ABACBS short talk SVclone Inferring structural variant cancer cell fraction Supervisors: Chris Hovens, Niall Corcoran, Geoff Macintyre, Cheng-Soon Ong and Tony Papenfuss Marek Cmero, PhD Candidate – Dept. Surgery/CiS (Currently based at Murdoch Children’s Research Institute)

Cancer is an evolutionary process

Different cancers are driven by different types of mutations Source: Ciriello et al. 2013, doi:10.1038/ng.2762

chrA chrB Ref Donor Deletion Ref Donor Tandem duplication Ref Donor Translocation Ref Donor Interspersed duplication Ref Donor Inversion Inter-chromosomal translocation What is structural variation (SV)? Copy-number Aberrations (CNAs) Balanced rearrangements chrA chrB Ref Donor Deletion Ref Donor Tandem duplication Ref Donor Translocation Ref Donor Interspersed duplication Ref Donor Inversion Inter-chromosomal translocation Copy-number aberrations alone do not completely capture structural variation of cancer

Clonal analysis using whole-genome sequencing

Estimating clonal frequencies through VAF Calculating Variant Allele Frequency (VAF) TCTTCATTTGCAGCTAGTCGTGTGGGCTTAGT TCTTCATTTGCAGCTAGTCGTGTGGGCTTAGT TCTTCATTTGCAGCTAGTCGTGTGGGCTTAGT TCTTCATTTGCAGCTAGTCGTGTGGGCTTAGT TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT Coverage = 10 A: 6 REF G: 4 SNV VAF = 4/10 = 40% REF: TCTTCATTTGCAGCTAATCGTGTGGGCTTAGT reads

Calculating VAF of structural variants Breakpoint Breakpoint

Inferring tumour evolution through VAFs # variants # variants # variants

SVclone pipeline Calculate VAFs Infer CCFs

SVclone validation # variants # variants # variants

Point mutation vs. structural variant in pan-cancer samples Enriched in neutral subclonal SVs Fraction of subclonal SVs Fraction of subclonal point mutations

Subclonal neutral rearrangement phenotype (SCNR)

Summary • SVclone fills the gap for clonal analysis of structural variants • In pan-cancer cohort, found tumour subtype enriched in subclonal neutral rearrangements (SCNR) with reduced overall survival

Acknowledgements The University of Melbourne/Royal Melbourne Hospital • *Dr. Christopher Hovens • *Dr. Niall Corcoran • Natalie Kurganovs • Stefano Mangiola • Kangbo Mo Cancer Research UK Cambridge Institute • *Dr. Geoffrey Macintyre • Dr. Florian Markowetz Data61/Australian National University • *Dr. Cheng-Soon Ong The Walter + Eliza Hall Institute • *Dr. Tony Papenfuss • Dr. Jan Schröder The University of Glasgow • Dr. Ke Yuan PCAWG Evolution and Heterogeneity Working Group (esp. Peter Van Loo, David Wedge and Stefan Dentro) People (*supervisors) Funding Thank you to Roger Riordan of the Cybec Foundation for his generous Urology Fellowship funding contribution Compute Advisory panel • Dr. HongJian Zhu, Dr. Andrew Lonie SVclone: https://github.com/mcmero/SVclone https://doi.org/10.1101/172486 (preprint)