ArticleGenome medicine2023
ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA.
Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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Who cites it
6 citing papers in PubMed, 1 synthesis or guideline pooled it, 7 citations in OpenAlex.
- Multiple time points for detecting circulating tumor DNA to monitor the response to neoadjuvant therapy in breast cancer: a meta-analysis.BMC cancer · 2025Pooled it
- Review
- Genetic immune escape in cancer: timing and implications for treatment.Trends in cancer · 2025Review
- Enabling sensitive and precise detection of ctDNA through somatic copy number aberrations in breast cancer.NPJ breast cancer · 2025Article
- Refphase: Multi-sample phasing reveals haplotype-specific copy number heterogeneity.PLoS computational biology · 2023Article
- ACT-Discover: identifying karyotype heterogeneity in pancreatic cancer evolution using ctDNA.Genome medicine · 2023Article
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Authors and funding
17 authors at 13 institutions in 3 countries.
Funding
Abstract
backgroundLiquid 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.
methodsTo 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.
resultsSCNAs 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.
conclusionsThis 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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