Longitudinal whole-exome sequencing of cell-free DNA for tracking the co-evolutionary tumor and immune evasion dynamics: longitudinal data from a single patient

Hastings, Robert K.; Openshaw, Mark R.; Vázquez, Miguél; Moreno-Cárdenas, Ana Belén; Fernández-García, Daniel; Martinson, Luke; Kulbicki, K.; Primrose, Lindsay; Guttery, David S.; Page, Karen M.; Toghill, Bradley J.; Richards, C. J.; Thomas, Anne; Tabernero, Josep; Coombes, R. Charles; Ahmed, Sohrab; Toledo, Rodrigo A.; Shaw, Jacqui A.

doi:10.1016/j.annonc.2021.02.007

Cited by 6 publications

(5 citation statements)

References 4 publications

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“…WES was performed in 55 baseline biological samples available at VHIO’s sample biobank (19 germline DNA, 22 tumor DNA, 5 patient-derived xenograft DNA and 9 plasma cfDNA) from 28 patients from the discovery cohort. Genomic libraries were prepared using 10–15 ng of cfDNA and the ThruPLEX DNA or Plasma-seq Kit (Rubicon Genomics; now commercialized as the SMARTer ThruPLEX plasma-seq kit by Takara Bio) 37 , 38 . Quality control of libraries was carried out in TapeStation (Agilent), and amplified profiles of ~300 base pairs were considered for downstream analysis.…”

Section: Methodsmentioning

confidence: 99%

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Élez

Ros

Fernández

et al. 2022

Nat Med

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Anti-BRAF/EGFR therapy was recently approved for the treatment of metastatic BRAFV600E colorectal cancer (mCRCBRAF-V600E). However, a large fraction of patients do not respond, underscoring the need to identify molecular determinants of treatment response. Using whole-exome sequencing in a discovery cohort of patients with mCRCBRAF-V600E treated with anti-BRAF/EGFR therapy, we found that inactivating mutations in RNF43, a negative regulator of WNT, predict improved response rates and survival outcomes in patients with microsatellite-stable (MSS) tumors. Analysis of an independent validation cohort confirmed the relevance of RNF43 mutations to predicting clinical benefit (72.7% versus 30.8%; P = 0.03), as well as longer progression-free survival (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.12–0.75; P = 0.01) and overall survival (HR, 0.26; 95% CI, 0.10–0.71; P = 0.008), in patients with MSS-RNF43mutated versus MSS-RNF43wild-type tumors. Microsatellite-instable tumors invariably carried a wild-type-like RNF43 genotype encoding p.G659fs and presented an intermediate response profile. We found no association of RNF43 mutations with patient outcomes in a control cohort of patients with MSS-mCRCBRAF-V600E tumors not exposed to anti-BRAF targeted therapies. Overall, our findings suggest a cross-talk between the MAPK and WNT pathways that may modulate the antitumor activity of anti-BRAF/EGFR therapy and uncover predictive biomarkers to optimize the clinical management of these patients.

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Section: Methodsmentioning

confidence: 99%

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

Élez

Ros

Fernández

et al. 2022

Nat Med

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“…10 Hospital Universitario La Paz, Madrid, Spain. 11 Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain. 12 Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.…”

Section: Supplementary Informationunclassified

“…Non-invasive liquid biopsies, from which circulating tumour DNA (ctDNA) can be isolated, represent an important alternative strategy for gaining insight into tumour evolutionary dynamics over time, although existing approaches typically study point mutations, rather than SCNAs [9][10][11]. Similarly, obtaining patient-derived xenografts (PDXs) of tissue biopsies, which provide very pure near-replicas of patient tumours, can provide a useful model to further understand cancer genomics while simultaneously overcoming the challenge of low tumour content in this disease and thereby enabling analysis of SCNAs [12,13].…”

