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bioRxiv · 10.1101/2025.11.20.689492

LongPhase-S: purity estimation and variant recalibration with somatic haplotying for long-read sequencing

Ho, M.-E.·Zheng, Z.·Luo, R.·Chiang, H.-H.·Huang, Y.-T.
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Abstract

Accurate detection of somatic variants is crucial for precision oncology, and long-read sequencing offers unprecedented advantages in resolving complex cancer genomes. However, most long-read somatic callers rely on phasing built for a diploid genome, an assumption violated by various contamination, subclonal heterogeneity, and aneuploidy in tumors. We present LongPhase-S, a novel method that jointly reconstructs somatic haplotypes, infers tumor purity, and recalibrates somatic variants in a purity-aware manner for paired tumor-normal long-read sequencing. By anchoring each somatic read to a parental germline lin-eage, LongPhase-S provides a phase-resolved view in which germline and somatic reads are disentangled across the genome. Building on somatic haplotyping, LongPhase-S trains a phase-aware purity estimator that outperformed existing methods. Using eight benchmark datasets comprising six cancer cell lines, including breast, melanoma, and lung cancers, LongPhase-S boosted the accuracy of state-of-the-art somatic callers wuth the estimated purity and somatic haplotypes. Specifically, mean F1 scores increased by 4.5% and 7.1% for single-nucleotide variants and insertions and deletions with ClairS, and by 1.2% and 0.5% with DeepSomatic. Collectively, these results showed that somatic haplotyping is a critical yet missing piece in existing somatic callers, which enables purity-aware and phase-resolved variant interpretation in heterogneous tumors.

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Ho, M.-E., Zheng, Z., Luo, R., Chiang, H.-H., Huang, Y.-T.. 2025-11-24. LongPhase-S: purity estimation and variant recalibration with somatic haplotying for long-read sequencing. https://doi.org/10.1101/2025.11.20.689492

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