1O - SPICE: Probabilistic reconstruction of copy-number evolution in metastatic cancers

Background

Somatic copy number alterations (SCNAs) are frequent genetic alterations that accumulate in tumour cells during cancer evolution and amplify or delete large genomic regions. SCNAs have been implicated to drive cancer progression, leading to the expansion of tumour clones with the ability to metastasise or resist treatment. Since these driver SCNA events and related genes remain unknown, cancer sequencing studies reconstruct the evolutionary history of SCNAs to identify recurrent patterns of SCNAs. However, these studies rely on the reconstruction of a single explanation for SCNA evolution, discarding the uncertainty innately related to this complex problem. In fact, modelling SCNA evolution is challenging and is characterised by a high number of different explanations for SCNA evolution that are equally plausible. Therefore, relying on a single solution might hinder the ability to infer recurrent SCNA events.

Methods

In this work, we introduce SPICE, a novel algorithm to reconstruct multiple equally plausible solutions for SCNA evolution, while also accounting for complex SCNAs and scaling to realistic numbers of SCNA profiles. The enumeration of multiple solutions thus enables SPICE to characterise the probability of different SCNA evolutionary patterns.

Results

We applied SPICE to 49 bulk samples from metastatic prostate cancers and we used the probabilistic results of SPICE to reveal preserved patterns of SCNA events that recurrently occur before or after metastatic spread. Moreover, by applying SPICE on 20,000 ovarian cancer single cells and 40,000 breast cancer single cells, we quantify the presence of well-known driver cancer genes that appear to be recurrently affected by similar events in the same tumour, providing evidence for parallel evolution of these events. Lastly, in addition to enabling the enumeration of multiple solutions for reconstructing SCNA evolution, we also demonstrate that SPICE’s results outperform previous methods using a novel, realistic simulation framework for SCNA evolution.

Conclusions

We have shown that our method resolves the uncertainty of previous phylogenetic studies to enable the characterisation of recurrent patterns of SCNA evolution and metastatic migrations.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Cancer Research UK.

Disclosure

C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GSK; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board, Current - since 2018: Genentech; Financial Interests, Personal, Advisory Board: Sarah Canon Research Institute; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Other, Consultancy: Medicxi; Financial Interests, Personal, Advisory Board, Member of the Science Advisory Board. Also had stock options until June 2021: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Advisory Board, 29 November - 1 December 2022: Novartis; Financial Interests, Personal, Invited Speaker, Oncology Collective - 2nd Nov - 4 Nov 2022 - Atlanta, USA: Roche; Financial Interests, Personal, Advisory Board, ctDNA advisory Board - 24th March 2023: AstraZeneca; Financial Interests, Personal, Invited Speaker, Pfizer Oncology 'Leading the revolution for the future: Pfizer; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, ApoGen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies: Archer Dx Inc.; Financial Interests, Institutional, Research Grant: Pfizer, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD 1and 2 clinical trials and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research grant from Oct 2019 - July 2023 - Genetics of CIN and SCNAs for Targeted Discovery (SCEPTRE): Ono Pharmaceutical; Financial Interests, Institutional, Research Grant, Research Grants from 2015: Roche; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Financial Interests, Institutional, Research Grant, from October 2022: Personalis; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD 1and 2 clinical trials: AstraZeneca; Non-Financial Interests, Personal, Member of Board of Directors, From 2019-2022: AACR; Non-Financial Interests, Personal, Other, Board of Directors: AACR; Non-Financial Interests, Personal, Advisory Role, EACR Advisory Council member: EACR. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Financial Interests, Personal, Invited Speaker, Speaker honorarium: Pfizer, Bristol Myers Squibb; Non-Financial Interests, Personal, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, Personal, Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. All other authors have declared no conflicts of interest.