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- Antonio Passaro (Milan, Italy)
1MO - Air Pollution Induced Non-Small Cell Lung Cancer: Towards Molecular Cancer Prevention
- Emilia Lim (London, United Kingdom)
Abstract
Background
A mechanistic basis for non-small cell lung cancer (NSCLC) initiation in never smokers, a disease with high frequency EGFR mutations (EGFRm), is unknown. Air pollution particulate matter (PM) is known to be associated with the risk of NSCLC, however a direct cause and mechanism remain elusive.
Methods
We analysed 463,679 individuals to address the associations of increasing 2.5μm PM (PM2.5) concentrations with cancer risk. We performed ultra-deep profiling of 247 normal lung tissue samples, analysed normal lung tissue from humans and mice following exposures to PM, and investigated the consequences of PM in mouse lung cancer models.
Results
Increasing PM2.5 levels are associated with increased risk of EGFRm NSCLC in England, S.Korea and Taiwan and with increased risk of mesothelioma, lung, anal, small intestine, GBM and laryngeal carcinomas in UK Biobank (HR>1.1 for each 1ug/m3 PM2.5 increment). 18-33% of normal lung tissue samples harbour driver mutations in EGFR and KRAS in the absence of malignancy. PM promotes a macrophage response and a progenitor-like state in lung epithelium harbouring mutant EGFR. Consistent with PM promoting NSCLC in at-risk epithelium harbouring driver mutations, PM accelerates tumourigenesis in three EGFR or KRAS driven lung cancer models in a dose-dependent manner. Finally, we uncover an actionable inflammatory axis driven by IL1B in response to PM, in agreement with reductions in lung cancer incidence with anti-IL1B therapy.
Conclusions
These results shed light on the etiology of EGFRm lung cancer and suggest that oncogenic mutations may be necessary but insufficient for tumour formation. These data reveal a mechanistic basis for PM driven lung cancer in the absence of classical carcinogen-driven mutagenesis, reminiscent of models of tumour initiation and promotion proposed 70 years ago, providing an urgent mandate to limit air pollution and reveal opportunities for molecular targeted cancer prevention.
Legal entity responsible for the study
The authors.
Funding
Cancer Research UK, Mark Foundation, Lung Cancer Research Foundation, Rosetrees Trust, Bristol Myers Squibb.
Disclosure
K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Monopteros Therapeutics; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: BMS. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; 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, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; 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, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: 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.
2MO - Tracking immunoediting from early to late stage lung cancer
- Sonya Hessey (London, United Kingdom)
Abstract
Background
Tumour cells acquire somatic mutations during cancer evolution, some of which result in neoantigens, novel peptides that elicit an immune response. As tumour cells bearing neoantigens are more likely to be eliminated by immune cells, tumours within T cell-rich environments might be expected to have ‘immunoedited’ tumour mutational landscapes characterised by neoantigen depletion. Although reduced neoantigen burden is associated with poor response to immunotherapy and survival in multiple cancer types, studies that have aimed to measure immunoediting signals from DNA sequencing data have obtained contrasting results. We hypothesise that these differences might relate to variation in immunoediting at distinct tumour evolutionary stages. Therefore, we investigated the immunoediting timelines of primary and metastatic tumour clones by mapping immunoediting signals to their phylogenetic trees.
Methods
Tumour phylogenies were reconstructed using somatic mutations identified from whole exome sequencing data obtained from 18 multi-region sampled primary tumours and 300 paired metastases from patients with non-small cell lung cancer co-recruited to the national TRACERx study and PEACE autopsy programme. We predicted the neoantigen status of all mutations and measured signals of immunoediting using four existing computational methods.
Results
We created a simulation framework based on TRACERx and PEACE sequencing data to establish the reliability of existing methods that measure immunoediting. Using this framework, we developed a new approach to quantify immunoediting that combines the best performing features of existing methods. We applied this method to primary and metastatic tumour clones which revealed that distinct phylogenetic branches have distinct immunoediting signals. Investigating these differences, we identified examples of immunoediting cessation following subclonal disruption of antigen presentation.
