PT  - JOURNAL ARTICLE
AU  - Thomas BK Watkins
AU  - Emma C Colliver
AU  - Mathew R Huska
AU  - Tom L Kaufmann
AU  - Emilia L Lim
AU  - Kerstin Haase
AU  - Peter Van Loo
AU  - Charles Swanton
AU  - Nicholas McGranahan
AU  - Roland F Schwarz
TI  - Refphase: Multi-sample reference phasing reveals haplotype-specific copy number heterogeneity
AID  - 10.1101/2022.10.13.511885
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.10.13.511885
4099  - http://biorxiv.org/content/early/2022/10/17/2022.10.13.511885.short
4100  - http://biorxiv.org/content/early/2022/10/17/2022.10.13.511885.full
AB  - 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 reference 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.Competing Interest StatementCS acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc - collaboration in minimal residual disease sequencing technologies), and Ono Pharmaceutical. He is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL's Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Centre Shanghai, Metabomed (until July 2022), and the Sarah Canon Research Institute C.S has received honoraria from Amgen, AstraZeneca, Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Illumina, and Roche-Ventana. CS had stock options in Apogen Biotechnologies and GRAIL until June 2021, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. NM has received consultancy fees and has stock options in Achilles Therapeutics. Patents: CS holds patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289); to targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), US patent relating to detecting tumour mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1) and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892). NM holds European patents relating to targeting neoantigens (PCT/EP2016/ 059401), identifying patient response to immune checkpoint blockade (PCT/ EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221).