EccDNA-oriented HGF potential role in platinum resistance and cancer progression based on differential abundance analysis of eccDNAs in lung cancer

Extrachromosomal circular DNAs (eccDNAs) play a role in tumorigenesis and tumor progression. This study aims to identify eccDNA biomarkers associated with platinum-based chemoresistance and to elucidate their underlying molecular mechanisms. Plasma samples were collected from four patients who did not respond to platinum-based chemotherapy and nine who did respond. We conducted eccDNA circle-sequencing and bioinformatics analyses to examine the distribution and abundance levels of eccDNAs. Our results showed that we purified and sequenced over 10,000 eccDNAs from the 13 plasma samples, with sizes ranging from 0.01 kb to 1000 kb. We found 310 eccDNAs that were differentially abundance between the platinum-based chemotherapy responders and non-responders. Of these, 190 eccDNAs were upregulated in non-responders and were primarily involved in endocytosis and the degradation of valine, leucine, and isoleucine. The PPI network highlighted 20 hub genes, with six candidate genes (HGF, KIF17, NUDT1, IFI16, TLR9, and ANKRD2) positively associated with resistance to platinum drugs in cancer cells. Notably, HGF was the only gene linked to poor disease-free survival in the 13 patients studied. HGF expression was negatively correlated with the sensitivity to Pluripotin, CEP-32496, SGI-1027, APR-246, and BGB-283. These findings suggest that HGF, identified through eccDNA sequencing, acts as an oncogene and may serve as a novel biomarker for platinum resistance and prognosis evaluation in lung cancer.