Conclusions
In summary, these findings suggest that immune selective pressures are dynamic from early to late stage disease and, as such, signals of immunoediting should be interpreted within the context of a tumour’s evolutionary history.
Clinical trial identification
TRACERx study: NCT01888601; PEACE study: NCT03004755.
Legal entity responsible for the study
The authors.
Funding
Cancer Research UK, Rosetrees Trust.
Disclosure
D. Moore: Financial Interests, Personal, Invited Speaker: AstraZeneca, Takeda; Financial Interests, Personal, Advisory Role: Thermo Fisher, Amgen, Janssen, Eli Lilly. 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, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; 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, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: 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; 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.
3MO - Genomic evolution of non-small cell lung cancer during the establishment and propagation of patient-derived xenograft models
- Robert Hynds (London, United Kingdom)
Abstract
Background
Patient-derived xenograft (PDX) models are a key tool in the pre-clinical oncology pipeline as a result of their in vivo propagation and proximity to patient material. The extent to which PDX models capture patient heterogeneity is therefore important for applications in pre-clinical and co-clinical studies. To improve our understanding of genomic selection and evolution in PDX models, we derived multiple PDX models from patients enrolled in TRACERx – a study of the evolutionary dynamics of non-small cell lung cancer (NSCLC) that uses a multi-region deep whole-exome sequencing (WES) approach.
Methods
We transplanted regional NSCLC tumor tissue subcutaneously into immunocompromised NSG mice. PDX models and matched patient tumor regions were subjected to WES.
Results
145 regional tumor samples from 44 patients were attempted, resulting in 63 xenografts. Of these, 47 regional xenografts were NSCLC-derived, while 16 were B-cell lymphoproliferative disease. Cryopreservation of tumor samples prior to injection did not alter PDX take rates. Histologically, broad similarity was observed between PDX models and corresponding patient tumor regions. Analysis of WES data revealed that PDX models are frequently monoclonal, but retain genomic similarity to the region of origin compared to spatially distinct tumor regions. On-going evolution occurs within PDX models but contributes less to genomic divergence than initial bottlenecking events. Specific mutational signatures can define the evolutionary trajectories of individual PDX models.
Conclusions
Overall, this study demonstrates that spatially defined PDX model libraries can be developed by multiple sampling of primary tumors. This approach may improve PDX take rates for individual patients and help to generate PDX model collections that represent the intratumor diversity of NSCLC.
Legal entity responsible for the study
University College London.
Funding
Cancer Research UK; Wellcome Trust; The Roy Castle Lung Cancer Foundation; The James Tudor Foundation.
Disclosure
R. Hynds: Financial Interests, Personal, Stocks/Shares: Achilles Therapeutics. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited Speaker Honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; 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. 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, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; 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, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: 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.
Invited Discussant: 1MO, 2MO & 3MO
- Antonio Passaro (Milan, Italy)
4MO - Multi-focal genomic dissection of synchronous primary and metastatic tissue from de novo metastatic prostate cancer
- Andrew J. Murtha (Vancouver, BC, Canada)
Abstract
Background
De novo metastatic castration-sensitive prostate cancer (mCSPC) is highly aggressive, but the lack of routine tumour tissue in this setting hinders genomic stratification and jeopardizes precision oncology efforts. Accurate molecular profiling at diagnosis is imperative for genomics-informed risk stratification and biomarker-guided treatment. Currently, it is unclear the extent that intrapatient heterogeneity impacts clinical cancer genotyping.
Methods
We performed genomic profiling of 607 synchronous primary foci, metastatic lesions, and cell-free DNA from a rare clinical trial cohort of 43 de novo mCSPC patients who underwent radical prostatectomy at diagnosis. Surgery is not currently standard practice in this disease setting. All samples were subjected to targeted DNA sequencing using a bespoke prostate cancer-specific panel and/or whole-exome sequencing.
