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

Autor: Ariana Huebner, James R. M. Black, Francesca Sarno, Roberto Pazo, Ignacio Juez, Laura Medina, Rocio Garcia-Carbonero, Carmen Guillén, Jaime Feliú, Carolina Alonso, Carlota Arenillas, Ana Belén Moreno-Cárdenas, Helena Verdaguer, Teresa Macarulla, Manuel Hidalgo, Nicholas McGranahan, Rodrigo A. Toledo
Přispěvatelé: Institut Català de la Salut, [Huebner A] Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK. [Black JRM] Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK. [Sarno F] Peaches Biotech, Madrid, Spain. [Pazo R] Hospital Universitario Miguel Servet, Zaragoza, Spain. [Juez I] Hospital Universitario de Fuenlabrada, Madrid, Spain. [Medina L] IBIMA, Virgen de La Victoria, Malaga, Spain. [Arenillas C, Toledo RA] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain. [Moreno-Cárdenas AB] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. [Verdaguer H, Macarulla T] Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain. Vall d’Hebron Hospital Universitari, Barcelona, Spain, Vall d'Hebron Barcelona Hospital Campus
Rok vydání: 2023
Předmět:
Pàncrees - Càncer - Aspectes genètics
Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Pancreatic Neoplasms [DISEASES]
nucleótidos y nucleósidos de ácidos nucleicos::ácidos nucleicos::ácidos nucleicos libres de células::ADN tumoral circulante [COMPUESTOS QUÍMICOS Y DROGAS]
Nucleic Acids
Nucleotides
and Nucleosides::Nucleic Acids::Cell-Free Nucleic Acids::Circulating Tumor DNA [CHEMICALS AND DRUGS]
Genetic Phenomena::Genetic Structures::Chromosomes::Karyotype [PHENOMENA AND PROCESSES]
Marcadors tumorals
Genetics
Molecular Medicine
fenómenos genéticos::estructuras genéticas::cromosomas::cariotipo [FENÓMENOS Y PROCESOS]
Cariotips
neoplasias::neoplasias por localización::neoplasias del sistema digestivo::neoplasias pancreáticas [ENFERMEDADES]
Molecular Biology
Genetics (clinical)
Zdroj: Scientia
ISSN: 1756-994X
DOI: 10.1186/s13073-023-01171-w
Popis: Circulating tumour DNA; Pancreatic cancer; Tumour evolution ADN tumoral circulant; Càncer de pàncrees; Evolució tumoral ADN tumoral circulante; Cáncer de páncreas; Evolución tumoral 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. This work was supported by the European Research Council (ERC) no. 670582 (Call: ERC-2014-ADG) to Dr. Hidalgo. R.A.T is supported by the Miguel Servet-II Research Award and the 2021 call for Proyectos de generación de conocimiento by the Institute of Health Carlos III (ISCIII) of the Ministry of Economy [CP17/00199], the Olga Torres Foundation Award to emerging researchers [2017, to R.A.T, 2601], and received research grants from Novartis, Astrazeneca, and Beigene pharmaceuticals, not related to this study. N.M is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals.
Databáze: OpenAIRE
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