifically, in CTCs, ARID1A, KMTD2 and NOTCH3 are mutated in over 90% of cases. We also observed a significantly higher CNAs burden in CTCs compared to primary tumors. CTCs exomes are mostly globally amplified, witnessing a high ploidy. The concomitant alteration of TP53 and RB1 characteristic of SCLC occurs frequently. Also, samples can be clustered by the CNAs of genes known from the literature to be recurrently altered in their copy number in SCLC. In primary tumors, the signature of exposure to tobacco smoking is prominent, whereas this tobacco signature is masked or lost in CTCs. Mutational signatures of CTCs highlight defects in DNA repair mechanisms. Finally, pathway enrichment shows robust alterations of oncogenic pathways in both CTCs and primary tumor (p53 regulation, Notch signaling, hypoxia, …). Comparison of altered pathways between primary tumor and CTCs revealed that signaling pathways such as extracellular matrix organization or signaling by receptor tyrosine kinases (RTK) are likely to be specific for CTCs.
Conclusions
Pathway enrichment analysis of both CTCs and primary tumor from SCLC patients allowed us to identify altered pathways specific to CTCs.
Legal entity responsible for the study
R. Pedeux.
Funding
Academic, government, charities.
Disclosure
All authors have declared no conflicts of interest.