Results
Sequencing-derived tissue tumour fraction was heterogeneous and low across same-patient foci in ∼20% of patients. In samples with high tumour fraction, the genomic landscape of mCSPC closely resembled metastatic treatment-resistant prostate cancer. In same-patient samples, intra-prostate heterogeneity in mutation, copy number, and whole-genome duplication status was pervasive. Phylogenetic modelling demonstrated additional complexity in several patients driven by polyclonal metastatic seeding from the reservoir of primary populations. While the metastatic clones were often identified in the primary site, frequent discordance between select primary foci and synchronous metastases in clinically-relevant genes, plus highly variable per-sample tumour fraction, resulted in false genotyping of the dominant disease, when relying on a single tissue focus. However, in silico modelling demonstrated that analysis of multiple prostate diagnostic biopsy cores can rescue misassigned somatic genotypes.
Conclusions
Our work reveals extensive polyclonality that undermines standard precision genotyping in de novo mCSPC, nominates practical strategies for improved biomarker profiling and genomics-informed risk stratification, and offers deep biological insight into the relationship between primary and untreated metastases.
Clinical trial identification
Presenting data collected during the LoMP1/2 clinical trials: NCT02138721 and NCT03655886, respectively.
Legal entity responsible for the study
The authors.
Funding
Canadian Institutes of Health Research.
Disclosure
E. Kwan: Financial Interests, Personal, Other, Advisory board, Sponsor/funding (Travel, Accommodations, Expenses), Honoraria, Research grant (institutional): Astellas Pharma; Financial Interests, Personal, Other, Advisory board, Honoraria: Janssen; Financial Interests, Personal, Other, Advisory board, sponsor/funding (Travel, Accommodations, Expenses), Honoraria: Ipsen; Financial Interests, Personal, Sponsor/Funding, Travel, Accommodations, Expenses: Pfizer, Roche; Financial Interests, Personal, Other, Honoraria: Research Review; Financial Interests, Personal, Research Grant: AstraZeneca. M. Annala: Financial Interests, Personal, Ownership Interest: Fluivia. A.W. Wyatt: Financial Interests, Personal, Advisory Board: AstraZeneca, Astellas, Janssen, Merck; Financial Interests, Institutional, Research Grant: ESSA Pharma. All other authors have declared no conflicts of interest.
5MO - Hypomethylation of circulating retrotransposons: towards a non-invasive pan-cancer diagnosis
- Charlotte Proudhon (Paris, France)
Abstract
Background
The detection of circulating tumor DNA allows to non-invasively retrieve tumor molecular profiles and follow disease evolution. It promises optimal and individualized management of patients with cancer. However, despite remarkable progress, several technological obstacles still limit liquid biopsy widespread application. Indeed, detecting small fractions of tumor DNA released when the tumor burden is reduced remains a challenge and detectable recurrent mutations do not cover all patients.
Methods
We aimed to assess the universal potential of DNA methylation as circulating tumor biomarker using new highly sensitive strategies to detect common cancer-specific signatures in blood. We targeted hypomethylation of LINE-1 elements, a shared feature of multiple cancers, using a multiplex PCR-based targeted bisulfite method coupled to deep sequencing, together with computational tools to accurately align sequencing data in a genome reference-free manner. We implemented machine learning-based classifiers, integrating methylation patterns at single CpG sites and at the single molecule level, to discriminate cancer from healthy plasma samples.
Results
We detected 30-40,000 LINE-1 elements scattered throughout the genome, covering 82-125,000 CpG sites. Methylation of these LINE-1 elements, showed an extremely performant ability to discriminate between healthy and tumor plasmas from 6 different types of cancers with an area under the curve (AUC) of 0.95 (NHealthy = 123; NCancers = 393). This includes metastatic colorectal, breast, lung and uvea cancers but also non metastatic ovarian, gastric and breast cancers. These results have been validated on an independent cohort (NHealthy = 30; NCancers = 160) including metastatic colorectal, breast, gastric and lung cancers and non-metastatic ovarian cancers (AUC = 0.98).
