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bioRxiv · 10.64898/2026.09.14.751225

Somatic haplotype reconstruction and variant recalibration from tumor-only long-read sequencing

Chen, Z.-Y.·Zheng, Z.·Luo, R.·Fu, H.-F.·Yang, Y.-J.·Huang, Y.-T.
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Abstract

Separating somatic from germline variants and reconstructing somatic haplotypes are the two central problems of tumor-only cancer genome analysis. Long reads carry the linkage needed to solve both, but chromosome-scale loss of heterozygosity (LOH) and an unknown degree of normal-cell admixture blur the distinction between somatic and germline haplotypes. Here we present LongPhase-TO, the first method to reconstruct somatic haplotypes from a tumor sample alone. Rather than mapping somatic variants onto germline haplotypes, LongPhase-TO co-phases germline and somatic alleles in a unified graph, in which LOH and tumor DNA fraction are resolved internally from heterozygosity depletion and haplotype imbalance rather than a copy-number and ploidy model. Across eight datasets from six cancer cell lines, LongPhase-TO increased haplotype block N50 by a median of 2.9-fold relative to germline phasers. It also consistently improved somatic single-nucleotide variant (SNV) and indel calls from ClairS-TO and DeepSomatic-TO, raising mean F1 from 0.55 to 0.62 and 0.65 for SNVs and from 0.19 to 0.23 for indels, with the largest gains at low tumor DNA fraction. Across breast, melanoma and lung cancer cell lines, LongPhase-TO improves the accuracy of existing somatic callers and reconstructs megabase-scale somatic haplotypes.

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Chen, Z.-Y., Zheng, Z., Luo, R., Fu, H.-F., Yang, Y.-J., Huang, Y.-T.. 2026-09-19. Somatic haplotype reconstruction and variant recalibration from tumor-only long-read sequencing. https://doi.org/10.64898/2026.09.14.751225

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