133P - Exploring genomic instability at the single-cell level using a new method for the inference of copy number alterations

Background

Recent single-cell technologies enable the sequencing of the whole genome of thousands of individual cancer cells. Genomic instability is a hallmark of many solid tumours during cancer evolution, leading cancer cells to acquire high rates of somatic copy-number alterations (CNAs), which are genomic alterations that result in the amplification or deletion of large genomic regions, and are known to be involved in tumour progression, metastatic potential, and increased fitness. Over the years several computational methods have been introduced to identify CNAs from single-cell whole-genome DNA sequencing data, and they represent a great opportunity to study genomic instability at high resolution. However, due to noise and low coverage in single-cell data, current methods have limited accuracy in identifying CNAs, limiting our understanding of genomic instability.

Methods

To overcome these limitations here we present a new method, which improves the accuracy in breakpoint identification by using a more realistic model of read counts, and it incorporates haplotype phasing and uncertainty in the data to improve ploidy inference.

Results

We apply our proposed model on a public dataset comprising more than 30,000 ovarian and breast cancer cancer cells, as well as to more than 15,000 single-cells from 5 primary tumour regions and 5 metastatic sites of a patient in the TRACERx and PEACE cohort. From these analyses, we show that cancer cells in different primary tumours and different metastases are characterised by varying degrees of genomic instability, possibly highlighting different routes to cancer progression. We also show that our method can more accurately identify recurrent regions of high focal amplifications, which are frequent mechanisms to amplify high number of copies of key oncogenes.

Conclusions

We show how our method can be used to analyse genomic instability in large-scale datasets, and we show the relevance on developing methods to infer heterogeneity at the single-cell resolution.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Cancer Research UK.

Disclosure

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. 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. All other authors have declared no conflicts of interest.