Conclusions
Our method allows to dramatically increase the sensitivity of ctDNA detection in a cost-effective manner, providing an optimal trade-off between the number of targeted regions and sequencing depth. These results have important biomedical implications and should lead to the development of more efficient non-invasive diagnostic tests adapted to all types of cancers, based on the universality of these factors.
Legal entity responsible for the study
Charlotte Proudhon.
Funding
ANR-10-EQPX-03 Equipex; Laboratoire d’Excellence (LABEX) DEEP (11-LBX0044); CNRS Prematuration Program 2021; SiRIC Grant «INCa-DGOS-Inserm_12554».
Disclosure
All authors have declared no conflicts of interest.
6MO - Pan-cancer characterization of Receptor Tyrosine Kinases alterations to sort targetable drivers from passengers.
- Helene Vanacker (Lyon, France)
Abstract
Background
Receptor tyrosine kinases (RTK) or ligands have frequent genetic alterations in cancers. Either amplifications, missense mutations or fusions of RTK are biomarkers for some targeted therapies in a fraction of cancers, with heterogeneous responses to tyrosine kinase inhibitors (TKI), monoclonal antibodies (mabs) or andibody-drug conjugates (ADC).
Methods
An analysis of pan-cancer molecular and clinical outcome in RTK-altered cancers was conducted for 16 selected targetable RTK (EGFR, HER2, KIT, FLT3, TRKA-B-C, ROS1, ALK, RET, MET, and FGFR1-2-3-4). The molecular landscape of RTK-altered cancers was analyzed in pan-cancer public databases (MSK-impact / MSK-MET-Tropism) and institutional databases (DNA-targeted sequencing in PROFILER, PROFILER-2 (NCT03163732), RNA-seq FFPE database). The clinical profile and therapeutic activity of TKI, mabs, ADC monotherapy in genomic-driven clinical trials was analyzed through a systematic review of phase I-II-III studies published up to January 2022. Clinical efficacy of the best quality trials across cancer types, with efficacy defined as n>5 patients objective response rate (ORR) of 30% and/or median progression free survival (PFS) >6months.
Results
RTK-alterations encompass a variety of situations since only 2% (19/884) of cancers have a \"frequent” (prevalence >10%) RTK-alteration. On the whole, clinical efficacy of TKI-targeting strategies in RTK-altered cancers is not associated with RTK prevalence, but is shaped by the type of RTK-alterations (Table) and molecular co-alterations. Some of the main clinical and molecular characteristics of RTK-alterations in cancers are summarized in the table. The type of RTK-alterations have also variable genomic background in term of tumor mutation count, tumor mutational burden, tumor fusion burden, fraction genome altered. Mutual exclusivity was found statistically significant only in RTK-translocations and mutations of EGFR with KIT and FGFR3. Most of RTK copy number variations are co-occurrent. Despite strong clinical benefit a few number of RTK-translocations with atypical partners and/or underlying genomic instability challenge the notion of histology-agnosticism of RTK-translocations.
Missense Mutations Amplifications Translocations Remarks 2.9%(0-65%) 1%(0-39.2) 0.1%(0-16%) Difference (t-test p<10-6) Variable Weak Strong >1300 trials screened Role for cancer cellular background Efficient targeted strategies involve chemo-therapies and/or ADCs Translocation partner and underlying cancer type and genomic specificities
Conclusions
These analyses reveal the wide heterogeneity of RTK alterations pan-cancer defining clinical and genomic biomarkers to select patient for targeted therapies for unlabeled rare tumors/alterations. Single agent TKI may be proposed 1) fusions of RTK with expressed partner and few other genetic alterations 2) activating missense mutations in RTK involved in normal cell lineage physiology. ADC or mab+chemo may be preferred for amplifications.
Clinical trial identification
Soma data analyzed here provide from: 1) Public database from MSK-IMPACT trial (NCT03208374); 2) Institutional database from PROFILER (NCT01774409) and PROFILER 02 (NCT03163732) clinical trials.
Legal entity responsible for the study
The authors.
