From fragments to full pictures: how long-read sequencing platforms are revolutionizing oncology research

Short-read sequencing (SRS) has been the cornerstone of cancer genomics for nearly two decades; however, its inherent limitations in read length have restricted comprehensive characterisation of complex genomic features. Long-read sequencing (LRS) represents not merely a technical increment but a conceptual shift from computational inference of genomic structure to its direct observation. It enables 3-4-fold greater sensitivity for structural variant detection, unambiguous full-length transcript characterisation, native DNA methylation profiling without bisulfite conversion, and high-resolution HLA typing at 8-digit allele resolution. In haematological malignancies, these capabilities have identified cryptic rearrangements in 10-15% of cases previously classified as normal karyotype, enabled novel fusion transcript discovery influencing treatment stratification, and supported minimal residual disease monitoring at 10^- 4 to 10^- 5 sensitivity. Although cost, throughput, and bioinformatic standardisation remain barriers to widespread clinical adoption, LRS is poised to advance precision oncology through more accurate diagnosis, improved therapeutic stratification, and enhanced monitoring of disease progression and resistance particularly for haematological malignancies where its advantages are most clinically validated. The central argument of this review is that LRS does not merely improve upon SRS incrementally, but enables a qualitatively different mode of genomic inquiry: direct, single-molecule observation of structural, transcriptomic, and epigenetic features that were previously accessible only through indirect computational reconstruction. Hematological malignancies, where chromosomal translocations are pathognomonic, karyotypes are frequently complex, and clonal evolution drives relapse, represent the strongest and most clinically mature domain for LRS application today, and serve as the primary lens through which this review evaluates clinical translation.