134P - SPICE: Probabilistic reconstruction of copy-number evolution in cancer

Background

Somatic copy number alterations (CNAs) are frequent genetic alterations that accumulate in tumour cells during cancer evolution and amplify or delete large genomic regions. CNAs are implicated to drive cancer progression, providing cancer cells with the ability to metastasise or resist treatment. Therefore, cancer sequencing studies aim to reconstruct the evolutionary history of CNAs to investigate their role in cancer progression.

Methods

Whilst several phylogenetic methods have been introduced, these methods rely on the reconstruction of a single tumour phylogeny explaining CNA evolution, discarding the innate uncertainty of this complex problem. In fact, modelling CNA evolution is challenging and many different explanations for CNA evolution are equally plausible. Therefore, reconstructing a single phylogeny might hinder the ability to accurately characterise CNA evolution. In this work, we introduce SPICE (Subclone Probability Inference of Copy-number Evolution), a novel algorithm that enumerates equally plausible explanations of CNA evolution, enabling the estimation of the probabilities of CNA events.

Results

We show, using a novel, realistic simulation framework, that SPICE outperforms previous methods on simulated datasets by combining multiple inferred phylogenies. To highlight the impact of our method, we applied SPICE to 49 bulk samples from metastatic prostate cancers to detect the presence of known cancer driver genes that appear to be recurrently affected in the same tumour, providing evidence for parallel evolution. We also demonstrate the application of SPICE to reconstruct the evolution of 14,994 non-small cell lung cancer cells from 10 samples obtained from the primary tumour and metastases of one patient within the TRACERx study and PEACE autopsy programme. Finally, we leverage information regarding the uncertainty of inferred phylogenetic topologies to identify novel metastatic migration patterns and characterise the probability of migrations between different tumour sites.

Conclusions

In conclusion, we have shown that our method resolves the uncertainty of previous phylogenetic studies to enable the characterisation of recurrent patterns of CNA evolution, and the identification of novel metastatic migration patterns.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Cancer Research UK.

Disclosure

N. McGranahan: Financial Interests, Institutional, Stocks/Shares: Achilles Therapeutics. 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, Ad Board - 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, Advisory Board, Scientific Advisory Board and Stock options from September 2023: Relay Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Scientific Advisory Board: SAGA Diagnostics; 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, Personal, Stocks/Shares, Stock options: Relay 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; Financial Interests, Personal, Advisory Board, Cancer cachexia research advisory board: Pfizer; 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.