Funding
Funding of PROFILER and PROFILER 02 trials: partial funding by Roche, Fone panels (Fone or CDX) were performed by Foundation Medicine free of charge the Integrated Cancer Research Site LYriCAN (INCa-DGOS-Inserm_12563), NetSARC (INCA & DGOS), InterSARC (INCA), LabEx DEvweCAN (ANR-10-LABX 0061), PIA Institut Convergence Francois Rabelais PLAsCAN (PLASCAN, 17-CONV-0002), Fondation ARC contre le Cancer, La Ligue contre le Cancer (Canopée), and EURACAN (EC 739521).
Disclosure
M. Brahmi: Financial Interests, Institutional, Research Grant: Bayer, GSK. A. Dufresne: Financial Interests, Institutional, Principal Investigator: GSK, Bayer. P. Cassier: Financial Interests, Personal, Expert Testimony: Itéos, Amgen, Janssen; Non-Financial Interests, Personal, Advisory Role: OSE Immunotherapeutics; Financial Interests, Institutional, Research Grant: Bayer, GSK, Janssen, Lilly, AstraZeneca, Roche, Merck Serono, Toray industries, Novartis, Bristol Myers Squibb, Innate, Loxo, Blueprint, Celgene, AbbVie, Merck Sharp & Dohme. O. Tredan: Financial Interests, Institutional, Research Grant: BMS, MSD; Financial Interests, Personal, Expert Testimony: Roche, Pfizer, Novartis-Sandoz, Lilly, AstraZeneca, Pierre Fabre, Seagen, Daiichi Sankyo, Gilead, Eisai, Stemline. J. Blay: Financial Interests, Personal, Expert Testimony: GSK, AstraZeneca, Bayer, Novartis; Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, Bayer, Novartis. All other authors have declared no conflicts of interest.
7MO - Measuring proliferation rates of distinct tumour clones using single-cell DNA sequencing
- Olivia J. Lucas (London, United Kingdom)
Abstract
Background
Tumour proliferation rate is a key phenotypic feature of cancer, with higher rates linked to poorer clinical outcomes. Thus far, proliferation rates have been measured using pathological or experimental techniques on bulk tumour samples. However, tumours are heterogeneous compositions of distinct clones with varying levels of fitness. We hypothesise that identifying the most proliferative clones would enable the identification of genomic hallmarks of aggressive clones, or the prediction of their potential phenotype, e.g., metastatic potential. However, this has been unfeasible thus far.
Methods
We have developed a novel computational method using single-cell whole-genome DNA sequencing to measure proliferation rates in individual tumour clones. To generate a state-of-the-art ground-truth dataset for assessing the accuracy of this method, we have developed an experimental approach combining single-cell DNA sequencing with EdU cell labelling to reliably separate cells in different replication states. To apply our method, we have single-cell DNA sequenced >10,000 non-small cell lung cancer cells from longitudinal and metastatic tumour samples within the TRACERx study and PEACE autopsy programme. We have further analysed published data from >10,000 breast cancer cells.
Results
We have demonstrated that our method enables accurate estimates of proliferation rates using simulations and the generated ground-truth dataset, in contrast to previous preliminary approaches. While our estimates are concordant with previous bulk experimental studies (5-30%), we importantly have identified clonal heterogeneity in proliferation rates, in particular in tumour clones that likely metastasised, suggesting a link to dissemination potential. Furthermore, we have identified high proliferation clones which arose recently in the evolution of a breast tumour and may have a selective advantage.
Conclusions
We have developed a novel method that enables accurate identification of proliferation rates of individual tumour clones using single-cell DNA sequencing data, allowing the investigation of genomic hallmarks in highly proliferative clones that might lead to higher fitness.
Legal entity responsible for the study
The authors.
Funding
Cancer Research UK, Wellcome Trust, Rosetrees Trust.
Disclosure
M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; 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, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; 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, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and Chair of the Steering Committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Personal, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Personal, Invited Speaker, From 2019: 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.
Invited Discussant: 4MO, 5MO, 6MO & 7MO
- David SP Tan (, Singapore)