Section: Introductionmentioning

confidence: 99%

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

Huebner

Black

Sarno³

et al. 2023

Genome Med

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Background Liquid biopsies and the dynamic tracking of somatic mutations within circulating tumour DNA (ctDNA) can provide insight into the dynamics of cancer evolution and the intra-tumour heterogeneity that fuels treatment resistance. However, identifying and tracking dynamic changes in somatic copy number alterations (SCNAs), which have been associated with poor outcome and metastasis, using ctDNA is challenging. Pancreatic adenocarcinoma is a disease which has been considered to harbour early punctuated events in its evolution, leading to an early fitness peak, with minimal further subclonal evolution. Methods To interrogate the role of SCNAs in pancreatic adenocarcinoma cancer evolution, we applied whole-exome sequencing of 55 longitudinal cell-free DNA (cfDNA) samples taken from 24 patients (including 8 from whom a patient-derived xenograft (PDX) was derived) with metastatic disease prospectively recruited into a clinical trial. We developed a method, Aneuploidy in Circulating Tumour DNA (ACT-Discover), that leverages haplotype phasing of paired tumour biopsies or PDXs to identify SCNAs in cfDNA with greater sensitivity. Results SCNAs were observed within 28 of 47 evaluable cfDNA samples. Of these events, 30% could only be identified by harnessing the haplotype-aware approach leveraged in ACT-Discover. The exceptional purity of PDX tumours enabled near-complete phasing of genomic regions in allelic imbalance, highlighting an important auxiliary function of PDXs. Finally, although the classical model of pancreatic cancer evolution emphasises the importance of early, homogenous somatic events as a key requirement for cancer development, ACT-Discover identified substantial heterogeneity of SCNAs, including parallel focal and arm-level events, affecting different parental alleles within individual tumours. Indeed, ongoing acquisition of SCNAs was identified within tumours throughout the disease course, including within an untreated metastatic tumour. Conclusions This work demonstrates the power of haplotype phasing to study genomic variation in cfDNA samples and reveals undiscovered intra-tumour heterogeneity with important scientific and clinical implications. Implementation of ACT-Discover could lead to important insights from existing cohorts or underpin future prospective studies seeking to characterise the landscape of tumour evolution through liquid biopsy.

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“…Related studies (see Viney and Day, this volume) have explored cell-free circulating tumour DNA in blood samples for biomarkers that may improve prognosis and suggest earlier interventions (Magnani et al 2017;Hong et al 2019;Coombes et al 2019). Such 'liquid biopsies' offer huge advantages over solid tumour biopsies for the monitoring of disease since they are relatively easy to give as well as to receive, process and store (Hastings et al 2021). At the end of the visit, Jayne was in conversation with the head of the laboratory who said that he 'did not have green fingers' and wasn't a gardener.…”

Section: Walled Garden 1: the Tissue Bankmentioning

confidence: 99%

The Gardener and the Walled Garden

Day¹,

Smith²,

Ward³

2022

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Platforms for standardising and sharing data between research and care are in construction, as they have been for some years. Currently, they take the form of creating a large ‘knowledge bank’ linking health records and biological samples with explicit consent for research use. Researchers will be able to work with the data without being able to identify patients, through pseudonymising techniques. This virtual research space is described as a walled garden. In this chapter, we ask what/who/when is a person as they are disassembled, transformed, layered and valued; emerging from and disappearing into data that are disaggregated and segregated. Together—an anthropologist, an epidemiologist and a patient who is fortuitously known as the gardener and has participated in many research studies since 2013—we hope to re-aggregate data and reconstruct a fuller history in which the patient is recognisable. This enquiry necessarily raises questions about the different ways in which a person is figured and distributed through personal experience, ethnography and biomedicine.

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Longitudinal whole-exome sequencing of cell-free DNA for tracking the co-evolutionary tumor and immune evasion dynamics: longitudinal data from a single patient

Cited by 6 publications

References 4 publications

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

RNF43 mutations predict response to anti-BRAF/EGFR combinatory therapies in BRAFV600E metastatic colorectal cancer

ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA

The Gardener and the Walled Garden

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