Comprehensive detection of genetic and epigenetic alterations in cancer using long reads with TumorLens.

Accurately resolving the full spectrum of somatic alterations remains a major barrier in cancer genomics. Current short-read sequencing methods often prioritize SNVs and copy-number changes while overlooking SVs, haplotype-specific events, and epigenetic dysregulation. To bridge this gap, we present TumorLens, the first unified long-read framework that jointly detects SNVs, indels, SVs, large CNVs, loss-of-heterozygosity, and CpG methylation in a single assay. TumorLens introduces purity-aware long-read CNV/LoH modeling and personalized HLA-locus reconstruction, enabling the mechanistic interpretation of immune escape through allele-specific methylation profiling. Benchmarked across GIAB standards and clinical cohorts, TumorLens accurately recovered key somatic events, including interferon locus disruptions and HLA loss. Furthermore, it revealed pervasive global hypomethylation alongside focal hypermethylation in critical oncogenic pathways. By consolidating multi-omic layers into an end-to-end analytic pipeline, TumorLens establishes a new standard for comprehensive tumor profiling, accelerating the translation of long-read sequencing into precision oncology.