用于NSCLC个体化及肿瘤无关微小残留病检测的纠错血浆全基因组测序

Background: Sensitive and scalable detection of circulating tumour DNA (ctDNA) is essential for minimal residual disease (MRD) assessment following curative-intent treatment in non-small cell lung cancer (NSCLC). While personalised, tumour-guided approaches are highly sensitive, they typically rely on bespoke panel design, limiting scalability and constraining the breadth of biological signals that can be interrogated. Error-corrected whole-genome sequencing (WGS) offers the potential to overcome these limitations by enabling personalised MRD detection without custom sequencing panels, while supporting genome-wide and tumour-agnostic analyses. Methods: We analysed personalised WGS-based ctDNA detection using Ultima Genomics' ppmSeq in a TRACERx pilot cohort comprising 45 post-operative plasma samples from individuals with early-stage NSCLC during the landmark period. Landmark was previously defined as between days 10 and 120 post-operatively, prior to the start of adjuvant therapy or disease recurrence. Tumour-specific variants derived from tumour WGS were queried in genome-wide matched plasma. Plasma WGS was performed to a target coverage of 150x. Analytical sensitivity, ctDNA fraction distributions, and associations with relapse-free survival were assessed. Results: Error-corrected WGS enabled detection of tumour-informed variants at parts per million (ppm) allele fractions without bespoke panel design. Among MRD-positive samples, 13% exhibited ctDNA fractions below 10 ppm, and 72% were below 100 ppm, highlighting sensitivity across the ultra-low ctDNA range. The lowest ctDNA fraction called was 2.2 ppm. Landmark ctDNA detection by WGS was significantly associated with relapse-free survival, with a median relapse-free survival of 23.2 months in landmark-positive individuals (n = 37) compared with 98.7 months in landmark-negative individuals (n = 8, log-rank p = 0.042). Conclusions: These data provide early validation of personalised, tumour-guided ppmSeq ctDNA detection in early-stage NSCLC, with ctDNA quantification to parts per million. This approach is now being expanded to include up to 400 individuals from TRACERx (>1,500 plasma timepoints) to evaluate prognostic performance and scalability, positioning plasma WGS as a next-generation MRD platform that unifies personalised and tumour-agnostic monitoring from a single assay, including genome-wide error-corrected mutations, copy number, and fragmentation features for residual disease and relapse monitoring.