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Refphase: Multi-sample phasing reveals haplotype-specific copy number heterogeneity

Thomas B. K. Watkins
Emma C. Colliver
Matthew R. Huska
Tom L. Kaufmann
Emilia L. Lim
Cody B. Duncan
Kerstin Haase
Peter Van Loo
Charles Swanton
Nicholas McGranahan
Roland F. Schwarz

October 23, 2023

Most computational methods that infer somatic copy number alterations (SCNAs) from bulk sequencing of DNA analyse tumour samples individually. However, the sequencing of multiple tumour samples from a patient’s disease is an increasingly common practice. We introduce Refphase, an algorithm that leverages this multi-sampling approach to infer haplotype-specific copy numbers through multi-sample phasing. We demonstrate Refphase’s ability to infer haplotype-specific SCNAs and characterise their intra-tumour heterogeneity, to uncover previously undetected allelic imbalance in low purity samples, and to identify parallel evolution in the context of whole genome doubling in a pan-cancer cohort of 336 samples from 99 tumours.