Abstract 11P
Background
Cancer progression involves the acquisition of genetic alterations, such as point mutations and copy-number alterations (CNAs), through a complex evolutionary process. Previous studies have reconstructed this evolutionary process using either mutations or CNAs due to the limitations of bulk sequencing technologies. However, such approaches do not fully capture the interplay between these two genetic signals. The recent advent of single-cell DNA sequencing provides the higher resolution required to follow both genetic signals accurately in thousands of individual cells. However, the ultra-low sequencing coverage of single-cell data makes the direct reconstruction of tumour evolution challenging.
Methods
We developed a single-cell method that enables the reconstruction of tumour evolution using both mutations and CNAs by applying a statistical approach to genotype mutations in cancer cell subpopulations and leveraging existing methods for tumour phylogenetic reconstruction. Additionally, we link the reconstructed evolutionary patterns with the proliferation rates of cancer cell subpopulations and their metastatic migrations, inferred using existing methods.
Results
We applied our method to reconstruct the tumour phylogeny of ∼23,000 single cells sequenced from 5 primary tumour regions and 5 metastases sampled from a patient recruited to the non-small cell lung cancer cohort study TRACERx and the autopsy study PEACE. Using both mutations and CNAs, we found an anticorrelation between the proliferation rate of a cancer cell subpopulation and its evolutionary distance to the metastatic seeding subpopulation, suggesting that highly proliferative subpopulations have increased metastatic potential. Moreover, we identified drivers affected by both mutations and CNAs in these subpopulations.
Conclusions
Our method enables the accurate evolutionary reconstruction of both mutations and CNAs, revealing novel insights into metastatic cancer evolution, such as a link between high proliferation and increased metastatic potential within the same tumour.
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.
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